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1. Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

Author: Yuwei Wang, Gwen M. H. E. Dackus, Efraim H. Rosenberg, Sten Cornelissen, Leonora W. de Boo, Annegien Broeks, Wim Brugman, Terry W. S. Chan, Paul J. van Diest, Michael Hauptmann, Natalie D. ter Hoeve, Olga I. Isaeva, Vincent M. T. de Jong, Katarzyna Jóźwiak, Roelof J. C. Kluin, Marleen Kok, Esther Koop, Petra M. Nederlof, Mark Opdam, Philip C. Schouten, Sabine Siesling, Charlaine van Steenis, Adri C. Voogd, Willem Vreuls, Roberto F. Salgado, Sabine C. Linn, and Marjanka K. Schmidt
Subjects: BRCA1 status, Tumor-infiltrating lymphocytes, Triple-negative breast cancer, Chemotherapy-naïve, Long-term outcomes, Risk classification, Medicine
Abstract: Abstract Background Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. Methods We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models. Results Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and
Published: 2024
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2. B-cells and regulatory T-cells in the microenvironment of HER2+ breast cancer are associated with decreased survival: a real-world analysis of women with HER2+ metastatic breast cancer

Author: Tessa G. Steenbruggen, Denise M. Wolf, Michael J. Campbell, Joyce Sanders, Sten Cornelissen, Bram Thijssen, Roberto A. Salgado, Christina Yau, Nick O-Grady, Amrita Basu, Rajith Bhaskaran, Lorenza Mittempergher, Gillian L. Hirst, Jean-Philippe Coppe, Marleen Kok, Gabe S. Sonke, Laura J. van ‘t Veer, and Hugo M. Horlings
Subjects: HER2-positive, Metastatic breast cancer, Tumor immune microenvironment, Multiplex immunofluorescence, Spatial composition, Gene expression, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role in the response to treatment in HER2-positive breast cancer and could contain valuable prognostic information. Detailed information on the cancer-immune cell interactions in HER2-positive MBC is however still lacking. By characterizing the tumor immune microenvironment in patients with HER2-positive MBC, we aimed to get a better understanding why overall survival (OS) differs so widely and which alternative treatment approaches may improve outcome. Methods We included all patients with HER2-positive MBC who were treated with trastuzumab-based palliative therapy in the Netherlands Cancer Institute between 2000 and 2014 and for whom pre-treatment tissue from the primary tumor or from metastases was available. Infiltrating immune cells and their spatial relationships to one another and to tumor cells were characterized by immunohistochemistry and multiplex immunofluorescence. We also evaluated immune signatures and other key pathways using next-generation RNA-sequencing data. With nine years median follow-up from initial diagnosis of MBC, we investigated the association between tumor and immune characteristics and outcome. Results A total of 124 patients with 147 samples were included and evaluated. The different technologies showed high correlations between each other. T-cells were less prevalent in metastases compared to primary tumors, whereas B-cells and regulatory T-cells (Tregs) were comparable between primary tumors and metastases. Stromal tumor-infiltrating lymphocytes in general were not associated with OS. The infiltration of B-cells and Tregs in the primary tumor was associated with unfavorable OS. Four signatures classifying the extracellular matrix of primary tumors showed differential survival in the population as a whole. Conclusions In a real-world cohort of 124 patients with HER2-positive MBC, B-cells, and Tregs in primary tumors are associated with unfavorable survival. With this paper, we provide a comprehensive insight in the tumor immune microenvironment that could guide further research into development of novel immunomodulatory strategies. Graphical Abstract
Published: 2023
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3. Immune landscape of breast tumors with low and intermediate estrogen receptor expression

Author: Leonie Voorwerk, Joyce Sanders, Milou S. Keusters, Sara Balduzzi, Sten Cornelissen, Maxime Duijst, Esther H. Lips, Gabe S. Sonke, Sabine C. Linn, Hugo M. Horlings, and Marleen Kok
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Immune checkpoint blockade (ICB) is currently approved for patients with triple-negative breast cancer (TNBC), whereas responses to ICB are also observed in a small subgroup of Estrogen Receptor (ER)-positive breast cancer. The cut-off for ER-positivity (≥1%) is based on likelihood of endocrine treatment response, but ER-positive breast cancer represents a very heterogeneous group. This raises the question whether selection based on ER-negativity should be revisited to select patients for ICB treatment in the context of clinical trials. Stromal tumor-infiltrating lymphocytes (sTILs) and other immune parameters are higher in TNBC compared to ER-positive breast cancer, but it is unknown whether lower ER levels are associated with more inflamed tumor microenvironments (TME). We collected a consecutive series of primary tumors from 173 HER2-negative breast cancer patients, enriched for tumors with ER expression between 1 and 99% and found levels of stromal TILs, CD8 + T cells, and PD-L1 positivity in breast tumors with ER 1–9% and ER 10–50% to be comparable to tumors with ER 0%. Expression of immune-related gene signatures in tumors with ER 1–9% and ER 10–50% was comparable to ER 0%, and higher than in tumors with ER 51–99% and ER 100%. Our results suggest that the immune landscape of ER low tumors (1–9%) and ER intermediate tumors (10–50%) mimic that of primary TNBC.
Published: 2023
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4. Breast cancer genomes from CHEK2 c.1100delC mutation carriers lack somatic TP53 mutations and display a unique structural variant size distribution profile

Author: Marcel Smid, Marjanka K. Schmidt, Wendy J. C. Prager-van der Smissen, Kirsten Ruigrok-Ritstier, Maartje A. C. Schreurs, Sten Cornelissen, Aida Marsal Garcia, Annegien Broeks, A. Mieke Timmermans, Anita M. A. C. Trapman-Jansen, J. Margriet Collée, Muriel A. Adank, Maartje J. Hooning, John W. M. Martens, and Antoinette Hollestelle
Subjects: CHEK2, Whole-genome sequencing, Somatic cancer genome, Mutational landscape, TP53 mutation, Structural variation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background CHEK2 c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactly CHEK2 c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC. Methods We sequenced primary BC (pBC) and normal genomes of 20 CHEK2 c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those from BRCA1/2 mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER− and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive a TP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome of CHEK2 c.1100delC carriers was compared with BC patients displaying somatic TP53 mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases. Results BC genomes from CHEK2 mutation carriers were most similar to ER+ BC genomes and least similar to those of BRCA1/2 mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. Somatic TP53 mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelic CHEK2 inactivation lacked somatic TP53 mutations and transcriptomic analysis indicated a shared biology with TP53 mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile. Conclusions CHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival of CHEK2 mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.
Published: 2023
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5. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author: Stefanie H. Mueller, Alvina G. Lai, Maria Valkovskaya, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Zomoruda Abu-Ful, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Thais Baert, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Hermann Brenner, Sara Y. Brucker, Saundra S. Buys, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Ji-Yeob Choi, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, CTS Consortium, Sten Cornelissen, Fergus J. Couch, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Laure Dossus, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Manuela Gago-Dominguez, Yu-Tang Gao, Montserrat García-Closas, José A. García-Sáenz, Jeanine Genkinger, Aleksandra Gentry-Maharaj, Felix Grassmann, Pascal Guénel, Melanie Gündert, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Elaine F. Harkness, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Weang-Kee Ho, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Dezheng Huo, ABCTB Investigators, Hidemi Ito, Motoki Iwasaki, Anna Jakubowska, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Daehee Kang, Elza K. Khusnutdinova, Sung-Won Kim, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, Ava Kwong, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Martha Linet, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Usha Menon, Kenneth Muir, Rachel A. Murphy, Heli Nevanlinna, William G. Newman, Dieter Niederacher, Katie M. O’Brien, Nadia Obi, Kenneth Offit, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Sue K. Park, Alpa V. Patel, Achal Patel, Charles M. Perou, Julian Peto, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Nadege Presneau, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Muhammad U. Rashid, Gad Rennert, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Michael O. Schneider, Christopher Scott, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Jacques Simard, Harald Surowy, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Soo Hwang Teo, Lauren R. Teras, Amanda E. Toland, Rob A. E. M. Tollenaar, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Robert Winqvist, Alicja Wolk, Anna H. Wu, Taiki Yamaji, Xiaohong R. Yang, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Douglas F. Easton, Harry Hemingway, Ute Hamann, and Karoline B. Kuchenbaecker
Subjects: Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, Medicine, Genetics, QH426-470
Abstract: Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q
Published: 2023
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6. Circadian PERformance in breast cancer: a germline and somatic genetic study of PER3 VNTR polymorphisms and gene co-expression

Author: Jaume Fores-Martos, Raimundo Cervera-Vidal, Julia Sierra-Roca, Carlos Lozano-Asencio, Vita Fedele, Sten Cornelissen, Hege Edvarsen, Irene Tadeo-Cervera, Pilar Eroles, Ana Lluch, Rafa Tabares-Seisdedos, Antonio Falcó, Laura J. Van’t Veer, Marjanka Schmidt, David A. Quigley, Anne-Lise Børresen-Dale, Vessela N. Kristensen, Allan Balmain, and Joan Climent
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Polymorphisms in the PER3 gene have been associated with several human disease phenotypes, including sleep disorders and cancer. In particular, the long allele of a variable number of tandem repeat (VNTR) polymorphism has been previously linked to an increased risk of breast cancer. Here we carried out a combined germline and somatic genetic analysis of the role of the PER3 VNRT polymorphism in breast cancer. The combined data from 8284 individuals showed a non-significant trend towards increased breast cancer risk in the 5-repeat allele homozygous carriers (OR = 1.17, 95% CI: 0.97–1.42). We observed allelic imbalance at the PER3 locus in matched blood and tumor DNA samples, showing a significant retention of the long variant (risk) allele in tumor samples, and a preferential loss of the short repetition allele (p = 0.0005). Gene co-expression analysis in healthy and tumoral breast tissue samples uncovered significant associations between PER3 expression levels with those from genes which belong to several cancer-associated pathways. Finally, relapse-free survival (RFS) analysis showed that low expression levels of PER3 were linked to a significant lower RSF in luminal A (p = 3 × 10−12) but not in the rest of breast cancer subtypes.
Published: 2021
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7. Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Author: Olivier Brouckaert, Anja Rudolph, Annouschka Laenen, Renske Keeman, Manjeet K. Bolla, Qin Wang, Adelheid Soubry, Hans Wildiers, Irene L. Andrulis, Volker Arndt, Matthias W. Beckmann, Javier Benitez, Carl Blomqvist, Stig E. Bojesen, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Georgia Chenevix-Trench, Ji-Yeob Choi, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mikael Eriksson, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Graham G. Giles, Anna González-Neira, Pascal Guénel, Per Hall, Antoinette Hollestelle, John L. Hopper, Hidemi Ito, Michael Jones, Daehee Kang, kConFab, Julia A. Knight, Veli-Matti Kosma, Jingmei Li, Annika Lindblom, Jenna Lilyquist, Artitaya Lophatananon, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, Keitaro Matsuo, Kenneth Muir, Heli Nevanlinna, Paolo Peterlongo, Katri Pylkäs, Suleeporn Saajrang, Caroline Seynaeve, Chen-Yang Shen, Xiao-Ou Shu, Melissa C. Southey, Anthony Swerdlow, Soo-Hwang Teo, Rob A. E. M. Tollenaar, Thérèse Truong, Chiu-chen Tseng, Alexandra J. van den Broek, Carolien H. M. van Deurzen, Robert Winqvist, Anna H. Wu, Cheng Har Yip, Jyh-Cherng Yu, Wei Zheng, Roger L. Milne, Paul D. P. Pharoah, Douglas F. Easton, Marjanka K. Schmidt, Montserrat Garcia-Closas, Jenny Chang-Claude, Diether Lambrechts, and Patrick Neven
Subjects: Breast cancer subtype, Age at breast cancer diagnosis, Parity, Age at first full-time pregnancy, Age at menarche, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. Methods We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. Results Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16–1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01–2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45–1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70–0.88, p
Published: 2017
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8. Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFNγ signaling in non-small cell lung cancer.

Author: Willemijn S M E Theelen, Thomas Kuilman, Katja Schulze, Wei Zou, Oscar Krijgsman, Dennis D G C Peters, Sten Cornelissen, Kim Monkhorst, Pranamee Sarma, Teiko Sumiyoshi, Lukas C Amler, Stefan M Willems, Johannes L G Blaauwgeers, Carel J M van Noesel, Daniel S Peeper, Michel M van den Heuvel, and Marcin Kowanetz
Subjects: Medicine, Science
Abstract: BackgroundIn non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics.Patients and methodsArchival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell response was determined.ResultsTumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed.ConclusionsThese results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.
Published: 2019
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9. Diabetes and Breast Cancer Subtypes.

Author: Heleen K Bronsveld, Vibeke Jensen, Pernille Vahl, Marie L De Bruin, Sten Cornelissen, Joyce Sanders, Anssi Auvinen, Jari Haukka, Morten Andersen, Peter Vestergaard, and Marjanka K Schmidt
Subjects: Medicine, Science
Abstract: Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes.This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07-5.55)), HER2-negative (OR = 2.84(95%CI:1.11-7.22)), and basal-like (OR = 3.14(95%CI:1.03-9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45)) and triple negative (OR = 2.60(95%CI:0.88-7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general.We found no compelling evidence that women with diabetes, treated with or without insulin, develop different breast cancer subtypes than women without diabetes. However, premenopausal women with diabetes tended to develop breast tumors that do not express hormonal receptors, which are typically associated with poor prognosis.
Published: 2017
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10. Evaluation of the EGFR polymorphism R497K in two cohorts of neoadjuvantly treated breast cancer patients.

Author: Marcelo Sobral-Leite, Esther H Lips, Hayra de Andrade Vieira-Monteiro, Letícia Carlos Giacomin, Daniely Regina Freitas-Alves, Sten Cornelissen, Lennart Mulder, Jelle Wesseling, Marjanka K Schmidt, and Rosane Vianna-Jorge
Subjects: Medicine, Science
Abstract: Pathological response of breast cancer to neoadjuvant chemotherapy (NAC) presents great variability, and new prognostic biomarkers are needed. Our aim was to evaluate the association of the epidermal growth factor receptor gene (EGFR) polymorphism R497K (rs2227983) with prognostic features and clinical outcomes of breast cancer, including the pathological response to NAC and the recurrence-free survival (RFS). Tumoral complete response (tCR) was defined by no remaining invasive cancer in the excised breast, whereas pathological complete response (pCR) was defined by no remaining invasive cancer both in the excised breast and lymph nodes. Two independent cohorts were analyzed: one from Brazil (INCA, n = 288) and one from The Netherlands (NKI-AVL, n = 255). In the INCA cohort, the variant (Lys-containing) genotypes were significantly associated with lower proportion of tCR (ORadj = 0.92; 95%CI = 0.85-0.99), whereas in the NKI-AVL cohort they were associated with tumor grade 3 (p = 0.035) and with triple-negative subtype (p = 0.032), but not with clinical outcomes. Such distinct prognostic associations may have arisen due to different neoadjuvant protocols (p < 0.001), or to lower age at diagnosis (p < 0.001) and higher proportion of tumor grade 3 (p = 0.018) at the NKI-AVL cohort. Moreover, NKI-AVL patients achieved better proportion of pCR (21.2% vs 8.3%, p < 0.001) and better RFS (HRadj = 0.48; 95% adjCI = 0.26-0.86) than patients from INCA. In conclusion, large scale studies comprehending different populations are needed to evaluate the impact of genome variants on breast cancer outcomes.
Published: 2017
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11. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author: Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, GENICA Network, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, KConFab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, and Montserrat Garcia-Closas
Subjects: Genetics, QH426-470
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P
Published: 2014
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12. Prognostic Value of Stromal Tumor-Infiltrating Lymphocytes in Young, Node-Negative, Triple-Negative Breast Cancer Patients Who Did Not Receive (neo)Adjuvant Systemic Therapy

Author: Vincent M.T. de Jong, Yuwei Wang, Natalie D. ter Hoeve, Mark Opdam, Nikolas Stathonikos, Katarzyna Jóźwiak, Michael Hauptmann, Sten Cornelissen, Willem Vreuls, Efraim H. Rosenberg, Esther A. Koop, Zsuzsanna Varga, Carolien H.M. van Deurzen, Antien L. Mooyaart, Alicia Córdoba, Emma J. Groen, Joost Bart, Stefan M. Willems, Vasiliki Zolota, Jelle Wesseling, Anna Sapino, Ewa Chmielik, Ales Ryska, Annegien Broeks, Adri C. Voogd, Sherene Loi, Stefan Michiels, Gabe S. Sonke, Elsken van der Wall, Sabine Siesling, Paul J. van Diest, Marjanka K. Schmidt, Marleen Kok, Gwen M.H.E. Dackus, Roberto Salgado, Sabine C. Linn, RS: GROW - R1 - Prevention, RS: CAPHRI - R5 - Optimising Patient Care, Epidemiologie, TechMed Centre, Health Technology & Services Research, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Pathology
Subjects: Adult, Cancer Research, IMPACT, Triple Negative Breast Neoplasms, GERMLINE MUTATIONS, HISTOPATHOLOGY, CHEMOTHERAPY, Prognosis, Neoadjuvant Therapy, Lymphocytes, Tumor-Infiltrating, Oncology, SDG 3 - Good Health and Well-being, Chemotherapy, Adjuvant, SURVIVAL OUTCOMES, Biomarkers, Tumor, Humans, TRIAL, Prospective Studies
Abstract: PURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population–based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.
Published: 2022

13. Supplementary Table 2 from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 70K, Availability of information on tumor morphology and receptor status for Europeans, by each included BCAC study.
Published: 2023

14. Supplementary Table Legend from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 45K.
Published: 2023

15. Supplementary Table 3 from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 57K, Genotyping characteristics of each BCAC participating study.
Published: 2023

16. Data from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls).Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors.Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer.Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.
Published: 2023

17. Supplementary Table 1 from 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Isabel dos-Santos-Silva, Julian Peto, Qin Wang, Manjeet Humphreys, Douglas F. Easton, Minouk Schoemaker, Michael Jones, Anthony Swerdlow, Alan Ashworth, Maya Ghoussaini, Alison M. Dunning, Fiona M. Blows, Paul Pharoah, Malcolm W.R. Reed, Ian W. Brock, Simon S. Cross, Angela Cox, Jingmei Li, Jianjun Liu, Kamila Czene, Per Hall, Madeleine M.A. Tilanus-Linthorst, Agnes Jager, Antoinette Hollestelle, Maartje J. Hooning, Caroline M. Seynaeve, John W.M. Martens, Robert A.E.M. Tollenaar, Peter Devilee, Nayana Weerasooriya, Anna Marie Mulligan, Julia A. Knight, Irene L. Andrulis, Mervi Grip, Arja Jukkola-Vuorinen, Katri Pylkäs, Robert Winqvist, Alexander Miron, Esther M. John, Gianluca Severi, Cariona A. McLean, Laura Baglietto, Graham Giles, Janet Olson, Xianshu Wang, Celine Vachon, Fergus J. Couch, Paolo Radice, Siranoush Manoukian, Loris Bernard, Paolo Peterlongo, Sabine Behrens, Katharina Buck, Dieter Flesch-Janys, Caroline Weltens, Robert Paridaens, Ann Smeets, Diether Lambrechts, Xiaoqing Chen, Jonathan Beesley, Georgia Chenevix-Trench, Vesa Kataja, Jaana M. Hartikainen, Veli-Matti Kosma, Arto Mannermaa, Sara Margolin, Annika Lindblom, Elza Khusnutdinova, Guzel Zinnatullina, Darya Prokofyeva, Marina Bermisheva, Yuriy Rogov, Natalia Antonenkova, Natalia Bogdanova, Carl Blomqvist, Kristiina Aittomäki, Taru A. Muranen, Heli Nevanlinna, Peter Hillemanns, Michael Bremer, Peter Schürmann, Thilo Dörk, Ursula Eilber, Shan Wang-Gohrke, Jenny Chang-Claude, Thomas Brüning, Christina Justenhoven, Hiltrud Brauch, Rita K. Schmutzler, Claus R. Bartram, Michael Golatta, Alfons Meindl, Anne Langheinz, Volker Arndt, Heiko Müller, Hermann Brenner, Christina Clarke Dur, Leslie Bernstein, Argyrios Ziogas, Hoda Anton-Culver, M. Pilar Zamora, José-Ignacio Arias-Pérez, Javier Benítez, Roger L. Milne, Børge G Nordestgaard, Henrik Flyger, Sune F. Nielsen, Stig E Bojesen, Claire Mulot, Pierre Laurent-Puig, Thérèse Truong, Pascal Guénel, Christof Sohn, Andreas Schneeweiss, Frederik Marme, Barbara Burwinkel, Michael Kerin, Ian Tomlinson, Elinor J. Sawyer, Ruediger Schulz-Wendtland, Arif B. Ekici, Matthias W. Beckmann, Peter A. Fasching, Surapon Wiangnon, Arkom Chaiwerawattana, Artitaya Lophatananon, Kenneth R. Muir, Linda M. Braaf, Sten Cornelissen, Annegien Broeks, Marjanka K. Schmidt, Maryam Mahmoodi, Melissa C. Southey, Carmel Apicella, John L. Hopper, Nichola Johnson, Nick Orr, Olivia Fletcher, Frank Dudbridge, and Helen Warren
Abstract: PDF file, 107K, Summary characteristics of the participating BCAC case-control studies.
Published: 2023

18. IFN-γ signature enables selection of neoadjuvant treatment in patients with stage III melanoma

Author: Irene L.M. Reijers, Disha Rao, Judith M. Versluis, Alexander M. Menzies, Petros Dimitriadis, Michel W. Wouters, Andrew J. Spillane, Willem M.C. Klop, Annegien Broeks, Linda J.W. Bosch, Marta Lopez-Yurda, Winan J. van Houdt, Robert V. Rawson, Lindsay G. Grijpink-Ongering, Maria Gonzalez, Sten Cornelissen, Jasper Bouwman, Joyce Sanders, Elsemieke Plasmeijer, Yannick S. Elshot, Richard A. Scolyer, Bart A. van de Wiel, Daniel S. Peeper, Alexander C.J. van Akkooi, Georgina V. Long, Christian U. Blank, Oral and Maxillofacial Surgery, Dermatology, Graduate School, AII - Infectious diseases, AII - Inflammatory diseases, and CCA - Cancer Treatment and Quality of Life
Subjects: Immunology, Immunology and Allergy
Abstract: Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.
Published: 2023

19. Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

Author: A.C.J. van Akkooi, Judith M. Versluis, Christian U. Blank, Charlotte L. Zuur, Elisa A. Rozeman, Willem M.C. Klop, Esmée P. Hoefsmit, Lindsay G Grijpink-Ongering, María Jesús González González, Sandra Adriaansz, Robyn P. M. Saw, Sydney Ch'ng, Sten Cornelissen, J Stretch, Annegien Broeks, Ton N. Schumacher, A A Torres Acosta, Hanna Eriksson, Ron M. Kerkhoven, B.A. van de Wiel, Petros Dimitriadis, Richard A. Scolyer, Oscar Krijgsman, Daniel S. Peeper, J.B.A.G. Haanen, Omgo E. Nieweg, Karolina Sikorska, Kerwin F. Shannon, Georgina V. Long, W.J. van Houdt, A.M. Menzies, H. Mallo, Irene L.M. Reijers, and Andrew J. Spillane
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Melanoma, Phases of clinical research, Ipilimumab, General Medicine, medicine.disease, General Biochemistry, Genetics and Molecular Biology, law.invention, Clinical trial, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Randomized controlled trial, law, 030220 oncology & carcinogenesis, Internal medicine, medicine, Adjuvant therapy, Biomarker (medicine), Nivolumab, business, medicine.drug
Abstract: Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P
Published: 2021

20. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Ana Peixoto, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Michael Untch, Susan J. Ramus, Kenneth Offit, John J. Spinelli, Clarice R. Weinberg, Kyriaki Michailidou, Javier Benitez, Rita K. Schmutzler, Lizet E. van der Kolk, Heli Nevanlinna, Annika Lindblom, Sara Margolin, Stella Koutros, Elza Khusnutdinova, Diana Eccles, Lenka Foretova, Wolfgang Janni, Jennifer T. Loud, Roger L. Milne, Patrick Neven, Thomas U. Ahearn, Hedy S. Rennert, Karolina Prajzendanc, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Pascal Guénel, Antoinette Hollestelle, Jolanta Lissowska, Ni Zhao, Melissa Christiaens, Hoda Anton-Culver, Ans M.W. van den Ouweland, Christopher A. Haiman, Debra Frost, Vessela N. Kristensen, Bernard Peissel, Muhammad Usman Rashid, Noura Mebirouk, Claudine Isaacs, Matthias W. Beckmann, Sofia Khan, Xia Jiang, Jack A. Taylor, Peter Hillemanns, Robert Winqvist, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Katherine L. Nathanson, Judy Garber, Siranoush Manoukian, Simon S. Cross, Flavio Lejbkowicz, Manjeet K. Bolla, Goska Leslie, Saundra S. Buys, Banu Arun, Xiaohong R. Yang, Peter Schürmann, Irene Konstantopoulou, Mia M. Gaudet, Rob A. E. M. Tollenaar, Joe Dennis, Louise Izatt, David E. Goldgar, Anna Jakubowska, Alicja Lukomska, Fabienne Lesueur, Susanna C. Larsson, Peter Devilee, Helen Byers, Bernd Holleczek, Marc Tischkowitz, Arif B. Ekici, Austin Miller, Carl Blomqvist, Christopher R. Hake, Paul D.P. Pharoah, Harvey A. Risch, Kristin K. Zorn, Mehdi Manoochehri, Kamila Czene, Peter A. Fasching, Trinidad Caldés, Hanna Huebner, Agnes Jager, William G. Newman, Lesley McGuffog, Maren T. Scheuner, Nick Orr, Susan M. Domchek, Antonis C. Antoniou, Peter Kraft, Pooja Middha Kapoor, Daniel R. Barnes, Christine L. Clarke, Douglas F. Easton, Bernadette A M Heemskerk-Gerritsen, Ross L. Prentice, Mark E. Sherman, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Diether Lambrechts, Mark H. Greene, Mark S. Goldberg, Peter J. Hulick, Maria Elena Martinez, Arto Mannermaa, Frans B. L. Hogervorst, Christian F. Singer, Johanna Rantala, Esther M. John, Jesse Nodora, Wendy K. Chung, Csilla Szabo, Mads Thomassen, Tracy A. O'Mara, Kelly-Anne Phillips, Manuela Gago-Dominguez, Jacques Simard, John L. Hopper, Jacopo Azzollini, Rudolf Kaaks, Haoyu Zhang, Eitan Friedman, Heiko Becher, János Papp, Thomas Rüdiger, Alison M. Dunning, Daniele Campa, Alfons Meindl, Lothar Häberle, Ana Blanco, Eric Hahnen, Barbara Wappenschmidt, Elaine F. Harkness, Audrey Y. Jung, Guanghao Qi, Zumuruda Abu Ful, Maria A. Caligo, Priyanka Sharma, Håkan Olsson, Elke M van Veen, Marion Piedmonte, Linetta B. Koppert, Usha Menon, Laura Matricardi, Jonine D. Figueroa, Wei Zheng, Milena Jakimovska, Katarzyna Białkowska, Renske Keeman, Matti A. Rookus, William J. Tapper, J. Peto, Paul L. Auer, Andreas Schneeweiss, Xiao-Ou Shu, Miriam Dwek, Elvira Mingazheva, Hermann Brenner, Emilija Lazarova, Atocha Romero, Rulla M. Tamimi, Laura Papi, Hans Wildiers, Catriona McLean, Montserrat Garcia-Closas, Matthias Rübner, Thomas Brüning, Graham G. Giles, Robert J. MacInnis, Hans Christiansen, Sten Cornelissen, Paul A. James, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Nilanjan Chatterjee, D. Gareth Evans, Ignacio Briceño, Mary B. Daly, Annegien Broeks, Evgeny N. Imyanitov, Jonathan Beesley, Snezhana Smichkoska, Thilo Dörk, Yon-Dschun Ko, Paolo Peterlongo, Celine M. Vachon, Claire Mulot, Kristiina Aittomäki, Liene Nikitina-Zake, Manuel R. Teixeira, Edith Olah, Florentia Fostira, Beth N. Peshkin, Pierre Laurent-Puig, M. B. Terry, Michael T. Parsons, Anna González-Neira, Julie Lecarpentier, Jacek Gronwald, Fergus J. Couch, Mariarosaria Calvello, Leigha Senter, Ute Hamann, Brigitte Rack, Marco Montagna, Simon A. Gayther, Barbara Burwinkel, Anne-Vibeke Lænkholm, Irene L. Andrulis, Sabine Behrens, Beth Y. Karlan, Anthony J. Swerdlow, Marjanka K. Schmidt, Cari M. Kitahara, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Melissa A. Troester, Diana Torres, Daniel Barrowdale, Elinor J. Sawyer, Hiltrud Brauch, Minouk J. Schoemaker, Dale P. Sandler, José A. García-Sáenz, Jennifer Stone, Qin Wang, Conxi Lázaro, Paolo Radice, Jan Lubinski, Jose E. Castelao, Natalia Bogdanova, Drakoulis Yannoukakos, Davide Bondavalli, Kristan J. Aronson, Gad Rennert, Wing-Yee Lo, Robert N. Hoover, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Andrew K. Godwin, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Penny Soucy, Jenny Chang-Claude, Kathleen Claes, Olufunmilayo I. Olopade, Jeffrey N. Weitzel, Stig E. Bojesen, Sara Y Brucker, Darcy L. Thull, Darya Prokofyeva, Taru A. Muranen, Ben Schöttker, Orland Diez, Susan M. Gapstur, Sarah Sampson, Bernardo Bonanni, Per Hall, Ana Vega, Medical Oncology, Surgery, and Clinical Genetics
Subjects: Oncology, medicine.medical_specialty, Linkage disequilibrium, Carcinogenesis, Estrogen receptor, Genome-wide association study, Breast Neoplasms, Triple Negative Breast Neoplasms, Biology, Gene mutation, Linkage Disequilibrium, Càncer de mama, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Genetics, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Carcinogènesi, Triple-negative breast cancer, 030304 developmental biology, Medicinsk genetik, 0303 health sciences, Genetic heterogeneity, BRCA1 Protein, medicine.disease, 3. Good health, Case-Control Studies, Female, Mutation, Genome-Wide Association Study, Medical Genetics, 030217 neurology & neurosurgery
Abstract: Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020

21. The interferon-gamma (IFN-y) signature from baseline tumor material predicts pathologic response after neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma

Author: Irene L.M. Reijers, Petros Dimitriadis, Elisa A. Rozeman, Oscar Krijgsman, Sten Cornelissen, Linda J.W. Bosch, Annegien Broeks, Alexander M. Menzies, Bart A. van de Wiel, Richard A. Scolyer, Georgina V. Long, and Christian U. Blank
Subjects: Cancer Research, Oncology
Abstract: 9539 Background: Neoadjuvant IPI + NIVO induces high pathologic response rates (pRR) of 74-78% in macroscopic stage III melanoma. Pathologic response ( < 50% viable tumor) is strongly associated with improved relapse-free survival (RFS); the previous OpACIN-neo study demonstrated a 2-year RFS of 96.9% in patients (pts) with pathologic response, whereas the 2-year RFS in non-responders was 35.5%. These data highlight the need for baseline biomarkers predictive for response and survival. Here, we present the predictive value of the 10-gene IFN-y expression signature algorithm (based on Ayers et al.) for pathologic response and relapse in a cohort of melanoma pts treated with neoadjuvant IPI + NIVO. Methods: Baseline tumor biopsies from lymph node metastases of stage III melanoma pts were used for IFN-y signature assessment. Pts were treated with a maximum of two cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg in the OpACIN-neo (arm B) and PRADO studies. RNA expression analysis was conducted using the nCounter® PanCancer Immune Profiling panel on the NanoString Flex machine (NanoString Technologies), which is clinically applicable due to its fast turn-around-time (two days). An IFN-y signature gene expression score (IFN-y score) was calculated using a NKI-developed algorithm. Association between IFN-y score and pathologic response or event-free survival (EFS) was examined by logistic regression and Cox analyses. The optimal cutoff between a high and low IFN-y score was defined based on a summary receiver operating characteristic (sROC) curve. Results: In total, 103 pts treated in the OpACIN-neo and PRADO studies had baseline tumor material available. Median age was 56 years, 62% was male, and 52% had a high baseline IFN-y score. The pRR of the total cohort was 70% (72/103 pts), including 56% (58/103) major pathologic response (MPR, 0-≤10% viable tumor) and 14% (14/103) partial responses (pPR, 10-≤50% viable tumor). 30% (31/103 pts) had no pathologic response. After a median follow-up of 25.2 months, 26 pts (25.2%) developed a melanoma relapse. The IFN-y score was significantly associated with response (OR 1.061, p < 0.001) and relapse (OR 0. 974, p = 0.029). The pRR was 89% (48/54) in pts with a high IFN-y score versus 49% (24/49) in those with a low IFN-y score (p < 0.001). Pts with a high IFN-y score were also less likely to develop a relapse (11% [6/54] versus 41% [20/49], p = 0.001). Conclusions: Pts with a high IFN-y score in pre-treatment biopsies are more likely to respond to neoadjuvant IPI + NIVO with favorable EFS. A rapid gene expression analysis enables the IFN-y score to be used in daily clinical practice to identify pts who might qualify for treatment escalation or de-escalation. The DONIMI study [NCT04133948] currently investigates different neoadjuvant treatment combinations in stage III melanoma pts based on their intratumoral IFN-y score.
Published: 2022

22. Immune landscape of breast tumors with low and intermediate estrogen receptor (ER) expression

Author: Leonie Voorwerk, Hugo M. Horlings, Joyce Sanders, Milou S. Keusters, Sten Cornelissen, Gabe S. Sonke, Sabine C. Linn, and Marleen Kok
Subjects: Cancer Research, Oncology
Abstract: 566 Background: Immune checkpoint blockade (ICB) is currently only approved for patients with triple-negative breast cancer (TNBC). However, the cut-off used for ER expression (
Published: 2022

23. Circadian PERformance in breast cancer : a germline and somatic genetic study of PER3(VNTR) polymorphisms and gene co-expression

Author: Hege Edvarsen, Ana Lluch, Antonio Falcó, Laura J. van't Veer, Carlos Lozano-Asencio, Allan Balmain, Anne Lise Børresen-Dale, Joan Climent, Raimundo Cervera-Vidal, Vita Fedele, Rafa Tabares-Seisdedos, Irene Tadeo-Cervera, Sten Cornelissen, Jaume Forés-Martos, Julia Sierra-Roca, Marjanka Schmidt, Vessela N. Kristensen, Pilar Eroles, David A. Quigley, Producción Científica UCH 2021, UCH. Departamento de Matemáticas, Física y Ciencias Tecnológicas, UCH. Departamento de Producción y Sanidad Animal, Salud Pública Veterinaria y Ciencia y Tecnología de los Alimentos, and UCH. ESI International Chair@CEU-UCH
Subjects: Locus (genetics), Biology, Genetic analysis, Germline, Breast cancer, Polimorfismo genético, Clinical Research, Polymorphism (computer science), Breast Cancer, Genetics, medicine, 2.1 Biological and endogenous factors, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, Genetic Testing, Aetiology, Allele, Cáncer - Aspectos genéticos, RC254-282, Cancer, Genetic polymorphisms, Cancer - Genetic aspects, Prevention, Human Genome, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Oncology, Allelic Imbalance, Cancer research
Abstract: Polymorphisms in the PER3 gene have been associated with several human disease phenotypes, including sleep disorders and cancer. In particular, the long allele of a variable number of tandem repeat (VNTR) polymorphism has been previously linked to an increased risk of breast cancer. Here we carried out a combined germline and somatic genetic analysis of the role of the PER3VNRT polymorphism in breast cancer. The combined data from 8284 individuals showed a non-significant trend towards increased breast cancer risk in the 5-repeat allele homozygous carriers (OR = 1.17, 95% CI: 0.97–1.42). We observed allelic imbalance at the PER3 locus in matched blood and tumor DNA samples, showing a significant retention of the long variant (risk) allele in tumor samples, and a preferential loss of the short repetition allele (p = 0.0005). Gene co-expression analysis in healthy and tumoral breast tissue samples uncovered significant associations between PER3 expression levels with those from genes which belong to several cancer-associated pathways. Finally, relapse-free survival (RFS) analysis showed that low expression levels of PER3 were linked to a significant lower RSF in luminal A (p = 3 × 10−12) but not in the rest of breast cancer subtypes.
Published: 2021

24. P01.15 Personalized combination of neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in macroscopic stage III melanoma patients stratified according to interferon-gamma (IFN-gamma) signature – the DONIMI study

Author: Acj van Akkooi, A.M. Menzies, Ilm Reijers, Christian U. Blank, Elisa A. Rozeman, Richard A. Scolyer, Sten Cornelissen, Oscar Krijgsman, Judith M. Versluis, Georgina V. Long, Ljw Bosch, J Bouwman, Disha Rao, Petros Dimitriadis, Andrew J. Spillane, and B.A. van de Wiel
Subjects: Oncology, medicine.medical_specialty, business.industry, Ipilimumab, Clinical trial, Internal medicine, medicine, Clinical endpoint, Stage III melanoma, Dosing, Nivolumab, Adverse effect, business, Ifn gamma, medicine.drug
Abstract: Background The previous OpACIN and OpACIN-neo studies investigating neoadjuvant IPI plus NIVO have demonstrated high pathologic response rates (74–78%) and favorable long-term outcomes for patients (pts) with a pathological response; at 36 and 18 months follow up only 1/71 (1.4%) responders has relapsed. In contrast, pathological non-responders have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline IFN-γ signature high pts were more likely to respond to IPI plus NIVO. The DONIMI study tests the combination of NIVO ± IPI combined with a class 1 histone deacetylase inhibitor, domatinostat (DOM), according to the pts IFN-γ signature. We have developed a neoadjuvant IFN-γ signature, based on the signature previously described by Ayers et al., that will be used for the first time to classify pts in this prospective trial. Trial design This two-center investigator-initiated phase 1b study aims to assess the safety and feasibility of neoadjuvant NIVO ± DOM ± IPI in 45 stage III melanoma pts with macroscopic de-novo or recurrent disease. IFN-γ signature high pts (n=20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240 mg q3wk) or Arm B (2 cycles NIVO 240 mg q3wk + DOM 200 mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n=25) will be randomized to Arm C (2 cycles NIVO 240 mg q3wk + DOM 200 mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240 mg q3wk + IPI 80 mg q3wk + DOM 200 mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200 mg BID, d1-14, q3wks), a lower dosing scheme (100 mg OD, d1-14, q3wks) or the same dosing scheme (200 mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 patients cannot adhere to the planned time of surgery (week 6 ± 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. To date, 7 patients have been enrolled. Clinical trial information NCT04133948 Disclosure Information I.L.M. Reijers: None. E.A. Rozeman: None. P. Dimitriadis: None. O. Krijgsman: C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Modest; BMS. L.J.W. Bosch: None. S. Cornelissen: None. J. Bouwman: None. J.M. Versluis: None. D. Rao: None. B. van de Wiel: None. A.J. Spillane: None. R.A. Scolyer: F. Consultant/Advisory Board; Modest; MSD, Neracare, Myriad, Novartis. A.M. Menzies: F. Consultant/Advisory Board; Modest; BMS, MSD Oncology, Novartis, Pierre Fabre, Roche. A.C.J. van Akkooi: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; Amgen, BMS, Novartis. F. Consultant/Advisory Board; Modest; Amgen, BMS, Novartis, MSD, Merck, Merck-Pfizer, 4SC. G.V. Long: F. Consultant/Advisory Board; Modest; Aduro, Amgen, BMS, Mass-Array, Pierre-Fabre, Novartis, Merck MSD, Roche. C.U. Blank: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Modest; BMS, Novartis, Nanostring. F. Consultant/Advisory Board; Modest; BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, Genmab, Pierre Fabre.
Published: 2020

25. Presence of a 34-gene signature is a favorable prognostic marker in squamous non-small cell lung carcinoma

Author: Thomas Kuilman, Oscar Krijgsman, Daniel S. Peeper, M. van den Heuvel, Dennis Peters, Katja Schulze, Maarten A. Ligtenberg, Sten Cornelissen, Kim Monkhorst, Willemijn S. M. E. Theelen, Stefan M. Willems, J. L. G. Blaauwgeers, C. J. M. van Noesel, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Pathology, AII - Cancer immunology, and CCA - Cancer biology and immunology
Subjects: 0301 basic medicine, Lung Neoplasms, Cell, lcsh:Medicine, Inflammation, INNATE, Biology, IMMUNITY, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Adenocarcinoma, NSCLC, General Biochemistry, Genetics and Molecular Biology, Natural killer cell, 03 medical and health sciences, 0302 clinical medicine, Immune system, All institutes and research themes of the Radboud University Medical Center, Carcinoma, Non-Small-Cell Lung, medicine, Carcinoma, Tumor Microenvironment, Gene signature, Humans, CANCER PATIENTS, Research, lcsh:R, General Medicine, Immunoprofiling, medicine.disease, Prognosis, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Carcinoma, Squamous Cell, Immunohistochemistry, Gene expression, medicine.symptom
Abstract: Background The tumor immune microenvironment is a heterogeneous entity. Gene expression analysis allows us to perform comprehensive immunoprofiling and may assist in dissecting the different components of the immune infiltrate. As gene expression analysis also provides information regarding tumor cells, differences in interactions between the immune system and specific tumor characteristics can also be explored. This study aims to gain further insights in the composition of the tumor immune infiltrate and to correlate these components to histology and overall survival in non-small cell lung cancer (NSCLC). Methods Archival tissues from 530 early stage, resected NSCLC patients with annotated tumor and patient characteristics were analyzed using the NanoString nCounter Analysis system. Results Unsupervised clustering of the samples was mainly driven by the overall level of inflammation, which was not correlated with survival in this patient set. Adenocarcinoma (AD) showed a significantly higher degree of immune infiltration compared to squamous cell carcinoma (SCC). A 34-gene signature, which did not correlate with the overall level of immune infiltration, was identified and showed an OS benefit in SCC. Strikingly, this benefit was not observed in AD. This difference in OS in SCC specifically was confirmed in two independent NSCLC cohorts. The highest correlation between expression of the 34-gene signature and specific immune cell populations was observed for NK cells, but although a plausible mechanism for NK cell intervention in tumor growth could be established in SCC over AD, this could not be translated back to immunohistochemistry, which showed that NK cell infiltration is scarce irrespective of histology. Conclusions These findings suggest that the ability of immune cell infiltration and the interaction between tumor and immune cells may be different between AD and SCC histology and that a subgroup of SCC tumors seems more susceptible to Natural Killer cell recognition and killing, whereas this may not occur in AD tumors. A highly sensitive technique like NanoString was able to detect this subgroup based on a 34-gene signature, but further research will be needed to assist in explaining the biological rationale of such low-level expression signatures.
Published: 2020

26. 9P BRCA1 promoter methylation confers a more favorable prognosis to systemically untreated young triple-negative breast cancer patients than tumour BRCA1 mutation

Author: N.D. ter Hoeve, Gwen M. H. E. Dackus, Willem Vreuls, Efraim H. Rosenberg, P. J. Van Diest, Annegien Broeks, Esther A. Koop, Sabine Siesling, Marleen Kok, Michael Hauptmann, Katarzyna Jozwiak, Y. Wang, Marjanka K. Schmidt, V. De Jong, Sten Cornelissen, Mark Opdam, Sabine C. Linn, Petra M. Nederlof, Adri C. Voogd, and N. Stathonikos
Subjects: Oncology, business.industry, Promoter methylation, Cancer research, Medicine, Hematology, Favorable prognosis, business, Triple-negative breast cancer, Brca1 gene
Published: 2021

27. LBA39 Personalized combination of neoadjuvant domatinostat, nivolumab (NIVO) and ipilimumab (IPI) in stage IIIB-D melanoma patients (pts) stratified according to the interferon-gamma signature (IFN-γ sign): The DONIMI study

Author: Petros Dimitriadis, Christian U. Blank, Richard A. Scolyer, Willem M.C. Klop, B.A. van de Wiel, A.C.J. van Akkooi, Irene L.M. Reijers, M.J.C. Gregorio, Andrew J. Spillane, Judith M. Versluis, Robert V. Rawson, Michel W.J.M. Wouters, Linda J.W. Bosch, G.V. Long, Sten Cornelissen, A.M. Menzies, Thomas E. Pennington, Marta Lopez-Yurda, Lindsay G Grijpink-Ongering, and Robyn P. M. Saw
Subjects: Oncology, medicine.medical_specialty, business.industry, Melanoma, Ipilimumab, Hematology, Stage iiib, medicine.disease, Internal medicine, medicine, Interferon gamma, Nivolumab, business, medicine.drug, Sign (mathematics)
Published: 2021

28. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Christine L. Clarke, Pierre Laurent-Puig, Mary B. Daly, Jacek Gronwald, Douglas F. Easton, M. B. Terry, Dominique Stoppa-Lyonnet, Mads Thomassen, Fergus J. Couch, José A. García-Sáenz, Mariarosaria Calvello, Florentia Fostira, Nadine Tung, Manuela Gago-Dominguez, Gad Rennert, Ute Hamann, Brigitte Rack, Csilla Szabo, Rudolf Kaaks, Kamila Czene, Simon A. Gayther, Sabine Behrens, John L. Hopper, kConFab Investigators, Barbara Burwinkel, Anne-Vibeke Lænkholm, Elaine F. Harkness, Audrey Y. Jung, János Papp, Usha Menon, Stephen J. Chanock, Lenka Foretova, Andrew K. Godwin, Snezhana Smichkoska, William J. Tapper, Melissa Christiaens, Muhammad Usman Rashid, Per Hall, Ana Vega, Elke M van Veen, Kathleen Claes, Pascal Guénel, Jennifer T. Loud, Roger L. Milne, Vessela N. Kristensen, Katarzyna Białkowska, Xia Jiang, Manuel R. Teixeira, Antoinette Hollestelle, Debra Frost, Noura Mebirouk, Beth N. Peshkin, Olufunmilayo I. Olopade, Bernd Holleczek, Andreas Schneeweiss, Hermann Brenner, Jeffrey N. Weitzel, Goska Leslie, Stig E. Bojesen, Peter J. Hulick, Xiaohong R. Yang, Mark S. Goldberg, Ignacio Briceño, Heli Nevanlinna, Maren T. Scheuner, Thilo Dörk, John J. Spinelli, Tracy A. O'Mara, Maria A. Caligo, Claire Mulot, Nick Orr, Anna González-Neira, Sara Y Brucker, Darcy L. Thull, Darya Prokofyeva, Paul L. Auer, Hans Wildiers, Jan Lubinski, Jose E. Castelao, Diana Eccles, Priyanka Sharma, Jonine D. Figueroa, Maria Elena Martinez, Wendy K. Chung, Rulla M. Tamimi, Taru A. Muranen, Wing-Yee Lo, Rob A. E. M. Tollenaar, Thomas Rüdiger, Natalia Bogdanova, Louise Izatt, Ben Schöttker, Thomas U. Ahearn, Hedy S. Rennert, Claudine Isaacs, Embrace Study, Jennifer Stone, Jolanta Lissowska, D. Gareth Evans, Matthias W. Beckmann, Peter Schürmann, Qin Wang, Orland Diez, Christopher R. Hake, Mehdi Manoochehri, Peter A. Fasching, Lesley McGuffog, Haoyu Zhang, Joe Dennis, Hanna Huebner, Judy Garber, Drakoulis Yannoukakos, Kenneth Offit, Yon-Dschun Ko, Celine M. Vachon, Robert N. Hoover, Marc Tischkowitz, Pooja Middha Kapoor, Agnes Jager, Davide Bondavalli, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Marjanka K. Schmidt, Edith Olah, Laura Papi, Conxi Lázaro, Arif B. Ekici, Paolo Radice, Austin Miller, Kristan J. Aronson, Harvey A. Risch, Jack A. Taylor, Robert Winqvist, Jacques Simard, Catriona McLean, Michael T. Parsons, Wei Zheng, Linetta B. Koppert, Susan M. Gapstur, Georgia Chenevix-Trench, Susan M. Domchek, Tjoung-Won Park-Simon, Zumuruda Abu Ful, Javier Benitez, Clarice R. Weinberg, Kyriaki Michailidou, Alfons Meindl, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Ana Blanco, Nilanjan Chatterjee, Montserrat Garcia-Closas, Thomas Brüning, Rita K. Schmutzler, Lizet E. van der Kolk, Peter Hillemanns, Beth Y. Karlan, Hoda Anton-Culver, Ans M.W. van den Ouweland, Banu Arun, J. Peto, Anthony J. Swerdlow, Marco Montagna, Ana Peixoto, Emmanouil Saloustros, Peter Kraft, Mark H. Greene, Evgeny N. Imyanitov, Siranoush Manoukian, Diether Lambrechts, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Milena Jakimovska, Dijana Plaseska-Karanfilska, Kristiina Aittomäki, Johanna Rantala, Kelly-Anne Phillips, Melissa A. Troester, Michael Untch, Susan J. Ramus, Arto Mannermaa, Christian F. Singer, Abctb Investigators, Bernard Peissel, Daniel Barrowdale, Elinor J. Sawyer, Jacopo Azzollini, Leigha Senter, Antonis C. Antoniou, Barbara Wappenschmidt, Hiltrud Brauch, Heiko Becher, Julie Lecarpentier, Sarah Sampson, Jonathan Beesley, Eitan Friedman, Dale P. Sandler, Minouk J. Schoemaker, Irene L. Andrulis, Paolo Peterlongo, Saundra S. Buys, Stella Koutros, Lothar Häberle, Christopher A. Haiman, Fabienne Lesueur, Cari M. Kitahara, Peter Devilee, Kristin K. Zorn, Karolina Prajzendanc, Monica Zuradelli, Simon S. Cross, William G. Newman, Ni Zhao, Jesse Nodora, Susanna C. Larsson, Helen Byers, Flavio Lejbkowicz, Trinidad Caldés, Eric Hahnen, Laura Matricardi, Daniel R. Barnes, Mark E. Sherman, Åke Borg, Angela Cox, Maartje J. Hooning, Anthony Howell, Volker Arndt, Diana Torres, Penny Soucy, Bernardo Bonanni, Ross L. Prentice, Marion Piedmonte, Xiao-Ou Shu, Elvira Mingazheva, Elza Khusnutdinova, Patrick Neven, Renske Keeman, Matti A. Rookus, Manjeet K. Bolla, Atocha Romero, Robert J. MacInnis, Jenny Chang-Claude, Irene Konstantopoulou, Emilija Lazarova, Annegien Broeks, Carl Blomqvist, Annika Lindblom, Bernadette A M Heemskerk-Gerritsen, Matthias Rübner, Graham G. Giles, Hans Christiansen, Liene Nikitina-Zake, Håkan Olsson, Wolfgang Janni, Sofia Khan, Katherine L. Nathanson, Alicja Lukomska, Miriam Dwek, Sara Margolin, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Elizabeth J. van Rensburg, Michael Jones, Frans B. L. Hogervorst, Esther M. John, Alison M. Dunning, Daniele Campa, Guanghao Qi, Sten Cornelissen, and Paul A. James
Subjects: 0303 health sciences, Estrogen receptor, Genome-wide association study, Biology, medicine.disease, Tumor heterogeneity, 3. Good health, Tumor Subtype, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Progesterone receptor, Susceptibility locus, medicine, Cancer research, Human Epidermal Growth Factor Receptor 2, 030304 developmental biology
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate PIn-silico analyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2019
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29. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Haoyu, Zhang, Thomas U, Ahearn, Julie, Lecarpentier, Daniel, Barnes, Jonathan, Beesley, Guanghao, Qi, Xia, Jiang, Tracy A, O'Mara, Ni, Zhao, Manjeet K, Bolla, Alison M, Dunning, Joe, Dennis, Qin, Wang, Zumuruda Abu, Ful, Kristiina, Aittomäki, Irene L, Andrulis, Hoda, Anton-Culver, Volker, Arndt, Kristan J, Aronson, Banu K, Arun, Paul L, Auer, Jacopo, Azzollini, Daniel, Barrowdale, Heiko, Becher, Matthias W, Beckmann, Sabine, Behrens, Javier, Benitez, Marina, Bermisheva, Katarzyna, Bialkowska, Ana, Blanco, Carl, Blomqvist, Natalia V, Bogdanova, Stig E, Bojesen, Bernardo, Bonanni, Davide, Bondavalli, Ake, Borg, Hiltrud, Brauch, Hermann, Brenner, Ignacio, Briceno, Annegien, Broeks, Sara Y, Brucker, Thomas, Brüning, Barbara, Burwinkel, Saundra S, Buys, Helen, Byers, Trinidad, Caldés, Maria A, Caligo, Mariarosaria, Calvello, Daniele, Campa, Jose E, Castelao, Jenny, Chang-Claude, Stephen J, Chanock, Melissa, Christiaens, Hans, Christiansen, Wendy K, Chung, Kathleen B M, Claes, Christine L, Clarke, Sten, Cornelissen, Fergus J, Couch, Angela, Cox, Simon S, Cross, Kamila, Czene, Mary B, Daly, Peter, Devilee, Orland, Diez, Susan M, Domchek, Thilo, Dörk, Miriam, Dwek, Diana M, Eccles, Arif B, Ekici, D Gareth, Evans, Peter A, Fasching, Jonine, Figueroa, Lenka, Foretova, Florentia, Fostira, Eitan, Friedman, Debra, Frost, Manuela, Gago-Dominguez, Susan M, Gapstur, Judy, Garber, José A, García-Sáenz, Mia M, Gaudet, Simon A, Gayther, Graham G, Giles, Andrew K, Godwin, Mark S, Goldberg, David E, Goldgar, Anna, González-Neira, Mark H, Greene, Jacek, Gronwald, Pascal, Guénel, Lothar, Häberle, Eric, Hahnen, Christopher A, Haiman, Christopher R, Hake, Per, Hall, Ute, Hamann, Elaine F, Harkness, Bernadette A M, Heemskerk-Gerritsen, Peter, Hillemanns, Frans B L, Hogervorst, Bernd, Holleczek, Antoinette, Hollestelle, Maartje J, Hooning, Robert N, Hoover, John L, Hopper, Anthony, Howell, Hanna, Huebner, Peter J, Hulick, Evgeny N, Imyanitov, Claudine, Isaacs, Louise, Izatt, Agnes, Jager, Milena, Jakimovska, Anna, Jakubowska, Paul, James, Ramunas, Janavicius, Wolfgang, Janni, Esther M, John, Michael E, Jones, Audrey, Jung, Rudolf, Kaaks, Pooja Middha, Kapoor, Beth Y, Karlan, Renske, Keeman, Sofia, Khan, Elza, Khusnutdinova, Cari M, Kitahara, Yon-Dschun, Ko, Irene, Konstantopoulou, Linetta B, Koppert, Stella, Koutros, Vessela N, Kristensen, Anne-Vibeke, Laenkholm, Diether, Lambrechts, Susanna C, Larsson, Pierre, Laurent-Puig, Conxi, Lazaro, Emilija, Lazarova, Flavio, Lejbkowicz, Goska, Leslie, Fabienne, Lesueur, Annika, Lindblom, Jolanta, Lissowska, Wing-Yee, Lo, Jennifer T, Loud, Jan, Lubinski, Alicja, Lukomska, Robert J, MacInnis, Arto, Mannermaa, Mehdi, Manoochehri, Siranoush, Manoukian, Sara, Margolin, Maria Elena, Martinez, Laura, Matricardi, Lesley, McGuffog, Catriona, McLean, Noura, Mebirouk, Alfons, Meindl, Usha, Menon, Austin, Miller, Elvira, Mingazheva, Marco, Montagna, Anna Marie, Mulligan, Claire, Mulot, Taru A, Muranen, Katherine L, Nathanson, Susan L, Neuhausen, Heli, Nevanlinna, Patrick, Neven, William G, Newman, Finn C, Nielsen, Liene, Nikitina-Zake, Jesse, Nodora, Kenneth, Offit, Edith, Olah, Olufunmilayo I, Olopade, Håkan, Olsson, Nick, Orr, Laura, Papi, Janos, Papp, Tjoung-Won, Park-Simon, Michael T, Parsons, Bernard, Peissel, Ana, Peixoto, Beth, Peshkin, Paolo, Peterlongo, Julian, Peto, Kelly-Anne, Phillips, Marion, Piedmonte, Dijana, Plaseska-Karanfilska, Karolina, Prajzendanc, Ross, Prentice, Darya, Prokofyeva, Brigitte, Rack, Paolo, Radice, Susan J, Ramus, Johanna, Rantala, Muhammad U, Rashid, Gad, Rennert, Hedy S, Rennert, Harvey A, Risch, Atocha, Romero, Matti A, Rookus, Matthias, Rübner, Thomas, Rüdiger, Emmanouil, Saloustros, Sarah, Sampson, Dale P, Sandler, Elinor J, Sawyer, Maren T, Scheuner, Rita K, Schmutzler, Andreas, Schneeweiss, Minouk J, Schoemaker, Ben, Schöttker, Peter, Schürmann, Leigha, Senter, Priyanka, Sharma, Mark E, Sherman, Xiao-Ou, Shu, Christian F, Singer, Snezhana, Smichkoska, Penny, Soucy, Melissa C, Southey, John J, Spinelli, Jennifer, Stone, Dominique, Stoppa-Lyonnet, Anthony J, Swerdlow, Csilla I, Szabo, Rulla M, Tamimi, William J, Tapper, Jack A, Taylor, Manuel R, Teixeira, MaryBeth, Terry, Mads, Thomassen, Darcy L, Thull, Marc, Tischkowitz, Amanda E, Toland, Rob A E M, Tollenaar, Ian, Tomlinson, Diana, Torres, Melissa A, Troester, Thérèse, Truong, Nadine, Tung, Michael, Untch, Celine M, Vachon, Ans M W, van den Ouweland, Lizet E, van der Kolk, Elke M, van Veen, Elizabeth J, vanRensburg, Ana, Vega, Barbara, Wappenschmidt, Clarice R, Weinberg, Jeffrey N, Weitzel, Hans, Wildiers, Robert, Winqvist, Alicja, Wolk, Xiaohong R, Yang, Drakoulis, Yannoukakos, Wei, Zheng, Kristin K, Zorn, Roger L, Milne, Peter, Kraft, Jacques, Simard, Paul D P, Pharoah, Kyriaki, Michailidou, Antonis C, Antoniou, Marjanka K, Schmidt, Georgia, Chenevix-Trench, Douglas F, Easton, Nilanjan, Chatterjee, and Montserrat, García-Closas
Subjects: BRCA1 Protein, Case-Control Studies, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Triple Negative Breast Neoplasms, Linkage Disequilibrium, Article, Genome-Wide Association Study
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1–3. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10−8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate (FDR)
Published: 2019

30. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author: Harald Surowy, Rulla M. Tamimi, Javier Benitez, Wing-Yee Lo, Celine M. Vachon, Nadege Presneau, John J. Spinelli, Ann Smeets, Hoda Anton-Culver, Veli-Matti Kosma, Christopher A. Haiman, Martha J. Shrubsole, Ross L. Prentice, Diana Eccles, Ursula Eilber, Loic Le Marchand, Katri Pylkäs, Jirong Long, Michael P. Lux, Sara Margolin, Hedy S. Rennert, Tom Maishman, Mary B. Daly, Rita K. Schmutzler, Julian Peto, Sune F. Nielsen, Eric Hahnen, Niclas Håkansson, Børge G. Nordestgaard, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Barbara Burwinkel, Rudolf Kaaks, Usha Menon, William J. Tapper, Argyrios Ziogas, Peter Hillemanns, Fares Al-Ejeh, Roger L. Milne, Wolfgang Janni, Pascal Guénel, Mikael Eriksson, Clarice R. Weinberg, Kyriaki Michailidou, Jonathan Beesley, Marike Gabrielson, J. Esteban Castelao, Margriet Collée, Janet E. Olson, Gad Rennert, Per Broberg, Rob A. E. M. Tollenaar, David Cox, Paolo Peterlongo, Helian Feng, Brian D. Carter, Nichola Johnson, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Kimberly F. Doheny, Paul L. Auer, Hans Wildiers, Jacques Simard, Michael Untch, Per Hall, Martine Dumont, Julie M. Cunningham, Thilo Dörk, Mary Beth Terry, Jenny Chang-Claude, Lang Wu, Irene L. Andrulis, Xiaohong R. Yang, Caroline Baynes, Isabel dos-Santos-Silva, Douglas F. Easton, Wei Shi, Emily Hallberg, Camilla Wendt, Hiltrud Brauch, Diana Torres, Olufunmilayo I. Olopade, David Van Den Berg, Georgia Chenevix-Trench, Alfons Meindl, Stig E. Bojesen, Jonine D. Figueroa, Dale P. Sandler, Vessela N. Kristensen, Christine L. Clarke, Wei Zheng, Manuela Gago-Dominguez, E Rozali, Henrik Flyger, Sheila Seal, Guanmengqian Huang, Marjanka K. Schmidt, Håkan Olsson, Christopher G. Scott, Kamila Czene, Laura Fachal, Rodney J. Scott, Jennifer Stone, Sara Y. Brucker, Qin Wang, David J. Hunter, Maya Ghoussaini, Christoph Engel, Keith Humphreys, Susan M. Gapstur, Daniel C. Tessier, Paolo Radice, John L. Hopper, Audrey Y. Jung, Lucy Xia, Atocha Romero, Chenjie Zeng, Peter A. Fasching, Jan Lubinski, Anna González-Neira, Nazneen Rahman, Robert N. Hoover, Thérèse Truong, Fergus J. Couch, Anna Marie Mulligan, Robert J. MacInnis, Ute Hamann, Hanne Meijers-Heijboer, Brigitte Rack, Simon S. Cross, Federico Canzian, J.-P. Meyer, Sara Lindström, Natalia Bogdanova, Trinidad Caldés, Olivia Fletcher, Peter Kraft, Elinor J. Sawyer, Alexander Gusev, Louise A. Brinton, Diether Lambrechts, Bingshan Li, Kristan J. Aronson, Jane Romm, Anja Rudolph, Peter Devilee, Qiuyin Cai, Arto Mannermaa, Elad Ziv, Alice S. Whittemore, Abigail Thomas, Hermann Brenner, Montserrat Garcia-Closas, Patrick Neven, Kristine Jones, Miriam Dwek, Sibylle Loibl, Heli Nevanlinna, Jolanta Lissowska, Susan L. Neuhausen, Elza Khusnutdinova, Marina Bermisheva, Alicja Wolk, Lin Fritschi, Xingyi Guo, Angela Cox, Michael Jones, Xiaoqing Chen, Esther M. John, Richard Barfield, Volker Arndt, Patricia Harrington, Quinten Waisfisz, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Stacey L. Edwards, Melissa C. Southey, Andreas Schneeweiss, Jack A. Taylor, Robert Winqvist, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Kathrin Thöne, Dieter Flesch-Janys, Mark S. Goldberg, Craig Luccarini, Sten Cornelissen, Jingmei Li, Michael J. Kerin, Myrto Barrdahl, Xiao-Ou Shu, Alison M. Dunning, Manjeet K. Bolla, Carl Blomqvist, Graham G. Giles, Hans Christiansen, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Belynda Hicks, Ivana Maleva Kostovska, Tongguang Cheng, Yingchang Lu, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Guo, Xingyi [0000-0001-5269-1294], Al-Ejeh, Fares [0000-0002-1553-0077], Li, Bingshan [0000-0003-2129-168X], Gusev, Alexander [0000-0002-7980-4620], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Collée, Margriet [0000-0002-9272-9346], Cox, Angela [0000-0002-5138-1099], Cunningham, Julie M [0000-0002-8159-3025], Fachal, Laura [0000-0002-7256-9752], Fletcher, Olivia [0000-0001-9387-7116], Hein, Alexander [0000-0003-2601-3398], Hicks, Belynda [0000-0001-8014-4888], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Khusnutdinova, Elza [0000-0003-2987-3334], Li, Jingmei [0000-0001-8587-7511], Menon, Usha [0000-0003-3708-1732], Nevanlinna, Heli [0000-0002-0916-2976], Nordestgaard, Børge G [0000-0002-1954-7220], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher G [0000-0003-1340-0647], Shrubsole, Martha J [0000-0002-5591-7575], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul DP [0000-0001-8494-732X], Milne, Roger L [0000-0001-5764-7268], Easton, Douglas F [0000-0003-2444-3247], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Human Genetics, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, Risk, medicine.medical_specialty, Gene Expression, Genome-wide association study, Breast Neoplasms, Biology, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Expression quantitative trait loci, Medical genetics, Female, Gene expression, Breast Cancer Genetics, Genome-Wide Association Study
Abstract: The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
Published: 2019

31. Absence of PD-L1 expression on tumor cells in the context of an activated immune infiltrate may indicate impaired IFN gamma signaling in non-small cell lung cancer

Author: Thomas Kuilman, Johannes L. G. Blaauwgeers, Dennis Peters, Sten Cornelissen, Marcin Kowanetz, Lukas C. Amler, Kim Monkhorst, Willemijn S. M. E. Theelen, Oscar Krijgsman, Stefan M. Willems, Daniel S. Peeper, Pranamee Sarma, Carel J. M. van Noesel, Wei Zou, Katja Schulze, Teiko Sumiyoshi, Michel M van den Heuvel, AII - Cancer immunology, CCA - Cancer biology and immunology, and Pathology
Subjects: Male, Lung Neoplasms, medicine.medical_treatment, Protein Expression, Programmed Cell Death 1 Receptor, Gene Expression, CD8-Positive T-Lymphocytes, Biochemistry, Lung and Intrathoracic Tumors, B7-H1 Antigen, 0302 clinical medicine, Cancer immunotherapy, Carcinoma, Non-Small-Cell Lung, Cellular types, Gene expression, Medicine and Health Sciences, Cytotoxic T cell, 030212 general & internal medicine, Immune Response, Aged, 80 and over, Regulation of gene expression, Immunity, Cellular, Insertion Mutation, Multidisciplinary, Agricultural and Biological Sciences(all), Immune cells, Middle Aged, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, White blood cells, Medicine, Immunohistochemistry, Female, Research Article, Signal Transduction, Adult, Cell biology, Blood cells, Science, Immunology, T cells, Cytotoxic T cells, Biology, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Research and Analysis Methods, Interferon-gamma, 03 medical and health sciences, Immune system, All institutes and research themes of the Radboud University Medical Center, Genetics, Gene Expression and Vector Techniques, medicine, Journal Article, Humans, Molecular Biology Techniques, Lung cancer, Molecular Biology, Immunohistochemistry Techniques, Aged, Neoplasm Staging, Molecular Biology Assays and Analysis Techniques, Biochemistry, Genetics and Molecular Biology(all), Biology and Life Sciences, Cancers and Neoplasms, medicine.disease, Non-Small Cell Lung Cancer, Histochemistry and Cytochemistry Techniques, Animal cells, Mutation, Immunologic Techniques, Cancer research, Biomarkers, CD8, Genetics and Molecular Biology(all)
Abstract: BackgroundIn non-small cell lung cancer (NSCLC), PD-L1 expression on either tumor cells (TC) or both TC and tumor-infiltrating immune cells (IC) is currently the most used biomarker in cancer immunotherapy. However, the mechanisms involved in PD-L1 regulation are not fully understood. To provide better insight in these mechanisms, a multiangular analysis approach was used to combine protein and mRNA expression with several clinicopathological characteristics.Patients and methodsArchival tissues from 640 early stage, resected NSCLC patients were analyzed with immunohistochemistry for expression of PD-L1 and CD8 infiltration. In addition, mutational status and expression of a selection of immune genes involved in the PD-L1/PD-1 axis and T-cell response was determined.ResultsTumors with high PD-L1 expression on TC or on IC represent two subsets of NSCLC with minimal overlap. We observed that PD-L1 expression on IC irrespective of expression on TC is a good marker for inflammation within tumors. In the tumors with the highest IC expression and absent TC expression an association with reduced IFNγ downstream signaling in tumor cells was observed.ConclusionsThese results show that PD-L1 expression on TC and IC are both independent hallmarks of the inflamed phenotype in NSCLC, and TC-negative/IC-high tumors can also be categorized as inflamed. The lack of correlation between PD-L1 TC and IC expression in this subgroup may be caused by impaired IFNγ signaling in tumor cells. These findings may bring a better understanding of the tumor-immune system interaction and the clinical relevance of PD-L1 expression on IC irrespective of PD-L1 expression on TC.
Published: 2019

32. Personalized combination of neoadjuvant domatinostat, nivolumab and ipilimumab in macroscopic stage III melanoma patients stratified according to the interferon-gamma signature: The DONIMI study

Author: Alexander M. Menzies, Christian U. Blank, Sten Cornelissen, Bart A. van de Wiel, María Jesús González González, Richard A. Scolyer, Georgina V. Long, Linda J.W. Bosch, Lindsay G Grijpink-Ongering, Jasper Bouwman, Annegien Broeks, Petros Dimitriadis, Oscar Krijgsman, Alexander C.J. van Akkooi, Judith M. Versluis, Elisa A. Rozeman, Marloes van Dijk, Irene L.M. Reijers, Andrew J. Spillane, and Disha Rao
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Ipilimumab, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Pathologic Response, Interferon gamma, Stage III melanoma, Nivolumab, business, 030215 immunology, medicine.drug
Abstract: TPS10087 Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23th, 2020. Clinical trial information: NCT04133948.
Published: 2020

33. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Vesa Kataja, Aida Karina Dieffenbach, Chia-Ni Hsiung, Catherine S. Healey, Gie Hooi Tan, Soo Hwang Teo, Domenico Palli, Frederik Marme, Katri Pylkäs, Roger L. Milne, Jaana M. Hartikainen, Gord Glendon, Susan L. Slager, Chen-Yang Shen, Fredrick R. Schumacher, Daniel F. Schmidt, Suleeporn Sangrajrang, Kee Seng Chia, Lorna Gibson, Pascal Guénel, Alice S. Whittemore, Jenny Chang-Claude, Yu Tang Gao, Hidemi Ito, Simon S. Cross, Sofia Khan, Marie Sanchez, Daniel Vincent, Daniel Herrero, Nicola Miller, Antoinette Hollestelle, Caroline M. Seynaeve, Christopher A. Haiman, Hermann Brenner, Kay-Tee Khaw, Loris Bernard, Habibul Ahsan, Melissa C. Southey, David Van Den Berg, Martha J. Shrubsole, Daniel O. Stram, William Blot, Mel Maranian, Robert Winqvist, Keitaro Matsuo, John W. M. Martens, Heli Nevanlinna, Mia M. Gaudet, Anna Jakubowska, Christine D. Berg, Paul D.P. Pharoah, Jacques Simard, Manjeet K. Bolla, Dieter Flesch-Janys, Mark S. Goldberg, Paul Brennan, Ching Wan Chan, Sune F. Nielsen, Sara Lindström, Mitul Shah, Matthias W. Beckmann, Craig Luccarini, Jonathan Beesley, Kyriaki Michailidou, Paolo Peterlongo, Marc J. Gunter, Anna González-Neira, Ji Yeob Choi, Per Hall, Sarah Stewart-Brown, Keith Humphreys, Hui Cai, Kathleen E. Malone, Elinor J. Sawyer, Louise A. Brinton, Marjanka K. Schmidt, Xiao-Ou Shu, Barbara Perkins, Lotte Maxild Mortensen, Chiu-Chen Tseng, Hanne Meijers-Heijboer, Minouk J. Schoemaker, Keun-Young Yoo, Julia A. Knight, Alan Ashworth, Stig E. Bojesen, Kamila Czene, Artitaya Lophatananon, Graham G. Giles, S. Ahmed, Kazuo Tajima, Douglas F. Easton, Maria Kabisch, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Irene L. Andrulis, Clare Turnbull, Caroline Baynes, Christine B. Ambrosone, Jan Lubinski, Muriel A. Adank, A. Meindl, Taru A. Muranen, Siranoush Manoukian, Susan M. Gapstur, Natalia Bogdanova, Alexander Hein, Annika Lindblom, Nazneen Rahman, Annegien Broeks, Lothar Haeberle, Federico Canzian, G Pita, Ming-Feng Hou, Hiroji Iwata, Drakoulis Yannoukakos, Diana Torres, Vessela N. Kristensen, Peter Devilee, Qiuyin Cai, Christi J Asperen, John L. Hopper, Diether Lambrechts, Michael Lush, Hans Wildiers, Joe Dennis, Sandra L. Halverson, Carl Blomqvist, Erik Van Limbergen, Malin Sund, Daehee Kang, Grethe I. Grenaker Alnæs, Marilie D. Gammon, Ursula Eilber, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Kirsimari Aaltonen, Olivia Fletcher, Jonine D. Figueroa, Angela Cox, Pei Ei Wu, Maartje J. Hooning, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Malcolm W.R. Reed, Emily Hallberg, Sara Margolin, Volker Arndt, Montserrat Garcia-Closas, Francois Bacot, Rita K. Schmutzler, Julian Peto, David J. Hunter, Thomas Brüning, Katarzyna Jaworska, Christof Sohn, Børge G. Nordestgaard, Enes Makalic, Hatef Darabi, Barbara Burwinkel, Petra P.H. Peeters, J. Margriet Collée, Rongxi Yang, Robert N. Hoover, Eiliv Lund, Fergus J. Couch, Ute Hamann, Jirong Long, Wei Zheng, Sabine Behrens, Giske Ursin, Muhammad G. Kibriya, Claire Mulot, Laure Dossus, Helen Tsimiklis, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Alison M. Dunning, Lisa B. Signorello, Valerie Gaborieau, Kenneth Muir, Anthony J. Swerdlow, Javier Benitez, Judith S. Brand, Sander Canisius, Hoda Anton-Culver, Veli-Matti Kosma, Thilo Dörk, Sten Cornelissen, Christa Stegmaier, Cheng Har Yip, Brian E. Henderson, Harald Surowy, Jingmei Li, Nur Aishah Taib, W. Ryan Diver, Carmel Apicella, Janet E. Olson, Kristiina Aittomäki, Celine M. Vachon, Regina M. Santella, Dimitrios Trichopoulos, Jianjun Liu, Nick Orr, Martine Dumont, Christian Sutter, Sue K. Park, Mikael Hartman, Susan L. Neuhausen, Hui Miao, M. Pilar Zamora, Anna H. Wu, Rob B. van der Luijt, Isabel dos-Santos-Silva, Graham Casey, Henrik Flyger, M. Rosario Alonso, Nuria Álvarez, Michael J. Kerin, Loic Le Marchand, Jose Ignacio Arias Perez, Mikael Eriksson, Esther M. John, Quinten Waisfisz, Qin Wang, Daniel C. Tessier, Paolo Radice, Robert A.E.M. Tollenaar, James McKay, Silje Nord, Hiltrud Brauch, José María Huerta, Stephen J. Chanock, Mervi Grip, Patrick Neven, Senno Verhoef, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, and CCA - Oncogenesis
Subjects: Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, Cohort Studies, brca1, Breast cancer, Research Support, N.I.H., Extramural, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, common variants, Journal Article, estrogen, chek2-asterisk-1100delc, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Non-U.S. Gov't, genotype imputation, risk, Genetic association, Research Support, Non-U.S. Gov't, Chromatin binding, Extramural, Cancer, Microarray Analysis, confer susceptibility, medicine.disease, 3. Good health, ovarian-cancer, Genetic Loci, Case-Control Studies, alleles, Female, Imputation (genetics), Genome-Wide Association Study, metaanalysis
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published
Published: 2015

34. Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Author: Javier Benitez, Sara Margolin, Diether Lambrechts, Alexandra J. van den Broek, Chen-Yang Shen, Veli-Matti Kosma, Matthias W. Beckmann, Siranoush Manoukian, Antoinette Hollestelle, Montserrat Garcia-Closas, Paul Brennan, Chiu-Chen Tseng, Marjanka K. Schmidt, Carolien H.M. van Deurzen, Peter A. Fasching, Melissa C. Southey, Manjeet K. Bolla, Robert Winqvist, Keitaro Matsuo, Douglas F. Easton, Carl Blomqvist, Adelheid Soubry, Paul D.P. Pharoah, Pascal Guénel, Jenna Lilyquist, Anna González-Neira, Hidemi Ito, Daehee Kang, Thérèse Truong, Fergus J. Couch, Renske Keeman, Kenneth Muir, Caroline Seynaeve, Katri Pylkäs, Simon S. Cross, Per Hall, Olivier Brouckaert, Roger L. Milne, Cheng Har Yip, Qin Wang, Sten Cornelissen, Anja Rudolph, Kamila Czene, Artitaya Lophatananon, Mikael Eriksson, Xiao-Ou Shu, Jonine D. Figueroa, Julia A. Knight, Arto Mannermaa, Jyh-Cherng Yu, Hans Wildiers, John L. Hopper, Wei Zheng, Jingmei Li, Rob A. E. M. Tollenaar, Anthony J. Swerdlow, Hermann Brenner, Henrik Flyger, Patrick Neven, Georgia Chenevix-Trench, Irene L. Andrulis, Paolo Peterlongo, Ji Yeob Choi, Annouschka Laenen, Annika Lindblom, Hiltrud Brauch, Anna H. Wu, Heli Nevanlinna, Michael Jones, Angela Cox, Volker Arndt, Soo-Hwang Teo, Jenny Chang-Claude, Stig E. Bojesen, Graham G. Giles, Suleeporn Saajrang, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Benitez, Javier [0000-0002-0923-7202], Blomqvist, Carl [0000-0003-3041-1938], Brauch, Hiltrud [0000-0001-7531-2736], Brenner, Hermann [0000-0002-6129-1572], Chenevix-Trench, Georgia [0000-0002-1878-2587], Cox, Angela [0000-0002-5138-1099], Eriksson, Mikael [0000-0001-8135-4270], González-Neira, Anna [0000-0002-5421-2020], Guénel, Pascal [0000-0002-8359-518X], Jones, Michael [0000-0001-7479-3451], Li, Jingmei [0000-0001-8587-7511], Matsuo, Keitaro [0000-0003-1761-6314], Peterlongo, Paolo [0000-0001-6951-6855], Pylkäs, Katri [0000-0002-2449-0521], Southey, Melissa C [0000-0002-6313-9005], Swerdlow, Anthony [0000-0001-5550-4159], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Lambrechts, Diether [0000-0002-3429-302X], Apollo - University of Cambridge Repository, Medical Oncology, Pathology, Department of Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, HUS Comprehensive Cancer Center, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), National Health and Medical Research Council (Australia), New South Wales Cancer Council (Reino Unido), Victorian Health Promotion Foundation, Dutch Cancer Society (Holanda), Agence Nationale de la Recherche (Francia), French Agency for Food, Environmental and Occupational Health & Safety (Francia), Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Centro de Investigación Biomedica en Red - CIBER, Federal Ministry of Education & Research (Alemania), Cancer Society of Finland, Ministry of Education, Culture, Sports, Science, and Technology (Japón), Japan Agency for Medical Research and Development, United States Army Medical Research and Development Command, California Breast Cancer Research Program, German Cancer Aid, Ministry of Higher Education (Malasia), Biomedical Research Council (Singapore), National Institutes of Health (Estados Unidos), and National Research Foundation of Korea
Subjects: 0301 basic medicine, Oncology, Triple Negative Breast Neoplasms, Cohort Studies, 0302 clinical medicine, HORMONE-RECEPTOR STATUS, Medizinische Fakultät, Risk Factors, Odds Ratio, Young adult, Reproductive History, POPULATION, Age at menarche, education.field_of_study, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Parity, PREGNANCY, 030220 oncology & carcinogenesis, Age at breast cancer diagnosis, kConFab, Menarche, Female, Cohort study, Research Article, Adult, medicine.medical_specialty, 3122 Cancers, Population, Breast Neoplasms, DIAGNOSIS, lcsh:RC254-282, Risk Assessment, MENARCHE, 1ST BIRTH, 03 medical and health sciences, Young Adult, AGE, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Journal Article, medicine, Biomarkers, Tumor, Humans, ddc:610, education, Aged, Gynecology, Pregnancy, business.industry, Odds ratio, medicine.disease, 030104 developmental biology, Age at first full-time pregnancy, Breast cancer subtype, business
Abstract: Background Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. Methods We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. Results Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16–1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01–2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45–1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70–0.88, p, published version, peerReviewed
Published: 2017

35. Association analysis identifies 65 new breast cancer risk loci

Author: Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P
Published: 2017

36. Evaluation of the EGFR polymorphism R497K in two cohorts of neoadjuvantly treated breast cancer patients

Author: Lennart Mulder, Hayra de Andrade Vieira-Monteiro, Esther H. Lips, Marjanka K. Schmidt, Jelle Wesseling, Marcelo Sobral-Leite, Daniely Regina Freitas-Alves, Rosane Vianna-Jorge, Sten Cornelissen, and Letícia Carlos Giacomin
Subjects: 0301 basic medicine, Oncology, Heredity, medicine.medical_treatment, Cancer Treatment, lcsh:Medicine, Geographical locations, Cohort Studies, 0302 clinical medicine, Genotype, Antineoplastic Combined Chemotherapy Protocols, Breast Tumors, Medicine and Health Sciences, Epidermal growth factor receptor, lcsh:Science, Multidisciplinary, Invasive carcinoma, biology, Pharmaceutics, ErbB Receptors, Genetic Mapping, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Cohort, Female, Lymph, Anatomy, Brazil, Research Article, medicine.medical_specialty, Breast Neoplasms, Variant Genotypes, Surgical and Invasive Medical Procedures, Lymphatic System, 03 medical and health sciences, Breast cancer, Drug Therapy, Diagnostic Medicine, Internal medicine, Breast Cancer, medicine, Genetics, Cancer Detection and Diagnosis, Humans, Chemotherapy, Pathological, Polymorphism, Genetic, business.industry, lcsh:R, Biology and Life Sciences, Cancers and Neoplasms, South America, medicine.disease, 030104 developmental biology, biology.protein, lcsh:Q, Lymph Nodes, People and places, business
Abstract: Pathological response of breast cancer to neoadjuvant chemotherapy (NAC) presents great variability, and new prognostic biomarkers are needed. Our aim was to evaluate the association of the epidermal growth factor receptor gene (EGFR) polymorphism R497K (rs2227983) with prognostic features and clinical outcomes of breast cancer, including the pathological response to NAC and the recurrence-free survival (RFS). Tumoral complete response (tCR) was defined by no remaining invasive cancer in the excised breast, whereas pathological complete response (pCR) was defined by no remaining invasive cancer both in the excised breast and lymph nodes. Two independent cohorts were analyzed: one from Brazil (INCA, n = 288) and one from The Netherlands (NKI-AVL, n = 255). In the INCA cohort, the variant (Lys-containing) genotypes were significantly associated with lower proportion of tCR (ORadj = 0.92; 95%CI = 0.85–0.99), whereas in the NKI-AVL cohort they were associated with tumor grade 3 (p = 0.035) and with triple-negative subtype (p = 0.032), but not with clinical outcomes. Such distinct prognostic associations may have arisen due to different neoadjuvant protocols (p < 0.001), or to lower age at diagnosis (p < 0.001) and higher proportion of tumor grade 3 (p = 0.018) at the NKI-AVL cohort. Moreover, NKI-AVL patients achieved better proportion of pCR (21.2% vs 8.3%, p < 0.001) and better RFS (HRadj = 0.48; 95% adjCI = 0.26–0.86) than patients from INCA. In conclusion, large scale studies comprehending different populations are needed to evaluate the impact of genome variants on breast cancer outcomes.
Published: 2017

37. Age- and Tumor Subtype Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Author: Sten Cornelissen, Richard van Hien, Muriel A. Adank, Argyrios Ziogas, Amy Trentham-Dietz, Frans B. L. Hogervorst, Hiltrud Brauch, Alison M. Dunning, Qin Wang, Stig E. Bojesen, Natalia Bogdanova, Hoda Anton-Culver, Sara Margolin, Elza Khusnutdinova, Marjanka K. Schmidt, Elinor J. Sawyer, Kenneth Offit, Lothar Haeberle, Veli-Matti Kosma, Natalia Antonenkova, Taru A. Muranen, Heli Nevanlinna, Polly A. Newcomb, Manjeet K. Bolla, Mieke Schutte, Vessela N. Kristensen, Andy C. H. Lee, Melissa C. Southey, Jenny Chang-Claude, Douglas F. Easton, Marina Bermisheva, Henrik Flyger, Lizet E. van der Kolk, Antonis C. Antoniou, Anna Jakubowska, Paul D.P. Pharoah, Ans M.W. van den Ouweland, Jan Lubinski, Angela Cox, Maartje J. Hooning, Graham G. Giles, Rita K. Schmutzler, Julian Peto, Anthony J. Swerdlow, Volker Arndt, Thilo Dörk, Barbara Burwinkel, Harald Surowy, Ian Tomlinson, Celine M. Vachon, Peter Hillemanns, Mark E. Robson, Michael Jones, Roger L. Milne, Esther M. John, Olivia Fletcher, Julie Soens, Per Hall, Quinten Waisfisz, Jonine D. Figueroa, Julia A. Knight, Rob A. E. M. Tollenaar, Irene L. Andrulis, Annika Lindblom, Annegien Broeks, Alfons Meindl, Peter A. Fasching, Montserrat Garcia-Closas, Georgia Chenevix-Trench, Thomas Brüning, Alice S. Whittemore, Caroline M. Seynaeve, Tjoung-Won Park-Simon, Eva Galle, Hermann Brenner, Hanne Meijers, Amanda B. Spurdle, Antoinette Hollestelle, Kamila Czene, Anja Rudolph, John L. Hopper, Arto Mannermaa, Simon S. Cross, Fergus J. Couch, Human genetics, CCA - Cancer biology, Antoniou, Antonis [0000-0001-9223-3116], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Pharoah, Paul [0000-0001-8494-732X], Wang, Jean [0000-0002-9139-0627], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, and Medical Oncology
Subjects: 0301 basic medicine, Oncology, Cancer Research, Estrogen receptor, Disease, 0302 clinical medicine, Receptors, 80 and over, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, skin and connective tissue diseases, Progesterone, Cancer, Sequence Deletion, Aged, 80 and over, education.field_of_study, Homozygote, Age Factors, ORIGINAL REPORTS, Middle Aged, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Risk assessment, Receptors, Progesterone, Adult, medicine.medical_specialty, Heterozygote, Clinical Sciences, Oncology and Carcinogenesis, Population, Breast Neoplasms, Risk Assessment, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, Breast Cancer, Genetics, medicine, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, education, CHEK2, Aged, business.industry, Case-control study, Odds ratio, medicine.disease, Estrogen, Checkpoint Kinase 2, 030104 developmental biology, Case-Control Studies, business
Abstract: Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Results Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10−20). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10−21]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10−4). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. Conclusion These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
Published: 2016

38. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium

Author: Javier Benitez, Frederik Marmé, Nichola Johnson, Ian W. Brock, Fiona M. Blows, Natalia Bogdanova, Arto Mannermaa, Peter Hillemanns, Hoda Anton-Culver, Anthony J. Swerdlow, Roger L. Milne, Jonathan Beesley, Veli-Matti Kosma, Guzel Zinnatullina, Paolo Peterlongo, Irene L. Andrulis, Annika Lindblom, Dieter Flesch-Janys, Ann Smeets, Arif B. Ekici, Pascal Guénel, Vesa Kataja, Thomas Brüning, Graham G. Giles, Isabel dos-Santos-Silva, Douglas F. Easton, Yuriy Rogov, Ruediger Schulz-Wendtland, Pierre Laurent-Puig, Thilo Dörk, Malcolm W.R. Reed, Heiko Müller, Linda M. Braaf, Janet E. Olson, Cariona A. McLean, Leslie Bernstein, Elinor J. Sawyer, Jaana M. Hartikainen, Siranoush Manoukian, Robert Paridaens, Marina Bermisheva, Natalia Antonenkova, Ian Tomlinson, Thérèse Truong, Minouk J. Schoemaker, Anna Marie Mulligan, Elza Khusnutdinova, Xianshu Wang, Christof Sohn, Katri Pylkäs, Caroline M. Seynaeve, Christina Clarke Dur, Caroline Weltens, Sune F. Nielsen, Carl Blomqvist, Nick Orr, Hiltrud Brauch, Maryam Mahmoodi, Shan Wang-Gohrke, Melissa C. Southey, Fergus J. Couch, Olivia Fletcher, Mervi Grip, Nayana Weerasooriya, Georgia Chenevix-Trench, Rita K. Schmutzler, Julian Peto, Jenny Chang-Claude, Peter Schürmann, Frank Dudbridge, John W.M. Martens, Robert Winqvist, Surapon Wiangnon, Celine M. Vachon, Arkom Chaiwerawattana, Hermann Brenner, Artitaya Lophatananon, Arja Jukkola-Vuorinen, Peter A. Fasching, Børge G. Nordestgaard, Manjeet K. Humphreys, Barbara Burwinkel, Kristiina Aittomäki, Marjanka K. Schmidt, Argyrios Ziogas, Michael Bremer, Paul D.P. Pharoah, Loris Bernard, Alexander Miron, Sara Margolin, Kamila Czene, Diether Lambrechts, Claus R. Bartram, Annegien Broeks, Maya Ghoussaini, John L. Hopper, Simon S. Cross, Matthias W. Beckmann, Per Hall, Agnes Jager, Stig E. Bojesen, Michael Jones, Darya Prokofyeva, Julia A. Knight, Alan Ashworth, Taru A. Muranen, Xiaoqing Chen, Esther M. John, Claire Mulot, Alfons Meindl, Ursula Eilber, Laura Baglietto, José Ignacio Arias-Perez, Peter Devilee, Henrik Flyger, Sten Cornelissen, Jingmei Li, Katharina Buck, Carmel Apicella, Michael J. Kerin, Gianluca Severi, Alison M. Dunning, Kenneth Muir, Anne Langheinz, Andreas Schneeweiss, Heli Nevanlinna, Michael Golatta, Christina Justenhoven, Antoinette Hollestelle, Jianjun Liu, Helen R. Warren, Sabine Behrens, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Qin Wang, Paolo Radice, Volker Arndt, Robert A.E.M. Tollenaar, M. Pilar Zamora, Medical Oncology, Surgery, and Clinical Genetics
Subjects: Oncology, Pathology, Epidemiology, Estrogen receptor, population, Genome-wide association study, genetic risk, 0302 clinical medicine, Receptors, common variants, Progesterone, 0303 health sciences, education.field_of_study, identifies 2, Chromosome Mapping, Single Nucleotide, Middle Aged, 5p12, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, alleles, Female, Chromosomes, Human, Pair 9, Receptors, Progesterone, linkage, Human, Pair 9, medicine.medical_specialty, Population, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Chromosomes, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Polymorphism, Allele, education, Aged, 030304 developmental biology, menarche, Case-control study, Cancer, medicine.disease, confer susceptibility, Estrogen, Case-Control Studies, genome-wide association, Genome-Wide Association Study
Abstract: Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.
Published: 2016

39. 11q13 is a susceptibility locus for hormone receptor positive breast cancer

Author: Dong Young Noh, Pascal Guénel, Graeme Elliott, Vesa Kataja, Shamil Gancev, Xianshu Wang, Shan Wang-Gohrke, Annegien Broeks, Florence Menegaux, Hans Wildiers, Richard van Hien, Natalia Bogdanova, Jean Wang, Puttisak Puttawibul, Betül T. Yesilyurt, Peter Devilee, Gord Glendon, Katri Pylkäs, Mark E. Sherman, Jenny Chang-Claude, Federik Marme, Michael Bremer, Katarzyna Durda, Sarah Schott, Vessela N. Kristensen, Paolo Radice, Teresa Selander, Kamila Czene, Alfons Meindl, Gianluca Severi, Angela Cox, Maartje J. Hooning, Claus R. Bartram, John L. Hopper, Ursel Eilber, Michael Jones, M. Pilar Zamora, Stephen J. Chanock, Laura Baglietto, Caroline M. Seynaeve, Daehee Kang, Thilo Dörk, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Loris Bernard, Stig E. Bojesen, Barbara Burwinkel, Douglas F. Easton, Arif B. Ekici, kConFab Investigators, Mervi Grip, Robert A.E.M. Tollenaar, Argyrios Ziogas, Jonathan Beesley, Paolo Peterlongo, Volker Arndt, Xiaoqing Chen, Nichola Johnson, Jaana M. Hartikainen, Ming-Feng Hou, Diether Lambrechts, Ruediger Schulz-Wendtland, Jan Lubinski, Taru A. Muranen, Heli Nevanlinna, Esther M. John, Graham G. Giles, Chen-Yang Shen, Jolanta Lissowska, Ian W. Brock, Grethe I. Grenaker Alnæs, Gillian S. Dite, Charlotte Lanng, Hiltrud Brauch, Anthony J. Swerdlow, MC Southey, Christina Justenhoven, Manjeet K. Humphreys, Keun-Young Yoo, Elinor J. Sawyer, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Fergus J. Couch, Peter Schürmann, Stefan Nickels, Jianjun Liu, Marjanka K. Schmidt, Zachary S. Fredericksen, Yuri I. Rogov, Ute Hamann, Elza Khusnutdinova, Hermann Brenner, Sara Margolin, Natalia Antonenkova, Peter A. Fasching, Matthias W. Beckmann, Johann H. Karstens, Montserrat Garcia-Closas, Patrick Neven, Thomas Brüning, Carl Blomqvist, Heiko Müller, Jyh Cherng Yu, Katarzyna Jaworska, Yon Ko, Pei Ei Wu, Arto Mannermaa, Rebecca Hein, Darya Prokofieva, Melissa C. Southey, Andreas Schneeweiss, Irene L. Andrulis, Christa Stegmaier, Robert Winqvist, Annika Lindblom, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Alexander Miron, Roger L. Milne, Marina Bermisheva, Dieter Flesch-Janys, Christof Sohn, Nicola Miller, Georgia Chenevix-Trench, Kristiina Aittomäki, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Siranoush Manoukian, Robert Paridaens, Anne Lise Børresen-Dale, Suthee Rattanamongkongul, Olivia Fletcher, Simon S. Cross, Artitaya Lophatananon, Isabel dos Santos Silva, Janet E. Olson, Nick Orr, Per Hall, Alan Ashworth, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Alison M. Dunning, Kenneth Muir, Sten Cornelissen, Carmel Apicella, Arja Jukkola-Vuorinen, Michael J. Kerin, ~, and Medical Oncology
Subjects: Oncology, hormone receptor status, Estrogen receptor, Genome-wide association study, 0302 clinical medicine, Risk Factors, Genotype, Receptors, single-nucleotide polymorphisms, common variants, Pair 11, Progesterone, Genetics (clinical), Genetics, 0303 health sciences, repair genes, Single Nucleotide, identifies 5, 11q13, Breast cancer susceptibility, Genome-wide association, Hormone receptor status, Polymorphisms, Risk factors, Breast Neoplasms, Chromosomes, Human, Pair 11, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, 3. Good health, ovarian-cancer, 030220 oncology & carcinogenesis, Human, brca1 mutations, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, Article, White People, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Polymorphism, 030304 developmental biology, breast cancer susceptibility, Odds ratio, tumor characteristics, medicine.disease, confer susceptibility, Estrogen, genome-wide association, family registry, Ovarian cancer, polymorphisms
Abstract: Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed
Published: 2016

40. Impact of Age at Primary Breast Cancer on Contralateral Breast Cancer Risk in BRCA1/2 Mutation Carriers

Author: Mike van Beek, Maryska L.G. Janssen-Heijnen, Cees J. Cornelisse, Vincent T.H.B.M. Smit, Pieter J. Westenend, Laura J. van't Veer, Maartje J. Hooning, Rob A. E. M. Tollenaar, Alexandra J. van den Broek, Caroline Seynaeve, Sten Cornelissen, Marjanka K. Schmidt, Sabine Siesling, Jan J. Jobsen, Annegien Broeks, Flora E. van Leeuwen, Emiel J. Th. Rutgers, Health Technology & Services Research, and Medical Oncology
Subjects: 0301 basic medicine, Oncology, Adult, Cancer Research, medicine.medical_specialty, Heterozygote, endocrine system diseases, DNA Mutational Analysis, Breast Neoplasms, Risk Assessment, Contralateral breast cancer, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Prevalence, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Neoplasm Staging, Netherlands, Retrospective Studies, BRCA2 Protein, business.industry, BRCA1 Protein, Hazard ratio, Age Factors, Retrospective cohort study, Neoplasms, Second Primary, Middle Aged, medicine.disease, Prognosis, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Mutation, Population study, Female, business, Risk assessment, Primary breast cancer, Follow-Up Studies
Abstract: Purpose To determine prospectively overall and age-specific estimates of contralateral breast cancer (CBC) risk for young patients with breast cancer with or without BRCA1/2 mutations. Patients and Methods A cohort of 6,294 patients with invasive breast cancer diagnosed under 50 years of age and treated between 1970 and 2003 in 10 Dutch centers was tested for the most prevalent BRCA1/2 mutations. We report absolute risks and hazard ratios within the cohort from competing risk analyses. Results After a median follow-up of 12.5 years, 578 CBCs were observed in our study population. CBC risk for BRCA1 and BRCA2 mutation carriers was two to three times higher than for noncarriers (hazard ratios, 3.31 [95% CI, 2.41 to 4.55; P < .001] and 2.17 [95% CI,1.22 to 3.85; P = .01], respectively). Ten-year cumulative CBC risks were 21.1% (95% CI, 15.4 to 27.4) for BRCA1, 10.8% (95% CI, 4.7 to 19.6) for BRCA2 mutation carriers and 5.1% (95% CI, 4.5 to 5.7) for noncarriers. Age at diagnosis of the first breast cancer was a significant predictor of CBC risk in BRCA1/2 mutation carriers only; those diagnosed before age 41 years had a 10-year cumulative CBC risk of 23.9% (BRCA1: 25.5%; BRCA2: 17.2%) compared with 12.6% (BRCA1: 15.6%; BRCA2: 7.2%) for those 41 to 49 years of age (P = .02); our review of published studies showed ranges of 24% to 31% before age 40 years (BRCA1: 24% to 32%; BRCA2:17% to 29%) and 8% to 21% after 40 years (BRCA1: 11% to 52%; BRCA2: 7% to 18%), respectively. Conclusion Age at first breast cancer is a strong risk factor for cumulative CBC risk in BRCA1/2 mutation carriers. Considering the available evidence, age-specific risk estimates should be included in counseling.
Published: 2016

41. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Author: Eugenia E. Calle, Alice J. Sigurdson, Susan E. Hankinson, Alfons Meindl, Hoda Anton-Culver, Letitia D. Smith, Richard van Hien, R.A.E.M. Tollenaar, Louise A. Brinton, Veli-Matti Kosma, Stephen J. Chanock, Laura Baglietto, Anna González-Neira, Jonathan J. Morrison, Olivia Fletcher, Radka Platte, Michele M. Doody, Sei Hyun Ahn, Douglas F. Easton, Henrik Flyger, Merethe Kumle, Georgia Chenevix-Trench, Chen-Yang Shen, Beata Peplonska, Kamila Czene, J. David Curb, Christi J. van Asperen, Per Hall, Natalia Antonenkova, Irene L. Andrulis, Mieke Schutte, Claus R. Bartram, John L. Hopper, Daehee Kang, Amanda B. Spurdle, Peter Kraft, David J. Hunter, Kristiina Aittomäki, Bruce H. Alexander, Bruce A.J. Ponder, Malcolm W.R. Reed, Julia A. Knight, Christine D. Berg, Melissa C. Southey, S. A. Fedorova, Giu Cheng Hsu, Catherine A. McCarty, Arto Mannermaa, Rebecca Hein, Gianluca Severi, Peter Schürmann, Diana Eccles, Argyrios Ziogas, Shou Tung Chen, Ian W. Brock, Fergus J. Couch, Garnet L. Anderson, Ellen L. Goode, Nichola Johnson, Sara Margolin, Paul D.P. Pharoah, Annika Lindblom, W. Ryan Diver, Ute Hamann, Robert N. Hoover, Michael R. Stratton, Iosif V. Zalutsky, Yuqing Li, Sten Cornelissen, Natalia Bogdanova, Caroline Seynaeve, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Robert Luben, Aleksandar Rajkovic, Stig E. Bojesen, Heather Spencer Feigelson, Saundra S. Buys, Marina Bermisheva, Barbara Burwinkel, Peter Devilee, Isabel dos Santos Silva, Jonathan Beesley, Thilo Dörk, Gilles Thomas, Lars J. Vatten, Tuomas Heikkinen, Ross L. Prentice, David G. Cox, D. Gareth Evans, Manjeet K. Humphreys, Marjanka K. Schmidt, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Janet E. Olson, Dallas R. English, Maya Ghoussaini, Heli Nevanlinna, Dong Young Noh, Jolanta Lissowska, Graeme Elliott, Vesa Kataja, Nazneen Rahman, Peter Hillemanns, Annegien Broeks, Roger L. Milne, Johann H. Karstens, Christina Justenhoven, Montserrat Garcia-Closas, Karen A. Pooley, Zachary S. Fredericksen, Jyh Cherng Yu, Angela Cox, Maartje J. Hooning, Alison M. Dunning, Ans M.W. van den Ouweland, Hiltrud Brauch, Regina G. Ziegler, Jianjun Liu, Parveen Bhatti, Kristian Hveem, Kevin B. Jacobs, Catherine S. Healey, Jenny Chang-Claude, Michael J. Thun, Rogier A. Oldenburg, Elza Khusnutdinova, Xianshu Wang, Keun-Young Yoo, Carl Blomqvist, Gloria Ribas, Graham G. Giles, and Javier Benitez
Subjects: Genotype, Breast Neoplasms, Genome-wide association study, Biology, Article, Chromosomes, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Chromosome Mapping, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 3, Disease Susceptibility, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Genetics, Genetic predisposition, medicine, 030304 developmental biology, Genetic association, 0303 health sciences, Genome, Pair 17, Cancer, medicine.disease, 3. Good health, TOX3, Pair 3, 030220 oncology & carcinogenesis, Breast disease, Human
Abstract: Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
Published: 2009

42. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

Author: Melissa C. Southey, Fredrick R. Schumacher, Robert Winqvist, Simon S. Cross, Katarzyna Durda, Anna Jakubowska, Paul D.P. Pharoah, Judith S. Brand, Christi J. van Asperen, Javier Benitez, Isabel dos-Santos-Silva, Douglas F. Easton, Roger L. Milne, Justo Lorenzo Bermejo, Hermann Brenner, Patrick Neven, Frederik Marmé, Marie Sanchez, Peter Bugert, Maria Kabisch, Anja Rudolph, Arto Mannermaa, Thilo Dörk, Diether Lambrechts, Anna González-Neira, Hoda Anton-Culver, Thomas Dünnebier, Matthias Ruebner, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Veli-Matti Kosma, Christopher A. Haiman, Dieter Flesch-Janys, Martha J. Shrubsole, Florence Menegaux, Catriona McLean, Olivia Fletcher, Kamila Czene, Mark S. Goldberg, Per Hall, Jacques Simard, Keith Humphreys, Qin Wang, Georgia Chenevix-Trench, Katarzyna Jaworska-Bieniek, Jan Lubinski, Loic Le Marchand, Katri Pylkäs, Barbara Perkins, Kristen S. Purrington, Daniel C. Tessier, Paolo Radice, Craig Luccarini, Sune F. Nielsen, Paolo Peterlongo, Nicola Miller, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, John L. Hopper, Annegien Broeks, Kristiina Aittomäki, Mieke Kriege, Sandrine Tchatchou, Frans B. L. Hogervorst, Jenny Chang-Claude, Robert A.E.M. Tollenaar, Angela Cox, Maartje J. Hooning, Brian E. Henderson, Seth W. Slettedahl, Montserrat Garcia-Closas, Thomas Brüning, Malcolm W.R. Reed, Francois Bacot, Alison M. Dunning, kConFab Investigators, Julian Peto, Børge G. Nordestgaard, Linetta B. Koppert, Volker Arndt, Rongxi Yang, Celine M. Vachon, Peter Devilee, Qiuyin Cai, Caroline Weltens, Hiltrud Brauch, Heli Nevanlinna, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Stig E. Bojesen, Giulietta Scuvera, Kyriaki Michailidou, Jolanta Lissowska, Marjanka K. Schmidt, Fergus J. Couch, Barbara Burwinkel, Ute Hamann, Jaana M. Hartikainen, Janet E. Olson, Natalia Bogdanova, Irene L. Andrulis, M. Pilar Zamora, Caroline Baynes, Gord Glendon, Wei Zheng, Taru A. Muranen, Drakoulis Yannoukakos, Caroline Seynaeve, Aida Karina Dieffenbach, Stefano Fortuzzi, Mel Maranian, Arif B. Ekici, Nick Orr, Annika Lindblom, Nichola Johnson, Arja Jukkola-Vuorinen, Anthony J. Swerdlow, Peter A. Fasching, Sten Cornelissen, Martine Dumont, Diana Torres, Helen Tsimiklis, Yon-Dschun Ko, Vesa Kataja, Shibo Ying, Jingmei Li, Carmel Apicella, Vessela N. Kristensen, Hatef Darabi, Christa Stegmaier, Stéphanie Peeters, Michael J. Kerin, Graham G. Giles, Elinor J. Sawyer, Minouk J. Schoemaker, Manjeet K. Bolla, Carl Blomqvist, Xianshu Wang, Joe Dennis, Stephen J. Chanock, Mervi Grip, Jose Ignacio Arias Perez, Mikael Eriksson, Daniel Vincent, Antoinette Hollestelle, Pascal Guénel, Shahana Ahmed, Henrik Flyger, Clinical Genetics, Medical Oncology, and Surgery
Subjects: Risk, Cancer Research, Candidate gene, kinase, Chromosomal Proteins, Non-Histone, Survivin, European Continental Ancestry Group, Estrogen receptor, cytokinesis, Original Manuscript, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, Cell Cycle Proteins, Biology, metaphase, Polymorphism, Single Nucleotide, White People, Inhibitor of Apoptosis Proteins, Breast cancer, SDG 3 - Good Health and Well-being, Medizinische Fakultät, cleavage furrow, Genotype, medicine, Aurora Kinase B, Humans, Genetic Predisposition to Disease, ddc:610, Allele, skin and connective tissue diseases, 3' Untranslated Regions, mitosis, Genetics, INCENP, aurora-b, General Medicine, medicine.disease, segregation, mammaglobin, Receptors, Estrogen, midbody, Case-Control Studies, Female, Genome-Wide Association Study
Abstract: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixedeffects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007 and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. Â© The Author 2015.
Published: 2015

43. Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Author: Rongxi Yang, Hoda Anton-Culver, Dieter Flesch-Janys, Veli-Matti Kosma, Alexander Miron, Siranoush Manoukian, Giulietta Scuvera, Sten Cornelissen, Fergus J. Couch, Beth Y. Karlan, Janet E. Olson, Katarzyna Durda, Muhammad Usman Rashid, Diana Eccles, Debra Frost, Antonis C. Antoniou, William J. Tapper, José Ignacio Arias, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Sara Margolin, Thilo Dörk, Pilar Zamora, Sune F. Nielsen, Laura Papi, Radka Platte, Fabio Capra, Marjanka K. Schmidt, Matthias W. Beckmann, Peter A. Fasching, Tjoung Won Park-Simon, Lesley McGuffog, Alfons Meindl, Amanda B. Spurdle, Barbara Wappenschmidt, Katherine L. Nathanson, Bernardo Bonanni, Christine L. Clarke, Julian Adlard, Fiona M. Blows, Arja Jukkola-Vuorinen, Isabel dos-Santos-Silva, Catriona McLean, Georgia Chenevix-Trench, Frederique Mariette, Malcolm W.R. Reed, Douglas F. Easton, Vesa Kataja, Frederik Marmé, Laura Baglietto, Christopher A. Haiman, Monica Barile, Uffe Birk Jensen, Thomas Brüning, Shan Wang-Gohrke, Thomas Rüdiger, Paolo Radice, Alessandra Viel, Annegien Broeks, Dee W. West, Loic Le Marchand, Mary Beth Terry, Jenny Chang-Claude, Lorraine Durcan, Raymonda Varon-Mateeva, Brian E. Henderson, Robert A.E.M. Tollenaar, Hansjoerg Plendl, Katri Pylkäs, Jane Carpenter, Mads Thomassen, Kenneth Offitt, Sabine Preisler-Adams, Dennis J. Slamon, Kamila Czene, D. Gareth Evans, Senno Verhoef, Jonine Figueroa, Anja Rudolph, Kristiina Aittomäki, Arto Mannermaa, Eric Hahnen, Jacek Gronwald, Aida Karina Dieffenbach, Johanna Rantala, Ruth Swann, Paolo Peterlongo, Melissa C. Southey, Liliana Varesco, Katarzyna Jaworska-Bieniek, Elena Provenzano, Henrik Flyger, Hiltrud Brauch, Trevor Cole, Alison M. Dunning, Sue Healey, Robert Winqvist, Soo Hwang Teo, Rachel E. Factor, Timothy R. Rebbeck, Jaana M. Hartikainen, Irene L. Andrulis, Louise Jones, Rosemary L. Balleine, Gord Glendon, Doris Steinemann, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Miriam Dwek, Heli Nevanlinna, Karin Kast, Nichola Johnson, Stefano Fortuzzi, Argyrios Ziogas, John W.M. Martens, Christa Stegmaier, Vernon S. Pankratz, Peter Devilee, Thomas Hansen, Christian Sutter, Vijai Joseph, Ana Osorio, Harald Surovy, Päivi Heikkilä, Kerstin Rhiem, Fredrick R. Schumacher, Susan L. Neuhausen, Michael T. Parsons, Jolanta Lissowska, Stig E. Bojesen, Jo Perkins, Christi J. van Asperen, Simon S. Cross, Susan M. Domchek, Alice S. Whittemore, J. Margriet Collée, Trinidad Caldés, Rosemarie Davidson, Judy Garber, Nina Ditsch, Norbert Arnold, Annika Lindblom, Taru A. Muranen, Rodney J. Scott, Hans Ulrich Ulmer, Åke Borg, Qin Wang, V. Arndt, Christoph Engel, Hermann Brenner, Esther M. John, Rita K. Schmutzler, Julian Peto, Jan Lubinski, Børge G. Nordestgaard, Diana Torres, Barbara Burwinkel, Natalia Bogdanova, Caroline Seynaeve, Steve Ellis, Per Hall, Daniela Zaffaroni, Peter Hillemanns, Yon Ko, Mark E. Robson, Arif B. Ekici, Roger L. Milne, Nadine Tung, Petra Seibold, Marco Montagna, Stephen J. Chanock, Louise Izatt, Andrew K. Godwin, Mervi Grip, Rohini Rau-Murthy, Anna González-Neira, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Daniel Barrowdale, Louise A. Brinton, Olivia Fletcher, Anita Bane, Dieter Niederacher, Angela Cox, Maartje J. Hooning, Barbara Pasini, Manjeet K. Bolla, Carl Blomqvist, Ros Eeles, Graham G. Giles, and Javier Benitez
Subjects: Oncology, Pathology, Cancer Research, endocrine system diseases, Receptor, ErbB-2, Genes, BRCA2, Genes, BRCA1, Triple Negative Breast Neoplasms, Tumor Status, ErbB-2, Medizinische Fakultät, Receptors, 10. No inequality, skin and connective tissue diseases, Progesterone, Medicine(all), Likelihood Functions, Age Factors, Middle Aged, Adult, Aged, Breast Neoplasms, Carcinoma, Female, Humans, Mutation, Neoplasm Grading, Neoplasm Staging, Receptors, Estrogen, Receptors, Progesterone, 3. Good health, Mutation (genetic algorithm), Receptor, Research Article, medicine.medical_specialty, Breast cancer, Germline mutation, Internal medicine, medicine, Clinical significance, ddc:610, business.industry, Cancer, medicine.disease, BRCA1, Estrogen, BRCA2, BRCA2 Mutation Carrier, Genes, Mutation testing, business
Abstract: Introduction The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management. Electronic supplementary material The online version of this article (doi:10.1186/s13058-014-0474-y) contains supplementary material, which is available to authorized users.
Published: 2014

44. 2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy

Author: Anne Lise Børresen-Dale, Anja Rudolph, Arto Mannermaa, Diana Eccles, Irene L. Andrulis, Chen-Yang Shen, Sara Margolin, Annika Lindblom, Diana Torres, Sue K. Park, Sandrine Tchatchou, Mitul Shah, Matthias W. Beckmann, Ann Smeets, Dieter Flesch-Janys, Silje Nord, Heli Nevanlinna, Vessela N. Kristensen, Graham G. Giles, Georgia Chenevix-Trench, Ji Yeob Choi, Hidemi Ito, Jianjun Liu, Shou Tung Chen, Hans Wildiers, Sten Cornelissen, Douglas F. Easton, Kristiina Aittomäki, Jaana M. Hartikainen, Laura Baglietto, Bernard Thienpont, Jingmei Li, Marjanka K. Schmidt, Gillian S. Dite, Fredrick R. Schumacher, Daehee Kang, Sajjad Rafiq, Hans Ulrich Ulmer, Carmel Apicella, Jia N. Foo, Brian E. Henderson, Keith Humphreys, Mervi Grip, Qin Wang, Arja Jukkola-Vuorinen, Peter A. Fasching, Keun-Young Yoo, Linda S. Lindström, Gord Glendon, Sue-Anne McLachlan, Robert A.E.M. Tollenaar, Kamila Czene, Hiroji Iwata, Manjeet K. Bolla, Diether Lambrechts, Taru A. Muranen, Alison M. Dunning, Carl Blomqvist, Ans M.W. van den Ouweland, Judith E. Brown, John L. Hopper, Cheng Har Yip, Tom Maishman, kConFab Investigators, Kelly-Anne Phillips, Mieke Kriege, Chiea Chuen Khor, Peter Devilee, Jenny Chang-Claude, Nur Aishah Taib, Emiel J. Th. Rutgers, William J. Tapper, Melissa C. Southey, Caroline Seynaeve, Maartje J. Hooning, Gianluca Severi, Christopher A. Haiman, Grethe I. Grenaker Alnæs, Ute Hamann, Veli-Matti Kosma, Robert Winqvist, Antoinette Hollestelle, Robert Luben, Lothar Haeberle, Laura J. van't Veer, Kazuo Tajima, Keitaro Matsuo, Yi Li, Loic Le Marchand, Katri Pylkäs, Paul D.P. Pharoah, Soo Hwang Teo, Joe Dennis, Vesa Kataja, Thomas Rüdiger, Gwo Fuang Ho, Chia-Ni Hsiung, Pei Ei Wu, Per Hall, Arif B. Ekici, Julia A. Knight, Petra Seibold, Kyriaki Michailidou, Erasmus MC other, Clinical Genetics, Medical Oncology, Pharoah, Paul [0000-0001-8494-732X], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Oncology, Genetics and Molecular Biology (all), Genetic Markers, medicine.medical_specialty, Population, General Physics and Astronomy, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, Kaplan-Meier Estimate, Biology, Bioinformatics, Biochemistry, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Linkage Disequilibrium, White People, 03 medical and health sciences, Physics and Astronomy (all), 0302 clinical medicine, Breast cancer, Drug Therapy, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, education, Prospective cohort study, Genotyping, 030304 developmental biology, Proportional Hazards Models, 0303 health sciences, education.field_of_study, Multidisciplinary, Proportional hazards model, Hazard ratio, Chemistry (all), General Chemistry, medicine.disease, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, Female, Biochemistry, Genetics and Molecular Biology (all)
Abstract: Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49–2.19); P for trend=1.90 × 10−9). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities., Studies have shown that breast cancer prognosis is hereditary. Here the authors show that a genetic variant in CCL20, a chemokine ligand involved in immune response, is significantly associated with breast cancer survival and may therefore represent an important therapeutic or prognostic target.
Published: 2014

45. Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

Author: Yu Tang Gao, Senno Verhoef, Sofia Khan, Brian E. Henderson, M. Pilar Zamora, Roger L. Milne, Qin Wang, Jaana M. Hartikainen, Joshua A. Betts, Montserrat Garcia-Closas, Gianluca Severi, Shahana Ahmed, Katarzyna Durda, Pascal Guénel, Hidemi Ito, Manjeet K. Bolla, Francois Bacot, Gord Glendon, Hermann Brenner, Chen-Yang Shen, Suleeporn Sangrajrang, James McKay, Fergus J. Couch, Nicholas W. Knoblauch, Vernon S. Pankratz, Dieter Flesch-Janys, Henrik Flyger, Pierre Laurent-Puig, Isabel dos Santos Silva, Heiko Müller, Nichola Johnson, Alfons Meindl, Nicola Miller, Christian R. Loehberg, Mark S. Goldberg, Mikael Hartman, Daniel C. Tessier, Paolo Radice, Ann Smeets, Ute Hamann, Xueling Sim, Irene L. Andrulis, Caroline Baynes, Annika Lindblom, Craig Luccarini, Laura Baglietto, Kristiina Aittomäki, Nils Schoof, Ana-Teresa Maia, Andrew K. Godwin, David Van Den Berg, Katri Pylkäs, Caroline M. Seynaeve, Madeleine M.A. Tilanus-Linthorst, Chiu-Chen Tseng, Angela Cox, Jirong Long, Stacey L. Edwards, Kerstin B. Meyer, Daniel R. Barnes, Per Hall, Melissa C. Southey, Wei Zheng, Stig E. Bojesen, Maartje J. Hooning, Daniel Herrero, William Blot, Don M. Conroy, Alison M. Dunning, John W.M. Martens, Artitaya Lophatananon, Christopher A. Haiman, Frederik Marmé, Sabapathy P. Balasubramanian, Florence Menegaux, Peter Kraft, Sarah Stewart-Brown, Julian Peto, Volker Arndt, Kenneth Muir, Daniel Klevebring, Robert Winqvist, Jose Ignacio Arias Perez, Joe Dennis, Sune F. Nielsen, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Valerie Gaborieau, Børge G. Nordestgaard, Anthony J. Swerdlow, Mitul Shah, M. Rosario Alonso, Keitaro Matsuo, Daniel O. Stram, Hui Cai, Anja Rudolph, Arto Mannermaa, Hiroji Iwata, Matthias W. Beckmann, Eranga N. Vithana, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Barbara Burwinkel, Annegien Broeks, Julia A. Knight, Alan Ashworth, Diether Lambrechts, Zoe Aitken, Marjanka K. Schmidt, Peter Bailey, Catherine S. Healey, Chia-Ni Hsiung, Anna González-Neira, Lisa B. Signorello, Thilo Dörk, Keun-Young Yoo, Maya Ghoussaini, J. H. Sng, J. Margriet Collée, Sten Cornelissen, Aiko Sueta, Melissa A. Brown, Nick Orr, Peter Lichtner, Hiltrud Brauch, Douglas F. Easton, Jonine D. Figueroa, Anna H. Wu, Kristine M. Hillman, Domenico Sardella, Dong Young Noh, Minouk J. Schoemaker, Fredrick R. Schumacher, Martine Dumont, Jianjun Liu, Kyriaki Michailidou, Stephen J. Chanock, Rita K. Schmutzler, Vesa Kataja, Kamila Czene, Natalia Antonenkova, Mervi Grip, Heli Nevanlinna, Georgia Chenevix-Trench, Peter Devilee, Qiuyin Cai, Pornthep Siriwanarangsan, Jolanta Lissowska, Christine B. Ambrosone, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Jenny Chang-Claude, Kirsimari Aaltonen, John L. Hopper, Bruce A.J. Ponder, Giuseppe Floris, Christa Stegmaier, Xianshu Wang, Cheng Har Yip, Christina Justenhoven, Vessela N. Kristensen, Jingmei Li, Shou Tung Chen, Karen A. Pooley, Jonathan Tyrer, Bernardo Bonanni, Sara Margolin, Päivi Heikkilä, Keith Humphreys, Martin O'Reilly, Sandra Deming-Halverson, Thomas L. Carroll, Pei Ei Wu, Soo Hwang Teo, Hui Miao, Stéphanie Peeters, Christof Sohn, Constance Chen, Jacques Simard, Jan Lubinski, Daehee Kang, Natalia Bogdanova, Juliet D. French, Christoph Engel, Adam M. Lee, Katarzyna Jaworska-Bieniek, Drakoulis Yannoukakos, Andreas Schneeweiss, Mel Maranian, Michael J. Kerin, Loic Le Marchand, Martha J. Shrubsole, Carl Blomqvist, Char Hong Ng, Daniel Vincent, Jonathan Beesley, Paolo Peterlongo, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Ed Dicks, Arif B. Ekici, Andrew H. Beck, Xiao-Ou Shu, Graham G. Giles, Stefan Nickels, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Surgery, and Cardiothoracic Surgery
Subjects: Messenger, Electrophoretic Mobility Shift Assay, Enhancer RNAs, Genome-wide association study, Medical and Health Sciences, prostate-cancer, 0302 clinical medicine, 2.1 Biological and endogenous factors, Genetics(clinical), Cyclin D1, Aetiology, RNA, Small Interfering, Pair 11, Promoter Regions, Genetic, Luciferases, Genetics (clinical), Cancer, estrogen-receptor, Genetics & Heredity, Genetics, Regulation of gene expression, 0303 health sciences, Tumor, Silencer Elements, Reverse Transcriptase Polymerase Chain Reaction, Single Nucleotide, Biological Sciences, Chromatin, Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, 030220 oncology & carcinogenesis, kConFab Investigators, Female, Transcriptional, GENICA Network, Human, Chromatin Immunoprecipitation, Enhancer Elements, Breast Neoplasms, GATA3 Transcription Factor, Biology, Small Interfering, Real-Time Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, Chromosomes, Cell Line, multiple loci, Promoter Regions, 03 medical and health sciences, down-regulation, Genetic, SDG 3 - Good Health and Well-being, Cell Line, Tumor, Binding Sites, Case-Control Studies, Chromosomes, Human, Pair 11, Humans, RNA, Messenger, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4, Breast Cancer, Polymorphism, Enhancer, Transcription factor, 030304 developmental biology, Neoplastic, gene-expression, susceptibility loci, growth-factor receptor-2, cell-cycle, Gene Expression Regulation, genome-wide association, Cancer research, RNA, mammary-gland, Chromatin immunoprecipitation
Abstract: Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. © 2013 The American Society of Human Genetics.
Published: 2013

46. Germ line variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome

Author: Tjoung Won Park-Simon, Astrid Irwanto, Heli Nevanlinna, Jolanta Lissowska, Jianjun Liu, Maral Jamshidi, Andreas Meyer, Peter Schürmann, Garrett Teoh Hor Keong, Alexandra J. van den Broek, Carl Blomqvist, Tuomas Heikkinen, Sampsa Hautaniemi, Sten Cornelissen, Montserrat Garcia-Closas, Thilo Dörk, Jonine D. Figueroa, Marko Laakso, Marjanka K. Schmidt, Kristiina Aittomäki, and Mark E. Sherman
Subjects: Oncology, Cancer Research, AMP-Activated Protein Kinases, 0302 clinical medicine, Genotype, Gene Regulatory Networks, Protein Phosphatase 2, RNA, Neoplasm, Neoplasm Metastasis, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Carcinoma, Ductal, Breast, Proto-Oncogene Proteins c-mdm2, Middle Aged, Prognosis, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Hormonal therapy, Female, Adult, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Single-nucleotide polymorphism, Breast Neoplasms, Nerve Tissue Proteins, Biology, Real-Time Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast cancer, Germline mutation, Internal medicine, medicine, Adjuvant therapy, Humans, Neoplasm Invasiveness, RNA, Messenger, Allele, Survival rate, Germ-Line Mutation, 030304 developmental biology, medicine.disease, Carcinoma, Lobular, Cancer research, Neoplasm Grading, Tumor Suppressor Protein p53
Abstract: Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3–0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7–0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2–0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6–0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5–0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients.
Published: 2012

47. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients

Author: de Elisabeth G. E. Vries, Femke E. Froklage, J G Schrama, M. de Bruin, Michael Hauptmann, M.J. van de Vijver, Esther H. Lips, Sjoerd Rodenhuis, Marieke A. Vollebergh, Sten Cornelissen, Jelle Wesseling, Marjanka K. Schmidt, M. J. Holtkamp, Petra M. Nederlof, Sabine C. Linn, H. van Tinteren, E. H. van Beers, L. F. A. Wessels, Cancer Center Amsterdam, Pathology, Other departments, and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
Subjects: Oncology, endocrine system diseases, Receptor, ErbB-2, OVARIAN-TUMORS, Carboplatin, Immunoenzyme Techniques, chemistry.chemical_compound, Antineoplastic Combined Chemotherapy Protocols, platinum salt, skin and connective tissue diseases, Promoter Regions, Genetic, In Situ Hybridization, Fluorescence, GENE-EXPRESSION, Comparative Genomic Hybridization, Predictive marker, BRCA1 Protein, Hematology, Chemotherapy regimen, Survival Rate, Treatment Outcome, Receptors, Estrogen, CARCINOMAS, PHASE-II, TRIAL, Female, Breast disease, Fluorouracil, Receptors, Progesterone, predictive marker, Epirubicin, medicine.drug, Adult, medicine.medical_specialty, Anthracycline, Breast Neoplasms, MUTATION CARRIERS, Breast cancer, array comparative genomic hybridisation, Internal medicine, Breast Cancer, medicine, Humans, Cyclophosphamide, business.industry, Cancer, Original Articles, DNA Methylation, medicine.disease, BRCA1, ESTROGEN-RECEPTOR, chemistry, Carcinoma, Basal Cell, Mutation, Cancer research, business, BRCA1 MUTATIONS, Thiotepa, high-dose chemotherapy, Follow-Up Studies
Abstract: Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. Patients and methods: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). Results: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-likeCGH tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-likeCGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-likeCGH tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). Conclusion: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.
Published: 2010

48. Genetic variants in TGFβ-1 and PAI-1 as possible risk factors for cardiovascular disease after radiotherapy for breast cancer

Author: Sten Cornelissen, Berthe M.P. Aleman, Naomi B. Boekel, Laura J. van't Veer, Richard van Hien, Marjanka K. Schmidt, Alexandra J. van den Broek, Flora E. van Leeuwen, and Florentine Hilbers
Subjects: Oncology, medicine.medical_specialty, Genotype, Angiogenesis, medicine.medical_treatment, Breast Neoplasms, Disease, Real-Time Polymerase Chain Reaction, Cardiovascular System, Transforming Growth Factor beta1, Breast cancer, Risk Factors, Internal medicine, Plasminogen Activator Inhibitor 1, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Aged, Proportional Hazards Models, Retrospective Studies, Gynecology, Polymorphism, Genetic, business.industry, Hazard ratio, Genetic variants, Genetic Variation, Retrospective cohort study, Hematology, Middle Aged, medicine.disease, Radiation therapy, Survival Rate, Cardiovascular Diseases, Female, business, Follow-Up Studies
Abstract: It has been established that radiotherapy can increase cardiovascular disease (CVD) risk. Genetic variants, which play a role in the tissue, damage response and angiogenesis regulating TGFβ pathway might give us insight into the mechanisms underlying radiation-induced CVD. We examined the effects of two polymorphisms, TGFβ1 29CT and PAI-1 5G4G, on CVD incidence.This retrospective cohort study included 422 10-year breast cancer survivors, aged50 years at diagnosis, treated between 1977 and 1995. We collected information on treatment, oncological follow-up, CVD, CVD risk factors and genotypes.During a mean follow-up of 19.4 years, 61 patients developed CVD. Internal mammary chain (IMC) irradiation, exposing a part of the heart to radiation, was associated with a hazard ratio of 2.36 (95% CI: 1.27-4.37, p=0.01) compared to no IMC irradiation. Compared to the C/C+C/T genotype, the T/T genotype of the TGFβ1 polymorphism was associated with hazard ratios of 1.79 (0.99-3.26, p=0.06) and 1.74 (0.90-3.34, p=0.10) in the total and IMC-irradiated group, respectively. We found no evidence for an association between PAI-1 5G4G and CVD risk.Our study suggests there might be an association between the TGFβ1 29CT polymorphism and CVD risk in long-term breast cancer survivors.
Published: 2010

49. Abstract 2793: Not HOXB13 p.G84E, but p.R217C appears to be associated with increased breast cancer risk in the Dutch population

Author: John W.M. Martens, Marjanka K. Schmidt, Sten Cornelissen, Wendy J. C. Prager-van der Smissen, Margriet Collée, Antoinette Hollestelle, Jingjing Liu, and Ans W.M. van den Ouweland
Subjects: Oncology, Gynecology, Cancer Research, medicine.medical_specialty, education.field_of_study, business.industry, Population, Cancer, Gene mutation, medicine.disease, Prostate cancer, Breast cancer, Germline mutation, Internal medicine, medicine, Missense mutation, education, business, Allele frequency
Abstract: Recently, the germline mutation G84E in HOXB13 was shown to be associated with an increased risk for prostate cancer. In breast cancer, HOXB13 has been found to be overexpressed. Moreover, high expression of HOXB13 has been shown to mediate poor response to tamoxifen therapy by suppressing estrogen receptor α and inducing IL-6 expression. Based on these observations, the HOXB13 G84E mutation might also be associated with breast cancer risk. So far, the association between HOXB13 G84E and breast cancer risk has been investigated in three different studies and contradictory results were obtained. The goal of this study is to detect if HOXB13 gene mutations in general associate with breast cancer risk. To this end, we sequenced the whole HOXB13 coding region to find mutations in 1250 non-BRCA1&2 familial breast cancer cases and 800 controls. In total, thirteen variants were detected, including seven missense mutations. The G84E mutation was identified in 4 of 1215 cases (0.33%) and 6 of 759 controls (0.79%). Interestingly, we detected another mutation G217C in 6 of 1206 cases (0.50%) and 1 of 765 controls (0.13%). The other five missense mutations were only found once. Because both the HOXB13 G84E and R217C mutations were predicted to be probably damaging, we further evaluated if these two mutations were associated with breast cancer risk. Therefore we expanded our case-control study to include a total of 4520 non-BRCA1&2 familial breast cancer cases and 3127 controls by Taqman genotyping. Our preliminary results show that the HOXB13 G84E mutation was found in 22 of 4449 cases (0.49%) and 23 of 3089 controls (0.74%). The carrier allele frequency was higher in controls than in cases, but not significantly different (OR = 0.66, 95% CI = 0.37-1.19, p = 0.17). Our results indicate that the HOXB13 G84E mutation is not associated with breast cancer risk. The HOXB13 R217C mutation was identified in 15 of 4478 cases (0.33%) and 3 of 3077 controls (0.10%). This difference was borderline significant (OR = 3.44, 95% CI = 1.00-11.91, p = 0.052) most likely due to low population frequency in combination with a relatively small sample size. The HOXB13 R217C mutation could thus be a novel moderate-risk breast cancer susceptibility allele, however a larger study is needed to confirm these results. In conclusion, the R217C mutation rather than the G84E mutation in HOXB13 appears to be associated with breast cancer risk. Citation Format: Jingjing Liu, Wendy JC Prager-van der Smissen, Sten Cornelissen, Margriet J. Collee, Ans W.M. van den Ouweland, Marjanka K. Schmidt, John W.M. Martens, Antoinette Hollestelle. Not HOXB13 p.G84E, but p.R217C appears to be associated with increased breast cancer risk in the Dutch population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2793. doi:10.1158/1538-7445.AM2015-2793
Published: 2015

50. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy

Author: Chen-Yang Shen, Keun-Young Yoo, Kazuo Tajima, Georgia Chenevix-Trench, Qin Wang, William J. Tapper, Kristiina Aittomäki, Douglas F. Easton, Anne Lise Børresen-Dale, Ann Smeets, Hidemi Ito, Heli Nevanlinna, Kamila Czene, Sabine C. Linn, Soo Hwang Teo, Tom Maishman, Ursula Eilber, Robert Luben, Jolanta Lissowska, Cheng Har Yip, Keitaro Matsuo, Sue K. Park, Sandrine Tchatchou, Lothar Haeberle, Anja Rudolph, Sajjad Rafiq, Ellen L. Goode, Nur Aishah Taib, Arto Mannermaa, Keith Humphreys, Sabine Behrens, Silje Nord, Javier Benitez, Alison M. Dunning, Irene L. Andrulis, Jaana M. Hartikainen, Sandra Alexandra J van den Broek, Joe Dennis, Gord Glendon, Taru A. Muranen, Arif B. Ekici, Veli-Matti Kosma, Madeleine M.A. Tilanus-Linthorst, Annika Lindblom, Emily Hallberg, Vessela N. Kristensen, Diana Eccles, Maartje J. Hooning, Sten Cornelissen, Stephen J. Chanock, Paul P.D. Pharoah, Diana Torres, Carolien H.M. van Deurzen, Jingmei Li, Celine M. Vachon, Pei-Ei Wu, Jenny Chang-Claude, Fergus J. Couch, Hans-Ulrich Ulmer, Jieping Lei, Sigrid Hatse, Vesa Kataja, Ute Hamann, Sara Margolin, Daehee Kang, Marjanka K. Schmidt, Hans Wildiers, Lara Sucheston, Janet E. Olson, Mitul Shah, Matthias W. Beckmann, Manjeet K. Bolla, Ji Yeob Choi, Per Hall, Carl Blomqvist, Thomas Rüdiger, Gwo Fuang Ho, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Chia-Ni Hsiung, Ming-Feng Hou, Hiroji Iwata, Diether Lambrechts, Kelly-Anne Phillips, Grethe I. Grenaker Alnæs, Peter A. Fasching, Montserrat Garcia-Closas, Kirsten B. Moysich, Agnes Jager, Pharoah, Paul [0000-0001-8494-732X], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Medical Oncology, Clinical Genetics, Pathology, and Surgery
Subjects: Oncology, medicine.medical_treatment, Estrogen receptor, 32 Biomedical and Clinical Sciences, Genome-wide association study, Kaplan-Meier Estimate, 0302 clinical medicine, Medizinische Fakultät, Surgical oncology, Antineoplastic Combined Chemotherapy Protocols, 2.1 Biological and endogenous factors, Prospective cohort study, health care economics and organizations, Cancer, 2 Aetiology, Medicine(all), 0303 health sciences, Interleukin-12 Subunit p40, Hazard ratio, Genomics, Middle Aged, Prognosis, Tumor Burden, 3. Good health, 3204 Immunology, Treatment Outcome, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, 4.2 Evaluation of markers and technologies, Signal Transduction, Research Article, Adult, medicine.medical_specialty, Breast Neoplasms, Single-nucleotide polymorphism, Protein Serine-Threonine Kinases, Polymorphism, Single Nucleotide, Immunomodulation, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Breast Cancer, Genetics, Biomarkers, Tumor, medicine, Humans, ddc:610, Neoplasm Staging, 030304 developmental biology, Chemotherapy, business.industry, Receptor, Transforming Growth Factor-beta Type II, 3211 Oncology and Carcinogenesis, medicine.disease, Cancer research, Neoplasm Grading, 4 Detection, screening and diagnosis, business, Receptors, Transforming Growth Factor beta
Abstract: Introduction Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy). Methods We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test. Results Three independent SNPs in TGFBR2 and IL12B were associated with OS (P C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10−4) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10−4), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10−4). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10−5) without study heterogeneity. Conclusions TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
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