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1. SNPs in lncRNA Regions and Breast Cancer Risk

Author

Maija Suvanto, Jonathan Beesley, Carl Blomqvist, Georgia Chenevix-Trench, Sofia Khan, and Heli Nevanlinna

Subjects
breast cancer, lncRNA, ultraconserved region, GABPB1-AS1, breast cancer risk, Genetics, QH426-470
Abstract

Long non-coding RNAs (lncRNAs) play crucial roles in human physiology, and have been found to be associated with various cancers. Transcribed ultraconserved regions (T-UCRs) are a subgroup of lncRNAs conserved in several species, and are often located in cancer-related regions. Breast cancer is the most common cancer in women worldwide and the leading cause of female cancer deaths. We investigated the association of genetic variants in lncRNA and T-UCR regions with breast cancer risk to uncover candidate loci for further analysis. Our focus was on low-penetrance variants that can be discovered in a large dataset. We selected 565 regions of lncRNAs and T-UCRs that are expressed in breast or breast cancer tissue, or show expression correlation to major breast cancer associated genes. We studied the association of single nucleotide polymorphisms (SNPs) in these regions with breast cancer risk in the 122970 case samples and 105974 controls of the Breast Cancer Association Consortium’s genome-wide data, and also by in silico functional analyses using Integrated Expression Quantitative trait and in silico prediction of GWAS targets (INQUISIT) and expression quantitative trait loci (eQTL) analysis. The eQTL analysis was carried out using the METABRIC dataset and analyses from GTEx and ncRNA eQTL databases. We found putative breast cancer risk variants (p < 1 × 10–5) targeting the lncRNA GABPB1-AS1 in INQUISIT and eQTL analysis. In addition, putative breast cancer risk associated SNPs (p < 1 × 10–5) in the region of two T-UCRs, uc.184 and uc.313, located in protein coding genes CPEB4 and TIAL1, respectively, targeted these genes in INQUISIT and in eQTL analysis. Other non-coding regions containing SNPs with the defined p-value and highly significant false discovery rate (FDR) for breast cancer risk association were discovered that may warrant further studies. These results suggest candidate lncRNA loci for further research on breast cancer risk and the molecular mechanisms.

Published
2020
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2. 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

3. High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome

Author

Maral Jamshidi, Rainer Fagerholm, Taru A. Muranen, Sippy Kaur, Swapnil Potdar, Sofia Khan, Eliisa Netti, John-Patrick Mpindi, Bhagwan Yadav, Johanna I. Kiiski, Kristiina Aittomäki, Päivi Heikkilä, Jani Saarela, Ralf Bützow, Carl Blomqvist, Heli Nevanlinna, University of Helsinki, HUS Gynecology and Obstetrics, University of Helsinki, Faculty Common Matters, University of Helsinki, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki Institute of Life Science HiLIFE, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, University of Helsinki, Medicum, University of Helsinki, HUSLAB, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Helsinki University Hospital Area, Faculty Common Matters (Faculty of Biology and Environmental Sciences), Clinicum, Medicum, Department of Pathology, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, INDIVIDRUG - Individualized Drug Therapy, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Diagnostic Center, HUS Comprehensive Cancer Center, and Department of Oncology

Subjects
p53, PROTEIN EXPRESSION, MICRORNAS, education, INVASION, 3122 Cancers, SUPPRESS, chemotherapy, anthracycline, survival, doxorubicin, Article, PROGNOSTIC-FACTORS, breast cancer, 3123 Gynaecology and paediatrics, metastasis, miR-30, BRCA2 MUTATIONS, lapatinib, skin and connective tissue diseases, RC254-282, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, EPITHELIAL-MESENCHYMAL TRANSITION, HER-2, HYBRIDIZATION, RESISTANCE
Abstract

Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (pBDDM = 0.035, HR = 0.63, 95% CI = 0.4–0.9) and breast cancer-specific survival (pBCS = 0.018, HR = 0.61, 95% CI = 0.4–0.9), especially in HER2-positive (pBDDM = 0.0009), ER-negative (pBDDM = 0.003), p53-positive (pBDDM = 0.011), and highly proliferating (pBDDM = 0.0004) subgroups, and after adjuvant chemotherapy (pBDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (pBDDM = 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (p &lt, 10−2) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (p &lt, 10−4) with an opposite impact on MCF7. According to the pathway analysis, the miR-30 family has a suppressive effect on cell motility and metastasis in breast cancer. Our results suggest prognostic and predictive potential for the miR-30 family, which warrants further investigation.

Published
2021

4. Association of germline variation with the survival of women with BRCA1/2 pathogenic variants and breast cancer

Author

Douglas F. Easton, Mads Thomassen, Georgia Chenevix-Trench, Kristiina Aittomäki, Marjanka K. Schmidt, Hebon Investigators, Esther M. John, Irene L. Andrulis, Maartje J. Hooning, Antonis C. Antoniou, Swe-Brca Investigators, Caroline Maria Rossing, Penny Soucy, Jacques Simard, Michael T. Parsons, Julie M. Cunningham, Paul A. James, Joe Dennis, Gabriel Wagner, Melissa C. Southey, Susan M. Domchek, Eric Hahnen, kConFab Investigators, Goska Leslie, Sofia Khan, Katherine L. Nathanson, Rita K. Schmutzler, Anna Jakubowska, Jeffrey N. Weitzel, Taru A. Muranen, Heli Nevanlinna, Barbara Wappenschmidt, Drakoulis Yannoukakos, Judy Garber, Marc Tischkowitz, Conxi Lázaro, Inge Søkilde Pedersen, Carl Blomqvist, Amanda B. Spurdle, Christian F. Singer, Susan L. Slager, Lesley McGuffog, Rainer Fagerholm, Manuel R. Teixeira, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital Area, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Muranen, Taru A. [0000-0002-5895-1808], Cunningham, Julie M. [0000-0002-8159-3025], Dennis, Joe [0000-0003-4591-1214], Leslie, Goska [0000-0001-5756-6222], Parsons, Michael T. [0000-0003-3242-8477], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Spurdle, Amanda B. [0000-0003-1337-7897], Pedersen, Inge Sokilde [0000-0002-9902-8040], Nathanson, Katherine L. [0000-0002-6740-0901], Lazaro, Conxi [0000-0002-7198-5906], Andrulis, Irene L. [0000-0002-4226-6435], Teixeira, Manuel R. [0000-0002-4896-5982], James, Paul [0000-0002-4361-4657], Weitzel, Jeffrey N. [0000-0001-6714-092X], Jakubowska, Anna [0000-0002-5650-0501], Yannoukakos, Drakoulis [0000-0001-7509-3510], Schmidt, Marjanka K. [0000-0002-2228-429X], Nevanlinna, Heli [0000-0002-0916-2976], Apollo - University of Cambridge Repository, Muranen, Taru A [0000-0002-5895-1808], Cunningham, Julie M [0000-0002-8159-3025], Parsons, Michael T [0000-0003-3242-8477], Easton, Douglas F [0000-0003-2444-3247], Spurdle, Amanda B [0000-0003-1337-7897], Nathanson, Katherine L [0000-0002-6740-0901], Andrulis, Irene L [0000-0002-4226-6435], Teixeira, Manuel R [0000-0002-4896-5982], Weitzel, Jeffrey N [0000-0001-6714-092X], and Schmidt, Marjanka K [0000-0002-2228-429X]

Subjects
0301 basic medicine, Oncology, Etiology, Genome-wide association study, Genome-wide association studies, Germline, 0302 clinical medicine, Breast cancer, PRIMARY THERAPY, Pharmacology (medical), skin and connective tissue diseases, Cancer genetics, RISK, medicine.diagnostic_test, Hazard ratio, article, INTERNATIONAL EXPERT CONSENSUS, Tumor Pathology, OVARIAN, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, 030220 oncology & carcinogenesis, Etiologia, EXPRESSION, medicine.medical_specialty, GENES, 3122 Cancers, 631/208/205/2138, lcsh:RC254-282, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, 631/67/68, Genetic variation, REVEALS, medicine, Radiology, Nuclear Medicine and imaging, Genetic testing, IDENTIFICATION, business.industry, FALSE DISCOVERY, Cancer, medicine.disease, 030104 developmental biology, CELLS, 692/4028/67/1347, business
Abstract

Germline genetic variation has been suggested to influence the survival of breast cancer patients independently of tumor pathology. We have studied survival associations of genetic variants in two etiologically unique groups of breast cancer patients, the carriers of germline pathogenic variants in BRCA1 or BRCA2 genes. We found that rs57025206 was significantly associated with the overall survival, predicting higher mortality of BRCA1 carrier patients with estrogen receptor-negative breast cancer, with a hazard ratio 4.37 (95% confidence interval 3.03–6.30, P = 3.1 × 10−9). Multivariable analysis adjusted for tumor characteristics suggested that rs57025206 was an independent survival marker. In addition, our exploratory analyses suggest that the associations between genetic variants and breast cancer patient survival may depend on tumor biological subgroup and clinical patient characteristics.

Published
2020

5. CIP2A interacts with TopBP1 and is selectively essential for DNA damage-induced basal-like breast cancer tumorigenesis

Author

Jochen Maurer, Denise C. Connolly, Prson Gautam, Jukka Westermarck, Karolina Pavic, Caroline Farrington, Umar Butt, René H. Medema, Anna Cvrljevic, Femke M. Feringa, Pauliina Kronqvist, Heikki Joensuu, Sofia Khan, Emilia Peuhu, Goutham Narla, Karin E. de Visser, Srikar G. Nagelli, Laura L. Elo, Xi Qiao, Tove J. Grönroos, Harri Sihto, Krister Wennerberg, Anni Laine, and Julia P. Vainonen

Subjects
0303 health sciences, DNA damage, Chromatin binding, RAD51, Cancer, Biology, medicine.disease, medicine.disease_cause, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, PARP1, Breast cancer, 030220 oncology & carcinogenesis, medicine, Cancer research, E2F1, Carcinogenesis, 030304 developmental biology
Abstract

Despite saturated genetic profiling of breast cancers, oncogenic drivers for the clinically challenging basal-like breast cancer (BLBC) subtype are still poorly understood. Here, we demonstrate that CIP2A is selectively essential for DNA damage-induced initiation of mouse BLBC tumors, but not of other cancer types. Mechanistically, CIP2A was discovered genome-widely the closest functional homologue for DNA-damage proteins TopBP1, RHNO, POLQ, NBN and PARP1. CIP2A directly interacts with the ATR-activation domain of TopBP1, and dampens both, chromatin binding of TopBP1 and RAD51, and G2/M checkpoint in DNA-damaged cells. CIP2A also drives BLBC-associated proliferative MYC and E2F1 signaling. Consistently with high DNA-damage response activity BLBCs, and CIP2A’s novel role in checkpoint signaling, CIP2A was found essential for DNA-damaged, and BRCA-mutant BLBC cells. Selective role for CIP2A as BLBC driver was supported by association of high CIP2A expression with poor patient prognosis only in BLBC, but not in other breast cancer types. Therapeutically, small molecule reactivators of PP2A (SMAPs) phenocopy CIP2A-dependent DNA damage response, and inhibit in vivo growth of patient-derived BLBC xenograft. In summary, we discover sub-type selective essential role for CIP2A in BLBC initiation and maintenance that can be explained by its newly discovered association with DNA-damage response, coordinated with regulation of proliferative signaling. The results also identify therapeutic strategy for CIP2A-dependent BLBCs.

Published
2020

6. Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women

Author

Fergus J. Couch, Brigitte Rack, Diana Eccles, Peter A. Fasching, Wolfgang Janni, Lorraine Durcan, Sofia Khan, Latha Kadalayil, John L. Hopper, Sue Gerty, William J. Tapper, Tom Maishman, Andrew Collins, Heli Nevanlinna, Jianjun Liu, Carl Blomqvist, Department of Obstetrics and Gynecology, Clinicum, University of Helsinki, Department of Oncology, and HUS Comprehensive Cancer Center

Subjects
0301 basic medicine, Oncology, General Physics and Astronomy, SUSCEPTIBILITY, VARIANTS, ANNOTATION, Germline, ADAMTS Proteins, 0302 clinical medicine, TUMOR PHENOTYPE, 3123 Gynaecology and paediatrics, lcsh:Science, skin and connective tissue diseases, GENE-EXPRESSION, Aged, 80 and over, RISK, Extracellular Matrix Proteins, Multidisciplinary, Incidence (epidemiology), METHYLATION, Middle Aged, Prognosis, 3. Good health, GENOME, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, Adolescent, Science, 3122 Cancers, Antineoplastic Agents, Breast Neoplasms, Single-nucleotide polymorphism, Quantitative trait locus, Amphiregulin, Polymorphism, Single Nucleotide, Article, Disease-Free Survival, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, AGE, Breast cancer, Internal medicine, Genetic variation, medicine, Humans, Pathological, Germ-Line Mutation, Survival analysis, Aged, IDENTIFICATION, business.industry, General Chemistry, medicine.disease, 030104 developmental biology, Cancer research, lcsh:Q, business, Genome-Wide Association Study
Abstract

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients aged ≤ 40 years at diagnosis. Here, we identify two SNPs associated with early-onset DFS, rs715212 (P meta = 3.54 × 10−5) and rs10963755 (P meta = 3.91 × 10−4) in ADAMTSL1. The effect of these SNPs is independent of classical prognostic factors and there is no heterogeneity between cohorts. Most importantly, the association with rs715212 is noteworthy (FPRP, Genetic variance can influence breast cancer prognosis. Here, the authors conduct a meta-analysis to explore genetic variance linked to breast cancer in young women, identifying a prognostic association with germline variation of ADAMTSL1.

Published
2017

7. FANCM mutation c.5791C>T is a risk factor for triple-negative breast cancer in the Finnish population

Author

Anna Tervasmäki, Heli Nevanlinna, Katri Pylkäs, Veli-Matti Kosma, Sofia Khan, Johanna Schleutker, Ralf Bützow, Liisa M. Pelttari, Robert Winqvist, Carl Blomqvist, Anne Kallioniemi, Maria Tengström, Anders Kvist, Kristiina Aittomäki, Åke Borg, Johanna I. Kiiski, Tuomo Mantere, Arto Mannermaa, Lääketieteen ja biotieteiden tiedekunta - Faculty of Medicine and Life Sciences, University of Tampere, Clinicum, University of Helsinki, Department of Obstetrics and Gynecology, Department of Pathology, Medicum, Department of Oncology, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, and HUS Comprehensive Cancer Center

Subjects
0301 basic medicine, Oncology, Cancer Research, PROTEIN EXPRESSION, DNA Repair, Epidemiology, FEATURES, VARIANT, Triple Negative Breast Neoplasms, FAMILIES, COMPLEMENTATION GROUP M, Breast cancer, 0302 clinical medicine, Gene Frequency, FANCM, 3123 Gynaecology and paediatrics, Risk Factors, Gene Duplication, Genotype, Odds Ratio, Medicine, Finland, Triple-negative breast cancer, Sequence Deletion, OVARIAN-CARCINOMA, 3. Good health, SUSCEPTIBILITY GENE, Population Surveillance, 030220 oncology & carcinogenesis, Female, Familial breast cancer, medicine.medical_specialty, 3122 Cancers, Nonsense mutation, Risk Assessment, 03 medical and health sciences, Genetiikka, kehitysbiologia, fysiologia - Genetics, developmental biology, physiology, Syöpätaudit - Cancers, Internal medicine, Humans, BRCA2 MUTATIONS, Genetic Predisposition to Disease, ANEMIA, Risk factor, Alleles, Gynecology, business.industry, DNA Helicases, Cancer, medicine.disease, 030104 developmental biology, Case-Control Studies, Mutation, business
Abstract

Purpose: The FANCM c.5101C>T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C>T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. Methods: We genotyped the FANCM c.5791C>mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C>T and c.5791C>T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C>T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. Results: The frequency of the FANCM c.5791C>T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87–4.32, P = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65–16.0, P = 0.005). The combined analysis for c.5101C>T and c.5791C>T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32–2.49, P = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77–5.35, P = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. Conclusions: These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.

Published
2017

8. 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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9. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Wing-Yee Lo, Dhanya Ramachandran, Christos Petridis, Fernando Salvador Moreno, Tongguang Cheng, Bernardo Bonanni, Ann Smeets, Susan E. Hankinson, Caroline Seynaeve, Suet-Feung Chin, Vessela N. Kristensen, Christopher G. Scott, Javier Benitez, William T. Newman, Brigitte Rack, Marjanka K. Schmidt, Diether Lambrechts, Alfons Meindl, Maria Escala-Garcia, Hoda Anton-Culver, Veli-Matti Kosma, Nadege Presneau, Daniel F. Schmidt, Douglas F. Easton, Ans M.W. van den Ouweland, Emmanouil Saloustros, Antoinette Hollestelle, Darya Prokofieva, Elinor J. Sawyer, Louise A. Brinton, Manuela Gago-Dominguez, Minouk J. Schoemaker, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Eva Galle, Catriona McLean, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Per Hall, Jaana M. Hartikainen, Leslie Bernstein, Jose Ignacio Arias Perez, Flavio Lejbkowicz, Qi Guo, Brian D. Carter, Martha S. Linet, Fredrick R. Schumacher, Yan Zhang, Mikael Eriksson, Hiltrud Brauch, Janet A. Dunn, Gord Glendon, Bernd Holleczek, William J. Tapper, Marike Gabrielson, Keith Humphreys, Rodney J. Scott, Tabea Kühl, Lorraine Durcan, David J. Hunter, Pascal Guénel, Tom Maishman, Mary B. Daly, Rami Nassir, Andreas Schneeweiss, Kamila Czene, Jonine D. Figueroa, Grethe I. Grenaker Alnæs, Julia A. Knight, Angel Carracedo, Susan M. Gapstur, Manuel R. Teixeira, Guanmengqian Huang, Paul L. Auer, Sara Y. Brucker, Johanna I. Kiiski, Adam R. Brentnall, Simon S. Cross, Joe Dennis, Nicola Miller, Walter C. Willett, Melissa C. Southey, Christoph Engel, Niclas Håkansson, Diana Eccles, John L. Hopper, Elaine F. Harkness, Audrey Y. Jung, Trinidad Caldés, Steven N. Hart, Sara Lindström, Michael P. Lux, Julie Lecarpentier, Lian Li, Robert Winqvist, Peter Kraft, Stephen J. Chanock, Thilo Dörk, Melanie Maierthaler, Rudolf Kaaks, Angela Cox, Maartje J. Hooning, José A. García-Sáenz, Christi J. van Asperen, Mervi Grip, Enes Makalic, Mia M. Gaudet, David E. Goldgar, Ross L. Prentice, Carolina Ellberg, Sune F. Nielsen, Federico Canzian, Rebecca Roylance, Aline Talhouk, Vassilios Georgoulias, Eunjung Lee, Siranoush Manoukian, Sara Margolin, Paul D.P. Pharoah, Hedy S. Rennert, Mitul Shah, Matthias W. Beckmann, Anthony Howell, Anne Lise Børresen-Dale, Christopher A. Haiman, V. Shane Pankratz, Anna González-Neira, Kathrin Thöne, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Ute Krüger, Mehdi Manoochehri, Arja Jukkola-Vuorinen, Loic Le Marchand, Katri Pylkäs, Peter Hillemanns, Dieter Flesch-Janys, Volker Arndt, Peter A. Fasching, Christine L. Clarke, Louise Hiller, Eric Hahnen, Jan Lubinski, Jose E. Castelao, Roger L. Milne, Linetta B. Koppert, Peter Devilee, Rob A. E. M. Tollenaar, Ian W. Brock, Claire Mulot, Mila Pinchev, Carlos Caldas, Michael Untch, Gadi Rennert, Aaron D. Norman, Per Broberg, Anthony J. Swerdlow, Lothar Haeberle, Heli Nevanlinna, Arto Mannermaa, Irene L. Andrulis, Angela George, Montserrat Garcia-Closas, Jolanta Lissowska, Jonathan Beesley, Paolo Peterlongo, Cari M. Kitahara, Rulla M. Tamimi, Annika Lindblom, Sabine Behrens, Nick Orr, David G. Cox, D. Gareth Evans, Jacques Simard, Diana Torres, Constance Turman, Celine M. Vachon, Qin Wang, Hans-Ulrich Ulmer, Maria Kabisch, Maria Elena Martinez, Paolo Radice, Maria Tengström, Dimitrios Mavroudis, Jean Abraham, Helena M. Earl, Alice S. Whittemore, Hermann Brenner, Rita K. Schmutzler, Børge G. Nordestgaard, Barbara Burwinkel, Michael Jones, Esther M. John, Patricia Harrington, Daniele Campa, Elke M. van Veen, Clara Pérez-Barrios, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Elza Khusnutdinova, Michael J. Kerin, Miriam Dwek, Sibylle Loibl, Manjeet K. Bolla, Carl Blomqvist, Sander Canisius, Graham G. Giles, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Emilie Cordina-Duverger, Arif B. Ekici, Yon-Dschun Ko, Pooja Middha, Alison M. Dunning, Katarzyna Kaczmarek, Bram Boeckx, Mary Beth Terry, Jenny Chang-Claude, Karoliona Prajzendanc, Renske Keeman, Camilla Wendt, Atocha Romero, Stig E. Bojesen, Robert J. MacInnis, Clare Turnbull, Lukas Schwentner, Xiaohong R. Yang, Henrik Flyger, Håkan Olsson, Wolfgang Janni, Sofia Khan, Clinicum, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, HUS Comprehensive Cancer Center, Medical Oncology, Surgery, and Clinical Genetics

Subjects
Oncology, Cancer Research, PROGNOSIS, Genome-wide association study, PATHWAY, Prognostic markers, Breast cancer, 0302 clinical medicine, Epidemiology of cancer, Cancer genetics, RISK, Hazard ratio, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENETIC-VARIATION, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, SURVIVAL, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 7, EXPRESSION, medicine.medical_specialty, CLINICAL-OUTCOMES, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Article, White People, NBCS Collaborators, RC0254, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Proportional Hazards Models, business.industry, Proportional hazards model, Genetic Variation, Cancer, Bayes Theorem, medicine.disease, business, Genome-Wide Association Study
Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Published
2019

10. Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author

Elinor J. Sawyer, Maria Kabisch, Louise A. Brinton, Joe Dennis, Frederik Marmé, Sofia Khan, Michael Lush, Soo-Hwang Teo, Giuseppe Floris, Thilo Dörk, Pascal Guénel, Chiu-Chen Tseng, Anja Rudolph, Arto Mannermaa, Vessela N. Kristensen, Manjeet K. Bolla, Daehee Kang, Peter A. Fasching, Qin Wang, Caroline Seynaeve, Sara Margolin, Hidemi Ito, Xingyi Guo, John W.M. Martens, Mikael Hartman, Matthias W. Beckmann, Bernard Thienpont, Kyriaki Michailidou, Ming-Feng Hou, Diether Lambrechts, Simon S. Cross, Heli Nevanlinna, Graham G. Giles, Robert A.E.M. Tollenaar, Alison M. Dunning, Anna H. Wu, Cheng Har Yip, Artitaya Lophatananon, William J. Blot, Irene L. Andrulis, Kenneth Muir, Stig E. Bojesen, Chia-Ni Hsiung, Arnaud Droit, Per Hall, Douglas F. Easton, Hui Cai, Jonathan Beesley, Hatef Darabi, Pilar Zamora, Paolo Peterlongo, Jiajun Shi, Wei Zheng, Antoinette Hollestelle, Alicia Beeghly-Fadiel, Siddhartha Kar, Mervi Grip, Jirong Long, Melissa C. Southey, Javier Benitez, Sander Canisius, Zhiguo Zhao, Annika Lindblom, Susan L. Neuhausen, Ji Yeob Choi, Robert Winqvist, Catriona McLean, Valerie Gaborieau, Keitaro Matsuo, Georgia Chenevix-Trench, Suleeporn Sangrajrang, Hoda Anton-Culver, Diana Torres, Jingmei Li, Julia A. Knight, Anna Jakubowska, Paul D.P. Pharoah, Ans M.W. van den Ouweland, Nichola Johnson, Montserrat Garcia-Closas, Thomas Brüning, Veli-Matti Kosma, Matha J. Shrubsole, Anthony J. Swerdlow, Xiao-Ou Shu, Ying Zheng, Henrik Flyger, Hermann Brenner, Angela Cox, Florentia Fostira, Maartje J. Hooning, Antonis C. Antoniou, Kamila Czene, Wanqing Wen, Volker Arndt, Siranoush Manoukian, Hui Miao, Anne Lise Børresen-Dale, Jenny Chang-Claude, Christopher A. Haiman, Janet E. Olson, Annegien Broeks, Peter Devilee, Qiuyin Cai, kConFab Investigators, Ching-Yu Cheng, Chen-Yang Shen, Nick Orr, Roger L. Milne, Loic Le Marchand, Ian Tomlinson, Thomas C. Putti, Alfons Meindl, Thérèse Truong, Amanda E. Toland, John L. Hopper, Fergus J. Couch, Olivia Fletcher, Marjanka K. Schmidt, Ute Hamann, Maya Ghoussaini, Yanfeng Zhang, Rita K. Schmutzler, Barbara Burwinkel, Jacques Simard, Silje Nord, Hiltrud Brauch, Natalia Bogdanova, and Jan Lubinski

Subjects
0301 basic medicine, Genetics, Cancer Research, Linkage disequilibrium, Haplotype, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, Breast cancer, Oncology, Genotype, medicine, Genetic association
Abstract

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Published
2016

11. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

Author

Javier Benitez, Alicia Beeghly-Fadiel, Roger L. Milne, Graham G. Giles, Florentia Fostira, Senno Verhoef, Qin Wang, Simon S. Cross, Jenny Chang-Claude, Jacques Simard, Vessela N. Kristensen, Hoda Anton-Culver, Kathleen E. Malone, Veli-Matti Kosma, Pascal Guénel, Esther M. John, Stig E. Bojesen, Jan Lubinski, Patricia Harrington, Giske Ursin, Muhammad G. Kibriya, Artitaya Lophatananon, Mieke Kriege, Fergus J. Couch, Maria Kabisch, Judith S. Brand, Ute Hamann, Henrik Flyger, Susan L. Neuhausen, Elinor J. Sawyer, Mikael Hartman, Robert Luben, Thilo Dörk, Wanqing Wen, Hiltrud Brauch, Marilie D. Gammon, Xiao-Ou Shu, Ben Shan Zhang, Minouk J. Schoemaker, M. Pilar Zamora, Jirong Long, Rita K. Schmutzler, Natalia Bogdanova, Sofia Khan, Siranoush Manoukian, Anne Lise Børresen-Dale, Barbara Burwinkel, Regina M. Santella, Ian Tomlinson, Manjeet K. Bolla, Shan Wang-Gohrke, Nichola Johnson, Thérèse Truong, Rob B. van der Luijt, Amanda E. Toland, Carl Blomqvist, Catriona McLean, Georgia Chenevix-Trench, Anthony J. Swerdlow, Jingmei Li, Habibul Ahsan, David J. Hunter, Kristiina Aittomäki, Hui Zhao, Hui Miao, Wei Zheng, Olivia Fletcher, Alison M. Dunning, Marjanka K. Schmidt, Kenneth Muir, Per Hall, Farzana Jasmine, Eunjung Lee, Melissa C. Southey, Robert Winqvist, Janet E. Olson, Anna Jakubowska, Paul D.P. Pharoah, Martine Dumont, Dieter Flesch-Janys, Barbara Perkins, Douglas F. Easton, Christopher A. Haiman, Jonine D. Figueroa, Julia A. Knight, Kamila Czene, Loic Le Marchand, Katri Pylkäs, Angela Cox, Maartje J. Hooning, Kyriaki Michailidou, John L. Hopper, Qiuyin Cai, Volker Arndt, Heli Nevanlinna, Sara Lindström, Hanne Meijers-Heijboer, Sara Margolin, Zhiguo Zhao, Mitul Shah, Matthias W. Beckmann, Alfons Meindl, Martha J. Shrubsole, Paolo Peterlongo, Frederik Marmé, Peter Kraft, Irene L. Andrulis, Annika Lindblom, Diana Torres, Anja Rudolph, Arto Mannermaa, Graham Casey, Alice S. Whittemore, Hermann Brenner, Patrick Neven, Kelly-Anne Phillips, Peter A. Fasching, Montserrat Garcia-Closas, Human genetics, CCA - Cancer biology, Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, and Medical Oncology

Subjects
0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, Epidemiology, Genome-wide association study, Type 2 diabetes, Breast cancer, 0302 clinical medicine, Risk Factors, Ethnicity, Odds Ratio, GWAS, Non-U.S. Gov't, Research Support, Non-U.S. Gov't, Middle Aged, 3. Good health, 030220 oncology & carcinogenesis, Public Health and Health Services, Female, medicine.medical_specialty, Oncology and Carcinogenesis, European Continental Ancestry Group, Non-P.H.S, Ethnic Groups, Breast Neoplasms, Research Support, Polymorphism, Single Nucleotide, Article, White People, N.I.H, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Internal medicine, Genetic susceptibility, Journal Article, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, business.industry, Case-control study, Genetic Variation, Extramural, nutritional and metabolic diseases, Cancer, Odds ratio, medicine.disease, Obesity, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, U.S. Gov't, business, Research Support, U.S. Gov't, Non-P.H.S, Demography
Abstract

Purpose: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.\ud Methods: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.\ud Results: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92–0.95, p = 4.13E−13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02–1.06, p = 1.26E−05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95–0.99, p = 8.05E−04).\ud Conclusions: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

Published
2016

12. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author

Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. 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Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 4 ] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA [ 5 ] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway [ 6 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy [ 7 ] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA [ 8 ] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA [ 9 ] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA [ 10 ] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland [ 11 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 12 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 13 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada [ 14 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 15 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA [ 16 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 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Subjects
0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

Published
2018

13. Meta-analysis of three genome-wide association studies identifies two loci that predict survival and treatment outcome in breast cancer

Author

Sofia Khan, Latha Kadalayil, Carl Blomqvist, William J. Tapper, Heli Nevanlinna, Kristiina Aittomäki, Rainer Fagerholm, Jianjun Liu, Diana Eccles, Department of Obstetrics and Gynecology, Clinicum, University of Helsinki, Medicum, Research Programs Unit, Genome-Scale Biology (GSB) Research Program, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, and HUS Comprehensive Cancer Center

Subjects
0301 basic medicine, Oncology, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Estrogen receptor, Genome-wide association study, PROGRESSION, survival, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, breast cancer, Internal medicine, Genotype, medicine, GWAS, TUMOR-SUPPRESSOR, Genetic association, CYCLIN D1, tamoxifen, ENDOCRINE THERAPY, business.industry, Hazard ratio, medicine.disease, 3. Good health, APOPTOSIS, 030104 developmental biology, ESTROGEN-RECEPTOR, GTPASES, 030220 oncology & carcinogenesis, Meta-analysis, AUTOPHAGY, business, Tamoxifen, RESISTANCE, Meta-Analysis, medicine.drug
Abstract

The majority of breast cancers are driven by the female hormone oestrogen via oestrogen receptor (ER) alpha. ER-positive patients are commonly treated with adjuvant endocrine therapy, however, resistance is a common occurrence and aside from ER-status, no unequivocal predictive biomarkers are currently in clinical use. In this study, we aimed to identify constitutional genetic variants influencing breast cancer survival among ER-positive patients and specifically, among endocrine-treated patients. We conducted a meta-analysis of three genome-wide association studies comprising in total 3,136 patients with ER-positive breast cancer of which 2,751 had received adjuvant endocrine therapy. We identified a novel locus (rs992531 at 8p21.2) associated with reduced survival among the patients with ER-positive breast cancer (P = 3.77 x 10(-8)). Another locus (rs7701292 at 5q21.3) was associated with reduced survival among the endocrine-treated patients (P = 2.13 x 10(-8)). Interaction analysis indicated that the survival association of rs7701292 is treatment-specific and independent of conventional prognostic markers. In silico functional studies suggest plausible biological mechanisms for the observed survival associations and a functional link between the putative target genes of the rs992531 and rs7701292 (RHOBTB2 and RAB9P1, respectively). We further explored the genetic interaction between rs992531 and rs7701292 and found a significant, treatment-specific interactive effect on survival among ER-positive, endocrine-treated patients (hazard ratio = 6.97; 95% confidence interval, 1.79-27.08, P-interaction = 0.036). This is the first study to identify a genetic interaction that specifically predicts treatment outcome. These findings may provide predictive biomarkers based on germ line genotype informing more personalized treatment selection.

Published
2018

14. Polymorphism at 19q13.41 Predicts Breast Cancer Survival Specifically after Endocrine Therapy

Author

Jianjun Liu, William J. Tapper, Diana Eccles, Kristiina Aittomäki, Sajjad Rafiq, Carl Blomqvist, Heli Nevanlinna, Sofia Khan, and Rainer Fagerholm

Subjects
Oncology, Cancer Research, Estrogen receptor, Kaplan-Meier Estimate, 0302 clinical medicine, Medicine, Prospective Studies, Prospective cohort study, Aged, 80 and over, 0303 health sciences, Homozygote, Hazard ratio, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, Treatment Outcome, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, Antineoplastic Agents, Hormonal, Genotype, Quantitative Trait Loci, Breast Neoplasms, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Breast cancer, Internal medicine, Humans, SNP, Endocrine system, Allele, Alleles, Aged, Proportional Hazards Models, 030304 developmental biology, Gynecology, business.industry, medicine.disease, Confidence interval, Multivariate Analysis, business, Chromosomes, Human, Pair 19, Genome-Wide Association Study
Abstract

Purpose: Although most patients with estrogen receptor (ER)–positive breast cancer benefit from endocrine therapies, a significant proportion do not. Our aim was to identify inherited genetic variations that might predict survival among patients receiving adjuvant endocrine therapies. Experimental Design: We performed a meta-analysis of two genome-wide studies; Helsinki Breast Cancer Study, 805 patients, with 240 receiving endocrine therapy and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer, 536 patients, with 155 endocrine therapy patients, evaluating 486,478 single-nucleotide polymorphisms (SNP). The top four associations from the endocrine treatment subgroup were further investigated in two independent datasets totaling 5,011 patients, with 3,485 receiving endocrine therapy. Results: A meta-analysis identified a common SNP rs8113308, mapped to 19q13.41, associating with reduced survival among endocrine-treated patients [hazard ratio (HR), 1.69; 95% confidence interval (CI), 1.37–2.07; P = 6.34 × 10−7] and improved survival among ER-negative patients, with a similar trend in ER-positive cases not receiving endocrine therapy. In a multivariate analysis adjusted for conventional prognostic factors, we found a significant interaction between the rs8113308 and endocrine treatment, indicating a predictive, treatment-specific effect of the SNP rs8113308 on breast cancer survival, with the per-allele HR for interaction 2.16 (95% CI, 1.30–3.60; Pinteraction = 0.003) and HR = 7.77 (95% CI, 0.93–64.71) for the homozygous genotype carriers. A biologic rationale is suggested by in silico functional analyses. Conclusions: Our findings suggest carrying the rs8113308 rare allele may identify patients who will not benefit from adjuvant endocrine treatment. Clin Cancer Res; 21(18); 4086–96. ©2015 AACR.

Published
2015

15. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Author

Christopher A. Haiman, Pascal Guénel, Hidemi Ito, Susan L. Neuhausen, Christy G. Woolcott, Graham G. Giles, Anthony J. Swerdlow, Per Hall, Kamila Czene, Artitaya Lophatananon, Åslaug Helland, Yu-Tang Gao, Vessela N. Kristensen, Manjeet K. Bolla, Anna H. Wu, Jacques Simard, John L. Hopper, Robert Luben, Julia A. Knight, Mark S. Goldberg, Thilo Dörk, Kay-Tee Khaw, Christopher G. Scott, Giuseppe Floris, Jennifer Stone, Madeleine M.A. Tilanus-Linthorst, Stig E. Bojesen, Daehee Kang, Qin Wang, Angela Cox, Fergus J. Couch, Jonathan Beesley, Maartje J. Hooning, Natalia Bogdanova, Brian E. Henderson, Paolo Peterlongo, Rulla M. Tamimi, Soo Hwang Teo, Diether Lambrechts, Ute Hamann, Wei Zheng, Volker Arndt, Juliet D. French, Stacey L. Edwards, Julian Peto, Ian Tomlinson, Ji Yeob Choi, Elinor J. Sawyer, Melissa C. Southey, Annegien Broeks, Arif B. Ekici, Heli Nevanlinna, Celine M. Vachon, Thérèse Truong, Amanda E. Toland, Javier Benitez, Barbara Burwinkel, Xiao-Ou Shu, Robert Winqvist, Pierre Antoine Dugué, Karen McCue, Mikael Hartman, Minouk J. Schoemaker, Keitaro Matsuo, Norbert Arnold, Deborah J. Thompson, Paolo Radice, Anna Jakubowska, Marjanka K. Schmidt, Hermann Brenner, Hoda Anton-Culver, Argyrios Ziogas, Jenny Chang-Claude, Alicia Beeghly-Fadiel, Veli-Matti Kosma, Hatef Darabi, Drakoulis Yannoukakos, Maya Ghoussaini, Rodney J. Scott, Maria Kabisch, Chen-Yang Shen, Suleeporn Sangrajrang, Montserrat Garcia-Closas, James McKay, Alfons Meindl, Christoph Engel, Joe Dennis, Chiu-Chen Tseng, Catriona McLean, Arja Jukkola-Vuorinen, Peter A. Fasching, Katharina Heusinger, Georgia Chenevix-Trench, Robert A.E.M. Tollenaar, Kyriaki Michailidou, Rita K. Schmutzler, Shivaani Mariapun, Silje Nord, Hiltrud Brauch, Peter Devilee, Isabel dos-Santos-Silva, Douglas F. Easton, Frederik Marmé, Vilde D. Haakensen, Wei-Yen Lim, Keith Humphreys, Siddhartha Kar, Anja Rudolph, Arto Mannermaa, Jan Lubinski, Anna González-Neira, Sara Margolin, Matthias W. Beckmann, Simon S. Cross, Anne Lise Børresen-Dale, Jonine D. Figueroa, Alison M. Dunning, Kenneth Muir, Sander Canisius, Jingmei Li, Carmel Apicella, Jyh-Cherng Yu, Gertraud Maskarinec, Roger L. Milne, Henrik Flyger, Irene L. Andrulis, Annika Lindblom, Sofia Khan, Diana Torres, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Surgery, Cardiothoracic Surgery, Pulmonary Medicine, Thompson, Deborah [0000-0003-1465-5799], Ghoussaini, Maya [0000-0002-2415-2143], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Genotype, Quantitative Trait Loci, Autophagy-Related Proteins, Estrogen receptor, Breast Neoplasms, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, White People, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Odds Ratio, medicine, Genetics, Humans, SNP, Genetics(clinical), Luciferases, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Chromosomes, Human, Pair 10, Haplotype, Age Factors, Chromosome Mapping, medicine.disease, 3. Good health, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, 030220 oncology & carcinogenesis, Trans-Activators, Regression Analysis, Female, Genome-Wide Association Study, Transcription Factors
Abstract

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Published
2015
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16. 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

17. INPP4B and RAD50 have an interactive effect on survival after breast cancer

Author

Sofia Khan, Xiaofeng Dai, Carl Blomqvist, Rainer Fagerholm, and Heli Nevanlinna

Subjects
Adult, Genome instability, Oncology, Cancer Research, medicine.medical_specialty, DNA Copy Number Variations, Transcription, Genetic, Receptor, ErbB-2, Genes, BRCA1, Breast Neoplasms, Disease, Biology, Bioinformatics, Breast cancer, Internal medicine, Databases, Genetic, Gene expression, medicine, Humans, PTEN, Gene, Aged, Proportional hazards model, Epistasis, Genetic, Middle Aged, Prognosis, medicine.disease, Phosphoric Monoester Hydrolases, Acid Anhydride Hydrolases, Tumor Burden, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, DNA Repair Enzymes, Receptors, Estrogen, Lymphatic Metastasis, Protein Biosynthesis, Rad50, biology.protein, Female, Receptors, Progesterone, Gene Deletion
Abstract

Genes sharing similar genomic landscape have the potential to interactively orchestrate certain clinicopathological features of a disease. Deletion of the RAD50 gene is a common event particularly in basal-like breast cancer, and often occurs together with deletions of BRCA1, RB1, TP53, PTEN, and INPP4B. In this study, we investigate whether these co-deleted genes have interactive effects on survival in breast cancer. Using publicly available TCGA data, we employed Cox’s proportional hazards models to test whether genomic deletions of these genes, or reduced protein or transcript levels associate with breast cancer patient survival in an interactive manner. Further validation was obtained at the transcriptional level by including 1,596 additional cases from 13 publicly available gene expression data sets from the KM-plotter database. Our results indicate that RAD50 and INPP4B associate interactively with breast cancer survival at the transcriptional, translational, and genomic levels in the TCGA data set (p(interaction) < 0.05). While neither of the genes was independently prognostic on its own, low INPP4B levels in combination with above median RAD50 abundance associated with increased hazard, both at the mRNA (HR 2.39, 95 % CI 1.20–4.76) and protein (HR 2.92, 95 % CI 1.42–6.00) levels, whereas concomitant deletion or low expression of both genes associated with unexpectedly improved survival. A similar pattern was observed in the KM-plotter data set (p(interaction) = 0.0067). We find that RAD50 and INPP4B expression levels have a synergistic influence on breast cancer survival, possibly through their effects on treatment response.

Published
2014

18. 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

19. Breast-Cancer Risk in Families with Mutations in PALB2

Author

Tuomas Heikkinen, Clare Turnbull, Penelope Miron, Deepak Subramanian, Florentia Fostira, Geoffrey J. Lindeman, Jeffrey N. Weitzel, Susan L. Neuhausen, Daniel Barrowdale, William D. Foulkes, Heli Nevanlinna, Sheila Seal, Katri Pylkäs, Paolo Radice, Andy C. H. Lee, Melissa C. Southey, Sofia Khan, Antonis C. Antoniou, Zhi Ling Teo, Carlo Tondini, Robert Winqvist, Marc Tischkowitz, Paolo Peterlongo, Jonathan Roberts, Douglas F. Easton, David E. Goldgar, Bruce Poppe, Nazneen Rahman, Patrick Concannon, Susan M. Domchek, Amanda E. Toland, Silvia Casadei, Paul A. James, Kristiina Aittomäki, Anne Kallioniemi, Drakoulis Yannoukakos, Mary Claire King, Irene L. Andrulis, Kim De Leeneer, Siranoush Manoukian, John L. Hopper, Jonine L. Bernstein, Fergus J. Couch, Eva Tomiak, Arto Mannermaa, Saundra S. Buys, Jukka S. Moilanen, and Kathleen Claes

Subjects
Pathology, endocrine system diseases, Receptor, ErbB-2, Genes, BRCA2, PALB2 Gene, 0302 clinical medicine, Family history, skin and connective tissue diseases, Sequence Deletion, Aged, 80 and over, 0303 health sciences, education.field_of_study, Obstetrics and Gynecology, Nuclear Proteins, General Medicine, Middle Aged, Penetrance, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Receptors, Progesterone, Fanconi Anemia Complementation Group N Protein, Adult, Risk, Heterozygote, medicine.medical_specialty, PALB2, Population, Breast Neoplasms, Single-nucleotide polymorphism, Article, 03 medical and health sciences, Breast cancer, Germline mutation, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, education, Gene, Germ-Line Mutation, Aged, 030304 developmental biology, business.industry, Tumor Suppressor Proteins, medicine.disease, Confidence interval, Cancer research, business, 030215 immunology
Abstract

Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown.We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation.The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P0.001) and by other familial factors (P=0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age.Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. (Funded by the European Research Council and others.).

Published
2014

20. Evaluation of the RHINO gene for breast cancer predisposition in Finnish breast cancer families

Author

Sara Vilske, Tuomas Heikkinen, Kristiina Aittomäki, Sofia Khan, Carl Blomqvist, Heli Nevanlinna, Elina Huovari, Johanna Schleutker, and Anne Kallioniemi

Subjects
Cancer Research, Candidate gene, Genotype, DNA repair, Population, Mutation, Missense, Breast Neoplasms, Locus (genetics), Single-nucleotide polymorphism, Biology, Breast cancer, medicine, Humans, Genetic Predisposition to Disease, education, Finland, Germ-Line Mutation, Genetics, education.field_of_study, DNA Repeat Expansion, Haplotype, medicine.disease, Oncology, Case-Control Studies, Female, Carrier Proteins, DNA Damage
Abstract

Hereditary predisposition to breast cancer is largely affected by the mutations in the genes of the DNA repair pathways. Novel genes involved in DNA repair are therefore prospective candidates also for breast cancer susceptibility genes. The RHINO (Rad9, Rad1, Hus1-interacting nuclear orphan) gene plays a central role in DNA damage response and in cell cycle regulation. RHINO interacts with Rad9-Rad1-Hus1 (9-1-1) complex and with ATR activator TopBP1, which recruit it to the site of DNA damage. We analyzed the effects of the germline variation in RHINO on breast cancer risk. We sequenced the coding region of the RHINO gene 466 index cases of Finnish breast cancer families and in 507 population controls. The genotypes of the most likely functional variant were further determined in a large dataset of 2,944 cases and 1,976 controls. We analyzed the common variation of the RHINO locus and determined the haplotypes using five SNPs in 1,531 cases and 1,233 controls. We identified seven variants including four missense variations, a 5′ UTR variant, a silent variant, and a nonsense variant c.250C>T, R84X (rs140887418). All variants were also present in control individuals with frequencies close to those of the cases (P > 0.05). The c.250C>T variant was present in 12 breast cancer patients (0.4 %) and of 16 controls (0.8 %) with the difference not statistically significant (OR = 0.50, 95 %CI: 0.24–1.06, P = 0.066). The haplotype frequencies did not differ in cases and controls (P = 0.59). Germline variation in the RHINO gene is unlikely to influence inherited susceptibility to breast cancer.

Published
2014

21. FANCM c.5101C > T mutation associates with breast cancer survival and treatment outcome

Author

Anne Kallioniemi, Anna Tervasmäki, Rainer Fagerholm, Jirina Bartkova, Johanna I. Kiiski, Maria Tengström, Kristiina Aittomäki, Tuomo Mantere, Veli-Matti Kosma, Carl Blomqvist, Maral Jamshidi, Liisa M. Pelttari, Katri Pylkäs, Sofia Khan, Heli Nevanlinna, Arto Mannermaa, Jiri Bartek, Robert Winqvist, Clinicum, Department of Obstetrics and Gynecology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, and HUS Gynecology and Obstetrics

Subjects
0301 basic medicine, Oncology, Cancer Research, Pathology, PROTEIN EXPRESSION, medicine.medical_treatment, Estrogen receptor, Kaplan-Meier Estimate, SUSCEPTIBILITY, FAMILIES, 0302 clinical medicine, FANCM, 3123 Gynaecology and paediatrics, Medicine, STALLED REPLICATION FORKS, Neoplasm Metastasis, Aged, 80 and over, Hazard ratio, Middle Aged, Prognosis, Combined Modality Therapy, 3. Good health, Phenotype, Treatment Outcome, TUMOR CHARACTERISTICS, 030220 oncology & carcinogenesis, Population Surveillance, Female, Adult, medicine.medical_specialty, Genotype, Nonsense mutation, 3122 Cancers, DNA repair, Breast Neoplasms, PARP-1, survival, Cancer Genetics and Epigenetics, 03 medical and health sciences, Young Adult, Breast cancer, breast cancer, Internal medicine, Biomarkers, Tumor, Humans, Point Mutation, BRCA2 MUTATIONS, ANEMIA, radiotherapy, Aged, Neoplasm Staging, Proportional Hazards Models, REPAIR, business.industry, Proportional hazards model, Point mutation, DNA Helicases, DNA, medicine.disease, Radiation therapy, 030104 developmental biology, Neoplasm Grading, business
Abstract

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple‐negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C > T mutation carriers and 3,832 non‐carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C > T mutation associated with poor 10‐year breast cancer‐specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09–2.52, p = 0.018), with a more pronounced survival effect among familial cases (HR = 2.93, 95% CI 1.5–5.76, p = 1.80 × 10−3). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR = 1.8, 95% CI 1.09–2.98, p = 0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR = 3.43, 95% CI 1.6–7.34, p = 1.50 × 10−3) but not among radiotherapy treated patients (HR = 1.35, 95% CI 0.82–2.23, p = 0.237). Significant interaction was found between the mutation and radiotherapy (p = 0.040). Immunohistochemical analyses show that c.5101C > T carriers have reduced PAR‐activity. Our results suggest that FANCM c.5101C > T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage., What's new? Variations in DNA repair genes can predispose individuals to breast cancer, with one example being FANCM c.5101C > T, a nonsense mutation in the Fanconi Anemia DNA repair pathway. In previous work, FANCM c.5101C > T was associated with increased breast cancer risk in the Finnish population. Here, the mutation is further shown to be associated with adverse breast cancer outcome. Mutation‐positive Finnish patients exhibited reduced long‐term survival and increased risk of disease recurrence. Survival was worse particularly for patients who were not treated with radiotherapy, indicating that FANCM c.5101C>T may interact with radiotherapy to improve disease outcome in mutation carriers.

Published
2016

22. Eukaryotic translation initiation factor 4E (eIF4E) expression is associated with breast cancer tumor phenotype and predicts survival after anthracycline chemotherapy treatment

Author

Olli Carpén, Carl Blomqvist, Päivi Heikkilä, Kristiina Aittomäki, Taina Korpela, Tuomas Heikkinen, Heli Nevanlinna, Sofia Khan, and Rainer Fagerholm

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Anthracycline, Breast Neoplasms, Triple Negative Breast Neoplasms, Kaplan-Meier Estimate, Biology, Metastasis, Breast cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Humans, Neoplasm Invasiveness, Doxorubicin, Cyclophosphamide, Epirubicin, Paraffin Embedding, Tissue microarray, Carcinoma, Hazard ratio, Cytarabine, Prognosis, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Eukaryotic Initiation Factor-4E, Phenotype, Treatment Outcome, Chemotherapy, Adjuvant, Tissue Array Analysis, Protein Biosynthesis, Cancer research, Female, Neoplasm Grading, medicine.drug
Abstract

Abnormal translation of mRNAs frequently occurring during carcinogenesis is among the mechanisms that can affect the expression of proteins involved in tumor development and progression. Eukaryotic initiation factor eIF4E is a key regulator of translation of many cancer-related transcripts and its expression is altered in various cancers and has been associated with worse survival. We determined the eIF4E protein levels using immunohistochemistry (IHC) in 1,233 breast tumors on tissue microarrays. We analyzed the effects of the IHC expression level on tumor characteristics and patient survival, also with stratification by adjuvant chemotherapy treatment. In 1,085 successfully stained tumors, high level of eIF4E protein expression was associated with features of aggressive tumor phenotype, namely grade, estrogen and progesterone receptor negativity, HER2 receptor positivity, and high expression of p53 and Ki67, and with triple negative subtype (p < 0.001). High eIF4E expression was associated with worse breast cancer-specific survival with a hazard ratio (HR) of 1.99 (95 % CI 1.32–3.00, p = 0.0008) and was in a multivariate analysis an independent prognostic factor. High eIF4E expression was associated with worse outcome also after detection of distant metastasis (HR = 1.88, 95 % CI 1.20–2.94, p = 0.0060). In the subgroup analysis the survival effect was strongest among patients treated with anthracycline chemotherapy (HR = 3.34, 95 % CI 1.72–6.48, p = 0.0002), whereas no such effect was seen among patients who had not received anthracycline with significant difference in heterogeneity between the two groups (p = 0.0358). High expression of eIF4E is associated with adverse tumor characteristics and predicts poor breast cancer-specific survival. This effect is emphasized in patients treated with anthracycline chemotherapy. eIF4E as a treatment predictive factor warrants further studies.

Published
2013

23. Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families

Author

Nasim Mavaddat, Carl Blomqvist, Liisa M. Pelttari, Andy C. H. Lee, Douglas F. Easton, Heli Nevanlinna, Rainer Fagerholm, Taru A. Muranen, Kristiina Aittomäki, Sofia Khan, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, HUS Gynecology and Obstetrics, Mavaddat, Nasim [0000-0003-0307-055X], Lee, Andrew [0000-0003-0677-0252], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Gerontology, Oncology, Multifactorial Inheritance, Cancer Research, Genotyping Techniques, LOCI, Disease, SUSCEPTIBILITY, PRS, Preclinical Study, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, HISTORY, Medicine, Family history, skin and connective tissue diseases, MUTATION, Finland, WOMEN, Pedigree, 3. Good health, Hereditary, 030220 oncology & carcinogenesis, Female, Algorithms, Risk, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Breast Neoplasms, 03 medical and health sciences, Internal medicine, Genetic variation, Humans, Genetic Predisposition to Disease, business.industry, Common variants, Case-control study, Genetic Variation, Odds ratio, medicine.disease, BRCA2, MODEL, 030104 developmental biology, Case-Control Studies, Polygenic risk score, business, Ovarian cancer
Abstract

The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on ~4000 additional individuals by comparing the affected to healthy family members, as well as in a case–control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26–1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case–control dataset (1.49 [1.38–1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment. Electronic supplementary material The online version of this article (doi:10.1007/s10549-016-3897-6) contains supplementary material, which is available to authorized users.

Published
2016

24. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author

Kenneth Offit, Hoda Anton-Culver, Ans M.W. van den Ouweland, Siranoush Manoukian, Christine L. Clarke, Kyriaki Michailidou, Antonis C. Antoniou, Maria Kabisch, Isabel dos-Santos-Silva, Douglas F. Easton, Curtis Olswold, Graham G. Giles, Tien Yin Wong, Ursula Eilber, Mads Thomassen, Christopher A. Haiman, Alice J. Sigurdson, Lothar Haeberle, Florence Menegaux, Ana Osorio, Marco Montagna, Katarzyna Jaworska-Bieniek, Eitan Friedman, Simon S. Cross, Daniel Barrowdale, Elinor J. Sawyer, Adam N. Freeman, Caroline Seynaeve, Min Hyuk Lee, Arnaud Droit, Per Hall, Minouk J. Schoemaker, Trinidad Caldés, Peter Hillemanns, Frederik Marmé, Jenny Lester, Michele M. Doody, Bernard Peissel, Peter Kraft, Elza Khusnutdinova, Anna H. Wu, Stéphanie Peeters, Georg Pfeiler, Pascal Guénel, Hidemi Ito, Xingyi Guo, Antoinette Hollestelle, Heli Nevanlinna, Kathleen Claes, Ylva Paulsson-Karlsson, Cecilia M. Dorfling, Roger L. Milne, Daehee Kang, Judith S. Brand, Diether Lambrechts, Olufunmilayo I. Olopade, Simona Agata, Saundra S. Buys, Muhammad Usman Rashid, Fabienne Lesueur, Alicia Beeghly-Fadiel, Peter Devilee, Manjeet K. Bolla, Natalia Antonenkova, Irene Konstantopoulou, Claudine Isaacs, Anja Rudolph, Carl Blomqvist, Tjoung Won Park-Simon, Judy Garber, Csilla Szabo, Francois Bacot, Arto Mannermaa, Yu-Tang Gao, Stig E. Bojesen, Susan L. Neuhausen, Marina Bermisheva, Qiuyin Cai, Zakaria Einbeigi, Christian F. Singer, Qin Wang, Kerstin Rhiem, Sofia Khan, Fiona Lalloo, Robert L. Nussbaum, Thilo Dörk, William J. Blot, Sylvie Mazoyer, Julia A. Knight, Katherine L. Nathanson, Clare Turnbull, Nazneen Rahman, Anne Lise Børresen-Dale, Chuen Neng Lee, Annegien Broeks, Martha J. Shrubsole, Ava Kwong, Jirong Long, Ian G. Campbell, Sara Margolin, Fergus J. Couch, Laima Tihomirova, Mary Beth Terry, Jenny Chang-Claude, Alice S. Whittemore, Joseph Vijai, Alfons Meindl, Xiao-Ou Shu, Shan Wang-Gohrke, Wei Zheng, Beth Y. Karlan, Jacques Simard, Angela Cox, Shahana Ahmed, Polly A. Newcomb, Ritu Salani, Chen-Yang Shen, Adalgeir Arason, Sandrine Tchatchou, Ute Hamann, Elizabeth J. van Rensburg, Michael Jones, Mark H. Greene, Anthony J. Swerdlow, Senno Verhoef, Jonine Figueroa, Hermann Brenner, Volker Arndt, Charles Joly Beauparlant, Esther M. John, Nadege Presneau, Jingmei Li, Laura Papi, Marjanka K. Schmidt, Montserrat Garcia-Closas, Uffe Birk Jensen, Georgia Chenevix-Trench, Paolo Peterlongo, Penny Soucy, Thomas Brüning, Jaana M. Hartikainen, Siddhartha Kar, Ji Yeob Choi, Manuel R. Teixeira, Phuong L. Mai, Alex Teulé, Jyh Cherng Yu, Paul Brennan, Maya Ghoussaini, Edith Olah, Henrik Flyger, Michael Friedlander, Soo Hwang Teo, Frans B. L. Hogervorst, Kathleen M. Egan, David J. Hunter, Kristiina Aittomäki, Joe Dennis, Anna González-Neira, Mikael Hartman, Alison M. Dunning, Doris Steinemann, Debra Frost, Melissa C. Southey, Ramunas Janavicius, Evgeny N. Imyanitov, Catherine M. Phelan, Amanda E. Toland, Anna Marie Mulligan, David ven den Berg, Rita K. Schmutzler, Julian Peto, Irene L. Andrulis, Chenjie Zeng, Kenneth Muir, Peter Schürmann, Saila Kauppila, Banu Arun, Jane Carpenter, Jeffrey N. Weitzel, Yael Laitman, Susan M. Domchek, Robert Winqvist, Caroline Baynes, Brita Arver, Marc Tischkowitz, Kamila Czene, Keitaro Matsuo, Barbara Burwinkel, Miriam Dwek, Kim De Leeneer, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Peter A. Fasching, Bernd Dworniczak, Susan J. Ramus, Lesley McGuffog, Andrea Gehrig, Michael J. Kerin, Thomas Hansen, Francesca Damiola, John L. Hopper, Loic Le Marchand, Peter J. Hulick, Annika Lindblom, Emily Hallberg, Miguel de la Hoya, Gaetana Gambino, Martine Dumont, Susan L. Slager, Bernardo Bonanni, Bent Ejlertsen, Norhashimah Hassan, Sue Healey, Orland Diez, Mary B. Daly, Carolyn B. Hendricks, Artitaya Lophatananon, Annelie Liljegren, Steven N. Hart, Jan Lubinski, Natalia Bogdanova, Drakoulis Yannoukakos, Steve Ellis, Silje Nord, Hiltrud Brauch, Gad Rennert, Conxi Lázaro, Daniel C. Tessier, Paolo Radice, Dominique Stoppa-Lyonnet, Nadine Tung, Andrew K. Godwin, Suleeporn Sangrajrang, Karoline Kuchenbaecker, Javier Benitez, Critical care, Anesthesiology, Peri-operative and Emergency medicine (CAPE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Fine-scale mapping, Genome-wide association study, HORMONE-RELATED PROTEIN, Epigenesis, Genetic, Breast cancer, Medizinische Fakultät, Databases, Genetic, Genotype, BRCA2 MUTATION CARRIERS, Odds Ratio, Medicine and Health Sciences, Pair 12, Medicine, Genetic risk factor, Promoter Regions, Genetic, Medicine(all), Genetics, BRCA1 Protein, PTHLH-CCDC91, Chromosome Mapping, LOCALIZATION, Single Nucleotide, PTHLH, 3. Good health, Enhancer Elements, Genetic, Population Surveillance, Female, Medical Genetics, BRAC1 mutation carriers, CCDC91, Alleles, Breast Neoplasms, Case-Control Studies, Computational Biology, European Continental Ancestry Group, Haplotypes, Heterozygote, Humans, Mutation, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Chromosomes, Human, Pair 12, Genetic Predisposition to Disease, Genome-Wide Association Study, Human, Research Article, EXPRESSION, Enhancer Elements, SUSCEPTIBILITY LOCI, 3122 Cancers, Single-nucleotide polymorphism, Chromosomes, White People, OVARIAN-CANCER, Càncer de mama, Promoter Regions, Databases, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Genetic, Journal Article, ddc:610, Polymorphism, GENOME-WIDE ASSOCIATION, Medicinsk genetik, Genetic association, Cancer och onkologi, business.industry, Haplotype, Case-control study, Biology and Life Sciences, Odds ratio, medicine.disease, ENHANCERS, 030104 developmental biology, Cancer and Oncology, METASTASIS, 3111 Biomedicine, GENETIC MODIFIERS, business, Genètica, Epigenesis
Abstract

Article, Background Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P, published version, peerReviewed

Published
2016

25. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author

Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, 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Subjects
0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund

Published
2016

26. RAD51B in Familial Breast Cancer

Author

kConFab, Jonine Figueroa, Elinor J. Sawyer, Manjeet K. Bolla, Carl Blomqvist, Jaana M. Hartikainen, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Fredrick Schumacher, Vessela N. Kristensen, Graham G. Giles, Isabel dos-Santos-Silva, Kamila Czene, Douglas F. Easton, Qin Wang, Javier Benitez, Janet E. Olson, Georgia Chenevix-Trench, John L. Hopper, Alicia Beeghly-Fadiel, Hoda Anton-Culver, Paolo Radice, Aocs Investigators, Nick Orr, Jacques Simard, Mervi Grip, Salla Ranta, Fergus J. Couch, Marjanka K. Schmidt, Kristiina Aittomäki, Caroline Seynaeve, Ute Hamann, Johanna Schleutker, Hilde Janssen, Robert Luben, Anna González-Neira, Peter A. Fasching, Pascal Guénel, Anja Rudolph, Arto Mannermaa, Melissa C. Southey, Ian Tomlinson, Thérèse Truong, Alison M. Dunning, Margriet Collée, Robert Winqvist, Johanna Mattson, Mikko Vuorela, Sara Vilske, Anne Lise Børresen-Dale, Johanna I. Kiiski, Paolo Peterlongo, Anna Jakubowska, Paul D.P. Pharoah, Alfons Meindl, Anthony J. Swerdlow, Roger L. Milne, Hermann Brenner, Joe Dennis, Montserrat Garcia-Closas, Thomas Brüning, Christopher A. Haiman, Martine Dumont, Wei Zheng, Per Hall, Gord Glendon, Jingmei Li, Laurien Van Dyck, Susan L. Neuhausen, Simon S. Cross, Irene L. Andrulis, Peter Devilee, Annika Lindblom, Emily Hallberg, Diana Torres, Sofia Khan, Kyriaki Michailidou, Rita K. Schmutzler, Julian Peto, Harald Surowy, Børge G. Nordestgaard, Barbara Burwinkel, Natalia Bogdanova, Drakoulis Yannoukakos, Heli Nevanlinna, Jan Lubinski, Liisa M. Pelttari, Efraim H. Rosenberg, Hiltrud Brauch, Thilo Dörk, Angela Cox, Viivi Nevanlinna, Maartje J. Hooning, Volker Arndt, Anne Kallioniemi, Stig E. Bojesen, Jenny Chang-Claude, Hatef Darabi, Obstetrics & Gynecology, Clinical Genetics, Gastroenterology & Hepatology, Medical Oncology, Brusgaard, Klaus, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, HUS Gynecology and Obstetrics, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Thierry, B, Zeps, N, Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Heredity, XRCC2, Genotyping Techniques, lcsh:Medicine, Genome-wide association study, 14Q24.1 RAD51L1, VARIANTS, Geographical Locations, 3123 Gynaecology and paediatrics, Cancer screening, Breast Tumors, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, Ethnicities, lcsh:Science, Finland, Genetics, RISK, education.field_of_study, Multidisciplinary, GERMLINE MUTATIONS, Genomics, Middle Aged, 3. Good health, Ovarian Cancer, Europe, DNA-Binding Proteins, Genetic Mapping, Male breast cancer, Female, Cancer Screening, Research Article, medicine.medical_specialty, Heterozygote, General Science & Technology, Population, 3122 Cancers, Mutation, Missense, Single-nucleotide polymorphism, Variant Genotypes, Breast Neoplasms, Genome Complexity, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Breast Cancer, medicine, Cancer Detection and Diagnosis, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Evolutionary Biology, Population Biology, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Odds ratio, medicine.disease, ta3122, GENE, Introns, 030104 developmental biology, Haplotypes, FANCONI-ANEMIA, People and Places, lcsh:Q, Population Groupings, business, Ovarian cancer, Gynecological Tumors, Population Genetics, Finns
Abstract

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk. ispartof: PLoS One vol:11 issue:5 ispartof: location:United States status: published

Published
2016

27. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Author

Stacey L. Edwards, Daniel Vincent, Antoinette Hollestelle, Melissa C. Southey, Thilo Dörk, Jonine Figueroa, Robert Winqvist, Wei Zheng, Keitaro Matsuo, Fergus J. Couch, Don M. Conroy, Anna Jakubowska, Paul D.P. Pharoah, Sara Margolin, Simon S. Cross, Joe Dennis, Rebecca Mayes, Annegien Broeks, Mitul Shah, Matthias W. Beckmann, Mahdi Moradi Marjaneh, Pei-Ei Wu, Javier Benitez, Hanna Fues Wahl, Ute Hamann, Rita K. Schmutzler, Guillermo Pita, Nichola Johnson, Suleeporn Sangrajrang, James McKay, Barbara Burwinkel, Hoda Anton-Culver, Pascal Guénel, Douglas F. Easton, Veli-Matti Kosma, Hidemi Ito, Angela Cox, Georgia Chenevix-Trench, M. Rosario Alonso, Mark S. Goldberg, Hatef Darabi, Volker Arndt, Qin Wang, Manjeet K. Bolla, Nick Orr, Soo Hwang Teo, Soo-Chin Lee, Penny Soucy, Jonathan Beesley, Paolo Peterlongo, Ji Yeob Choi, Anthony J. Swerdlow, Jacques Simard, Kamila Czene, Anna González-Neira, Jenny Chang-Claude, Heli Nevanlinna, Ian Tomlinson, Thérèse Truong, Chen-Yang Shen, Harald Surowy, Henrik Flyger, Marjanka K. Schmidt, Graham G. Giles, John L. Hopper, Celine M. Vachon, Olivia Fletcher, Stig E. Bojesen, Mikael Hartman, Arnaud Droit, Per Hall, Cheng Har Yip, Maya Ghoussaini, Artitaya Lophatananon, Mieke Kriege, Anna H. Wu, Siranoush Manoukian, Kyriaki Michailidou, Christopher A. Haiman, Roger L. Milne, Xiao-Ou Shu, Daniel O. Stram, Katri Pylkäs, Sofia Khan, Irene L. Andrulis, Annika Lindblom, Emily Hallberg, Diana Torres, Anja Rudolph, Arto Mannermaa, Hermann Brenner, Vessela N. Kristensen, Daehee Kang, Caroline Seynaeve, Elinor J. Sawyer, Silje Nord, Hiltrud Brauch, Jan Lubinski, Natalia Bogdanova, Juliet D. French, Susan L. Neuhausen, Montserrat Garcia-Closas, Thomas Brüning, Loic Le Marchand, Peter A. Fasching, Diether Lambrechts, Daniel C. Tessier, Peter Devilee, Eva Galle, Alfons Meindl, Alison M. Dunning, Siddhartha Kar, Kenneth Muir, Curtis Olswold, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Department of Obstetrics and Gynecology, Clinicum, School of Medicine / Clinical Medicine, Cancer Research UK (Reino Unido), European Research Council, NIH - National Cancer Institute (NCI) (Estados Unidos), Post-cancer GWAS Initiative, Dutch Cancer Society (Holanda), Biobanking and BioMolecular resources Research Infrastructure (Países Bajos), Instituto de Salud Carlos III, Finlands Akademi (Finlandia), 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, Stichting tegen Kanker, Deutsche Krebshilfe, National Health and Medical Research Council (Australia), Ministry of Economic Development, Innovation and Export Trade, Ministry of Higher Education (Malasia), Agency for Science, Technology and Research (Singapur), National Medical Research Council (Singapur), The Research Council of Norway, Southern and Eastern Norway Regional Health Authority, Finnish Cancer (Center of Excellence grant), Genetic Associations and Mechanisms in Oncology (GAME-ON) Initiative, Yorkshire Cancer Research, BRL (Basic Research Laboratory) program through the National Research Foundation of Korea - Ministry of Education, Science and Technology, NIH - National Cancer Institute (NCI). Specialized Programs of Research Excellence (SPOREs) (Estados Unidos), Hellenic Cooperative Oncology Group research grant, Institute of Cancer Research (Reino Unido), United States of Department of Health & Human Services, Medical Oncology, and Obstetrics & Gynecology

Subjects
0301 basic medicine, Vesicular Transport Proteins, Genome-wide association study, 0302 clinical medicine, Breast cancer, Genetics research, Medicine and Health Sciences, HUMAN GENOME, Genetics, Multidisciplinary, Chromosome Mapping, ASSOCIATION, Tag SNP, 3. Good health, 030220 oncology & carcinogenesis, Female, EXPRESSION, SUSCEPTIBILITY LOCI, Genotype, European Continental Ancestry Group, 3122 Cancers, Quantitative Trait Loci, Locus (genetics), Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, White People, REGION, RC0254, 03 medical and health sciences, SDG 3 - Good Health and Well-being, REVEALS, medicine, SNP, Humans, Genetic Predisposition to Disease, FUNCTIONAL VARIANTS, Genetic association, RISK LOCUS, CONSORTIUM, medicine.disease, ENHANCERS, 030104 developmental biology, Risk factors, Imputation (genetics), Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus., published version, peerReviewed

Published
2016
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28. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Author

Melissa C. Southey, Daniel Klevebring, Robert Winqvist, Irene L. Andrulis, Keitaro Matsuo, Anna Jakubowska, Susan L. Neuhausen, Paul D.P. Pharoah, Natalia Bogdanova, Lisa B. Signorello, Annika Lindblom, Kamila Czene, Drakoulis Yannoukakos, Caroline Seynaeve, Asaf Wyszynski, Michael D. Cole, John L. Hopper, kConFab Investigators, Elinor J. Sawyer, Qin Wang, Vessela N. Kristensen, Hidemi Ito, Paolo Radice, Daehee Kang, Sara Margolin, Hermann Brenner, Annegien Broeks, William J. Blot, Yu-Tang Gao, Mitul Shah, Matthias W. Beckmann, Wei Zheng, Brian E. Henderson, Peter Devilee, Javier Benitez, David Van Den Berg, Christopher A. Haiman, Thilo Dörk, Hatef Darabi, Ans M.W. van den Ouweland, Alfons Meindl, Frederik Marmé, Jacques Simard, Isabel dos-Santos-Silva, Jan Lubinski, Pei-Ei Wu, Veli-Matti Kosma, Katri Pylkäs, Mikael Hartman, Soo-Hwang Teo, Tien Yin Wong, Suleeporn Sangrajrang, Paolo Peterlongo, Douglas F. Easton, James McKay, Fergus J. Couch, Angela Cox, Maartje J. Hooning, Ji Yeob Choi, Anja Rudolph, Arto Mannermaa, Anna H. Wu, Ute Hamann, Montserrat Garcia-Closas, Christine B. Ambrosone, Janet E. Olson, Hiltrud Brauch, Rita K. Schmutzler, Julian Peto, Manjeet K. Bolla, Alison M. Dunning, Heli Nevanlinna, Børge G. Nordestgaard, Hui Miao, Yali Zhang, Kenneth Muir, Barbara Burwinkel, Nick Orr, Aida Karina Dieffenbach, Marjanka K. Schmidt, Jirong Long, Martine Dumont, Jenny Chang-Claude, Kristin Lam, Chen-Yang Shen, Anthony J. Swerdlow, Chi-Chen Hong, Peter A. Fasching, Stig E. Bojesen, Diether Lambrechts, Xiao-Ou Shu, Graham G. Giles, Christopher I. Amos, Joe Dennis, Hans Wildiers, Christian Lytle, Sofia Khan, Pascal Guénel, Elisa V. Bandera, Artitaya Lophatananon, Georgia Chenevix-Trench, Kyriaki Michailidou, Song Yao, Roger L. Milne, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Per Hall, Jonine D. Figueroa, Julia A. Knight, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Wang, Jean [0000-0002-9139-0627], Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Adult, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Breast cancer, SDG 3 - Good Health and Well-being, Genotype, Genetics, medicine, Medicine and Health Sciences, Humans, Genetic Predisposition to Disease, Copy-number variation, Enhancer, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), Genetic association, Aged, Sequence Deletion, Association Studies Articles, Case-control study, General Medicine, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Enhancer Elements, Genetic, Case-Control Studies, Chromosomes, Human, Pair 2, MCF-7 Cells, Female, Carrier Proteins, Insulin-Like Growth Factor Binding Protein 5
Abstract

Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

Published
2016

29. Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Author

Martine Tranchant, Fergus J. Couch, Meeri Otsukka, Sabine Behrens, Jirong Long, Nadia Obi, Kamila Czene, John L. Hopper, Heather Thorne, Robert Pilarski, Anja Rudolph, Simon S. Cross, Volker Harth, Gabrielle Colleran, Hatef Darabi, Thomas Van Brussel, Eunjung Lee, Anne Lotz, E. Krol-Warmerdam, M. Pilar Zamora, Qin Wang, Andy C. H. Lee, Annie Fung, Kara Sargus, Melissa C. Southey, Katja Butterbach, Nuria Álvarez, Francois Bacot, Jeffrey G. Meyer, Ian W. Brock, Jessica Clague De Hart, Pierre Laurent-Puig, Irene L. Andrulis, Pei Chao, Arnaud Droit, Per Hall, Daniel C. Tessier, Paolo Radice, Frederic Robidoux, Don M. Conroy, Irja Erkkilä, Daniel Vincent, Antoinette Hollestelle, Christopher A. Hilker, Alicia Beeghly-Fadiel, Muhabbet Celik, Peggy Reynolds, Caroline Baynes, Sophia S. Wang, Katri Pylkäs, Kang In Nee, Robert Winqvist, Henrik Flyger, Annette Heemskerk, Sara Margolin, Hui Cai, Julie M. Cunningham, Prat Boonyawongviroj, Bernardo Bonanni, Anthony J. Swerdlow, Dan Connley, Huiyan Ma, Valerie Gaborieau, David O. Nelson, Keitaro Matsuo, Sylvie La Boissière, Pornthep Siriwanarungsan, Hidemi Ito, Ursula Eilber, Matthias W. Beckmann, Sylvia Rabstein, Natalia Bogdanova, Anna Jakubowska, Yves Raoul, Robert A.E.M. Tollenaar, Frans B. L. Hogervorst, Hannah L Park, Pierre Kerbrat, Ying Zheng, Paul D.P. Pharoah, Wanqing Wen, Judith Heinz, Annika Lindblom, Christa Stegmaier, Manjeet K. Bolla, Loris Bernard, Anna H. Wu, Alison M. Dunning, Hermann Brenner, A. Green, Thilo Dörk, Chia-Ni Hsiung, Dennis Deapen, Michael G. Schrauder, Gilian Peuteman, S.E. Higham, Sabapathy P. Balasubramanian, Irene Feroce, Christina Justenhoven, Angela Jones, William J. Blot, Nichola Johnson, Petra Seibold, D. Bowtell, Jiajun Shi, Wei Zheng, U Hamann, Pascal Guenel, P. Webb, Soo Hwang Teo, Daniela Zaffaroni, J. Blom, Rita K. Schmutzler, Douglas F. Easton, Yani Lu, Witold Zatonski, Phuah Sze Yee, Susan L. Neuhausen, Kenneth Muir, Sofia Khan, Daehee Kang, Silke Landrith, Helena Kemiläinen, Maggie Angelakos, Rich Pinder, Javier Benitez, Til Olchers, Senno Verhoef, Fred Schumacher, Martha J. Shrubsole, Teresa Selander, Teh Yew Ching, Christof Sohn, Patrick Arveux, Dorota M. Gertig, Saila Kauppila, Mervi Grip, Florentia Fostira, Jenny Chang-Claude, Michael Stagner, Kathleen Corthouts, Ellen Van Der Schoot, H Nevanlinna, Peter Bugert, Christian Baisch, Eija Myöhänen, Sonja Wolf, Hoda Anton-Culver, Nicola Miller, Cheng Har Yip, Neonila Szeszenia-Dabrowska, Nicholas K. Hayward, Dieter Flesch-Janys, Barbara Burwinkel, J. Molenaar, Eileen Williams, Marjanka K. Schmidt, Yon Ko, Anja Nieuwlaat, Chen-Yang Shen, Veli-Matti Kosma, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Artitaya Lophatananon, Mikael Hartman, Jonathan Beesley, Bernard Peissel, Paolo Peterlongo, Ji Yeob Choi, Craig Luccarini, Rosalind A. Eeles, Niall M. McInerney, Bernard Thienpont, Xiao-Ou Shu, Léa Héguy, Maya Ghoussaini, Sander Canisius, Wing-Yee Lo, Suleeporn Sangrajrang, Nur Aishah Taib, June Yashiki, Kirsimari Aaltonen, Louise A. Brinton, Elinor J. Sawyer, Alina Vrieling, Angela Cox, Frederik Marmé, Matthias Rübner, Graham G. Giles, Sonja Oeser, Hans Christiansen, Andrew Rowan, Ed Dicks, Andeas Schneeweiß, Catriona McLean, Antonis C. Antoniou, B. Pesch, Eveline Niedermayr, Volker Arndt, Janet E. Olson, Dominiek Smeets, Jingmei Li, Georgia Chenevix-Trench, Claire Mulot, Siranoush Manoukian, Hans Fischer, Ellen Crepin, Arto Mannermaa, Ali Amin Al Olama, Helen Cramp, Ans M.W. van den Ouweland, Olivia Fletcher, Sharon A. Windebank, Peter Hillemanns, Nayana Weerasooriya, James V. Lacey, Leslie Bernstein, Romuald Le Scodan, Giulietta Scuvera, P. Parsons, Thomas C. Putti, Elaine Ryder-Mills, Sara Benlloch, Beata Peplonska, Stig E. Bojesen, Kimberley Chua, Stefan Nickels, Nick Orr, Roger L. Milne, Tuomas Heikkinen, Christopher A. Haiman, Natalia Antonenkova, Volker Hermann, Maria Kabisch, Kenneth Offit, Julia A. Knight, Angela Maniscalco, Arja Jukkola-Vuorinen, Hartwig Ziegler, Chenjie Zeng, Jacques Simard, Pamela L. Horn-Ross, Daphne S.C. Lee, Xingyi Guo, Jan Lubinski, Michael J. Kerin, Loic Le Marchand, Sune F. Nielsen, Peter Devilee, A. De Fazio, Qiuyin Cai, Annie Turgeon, Yoon Sook-Yee, Silje Nord, Petra Bos, Hiltrud Brauch, Kyriaki Michailidou, Shivaani Mariapun, Kari Mononen, Alfons Meindl, Peter B. Kang, Siddhartha Kar, Alessandra Rossi, G. Chenevix-Trench, Diether Lambrechts, Karl von Smitten, Zsofia Kote-Jarai, Emiel J. Th. Rutgers, Chiu-Chen Tseng, Peter A. Fasching, Lesley McGuffog, Annegien Broekss, Johann H. Karstens, Montserrat Garcia-Closas, Thomas Brüning, David C. Whiteman, Judi Maskiell, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Obstetrics & Gynecology

Subjects
Genetic Markers, Linkage disequilibrium, Epidemiology, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics, Molecular epidemiology, Case-control study, Chromosome Mapping, medicine.disease, Logistic Models, Oncology, Genetic marker, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 4, Genome-Wide Association Study
Abstract

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

Published
2015

30. Screening of HELQ in breast and ovarian cancer families

Author

Kristiina Aittomäki, Laura Kinnunen, Carl Blomqvist, Johanna I. Kiiski, Liisa M. Pelttari, Sofia Khan, Heli Nevanlinna, Department of Obstetrics and Gynecology, Clinicum, Department of Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Research Programs Unit, and HUS Gynecology and Obstetrics

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Population, 3122 Cancers, LOCI, DNA repair, Breast Neoplasms, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, XRCC2, 03 medical and health sciences, Breast cancer, Ovarian cancer, Internal medicine, Genetics, medicine, TUMORIGENESIS, Humans, BRCA2 MUTATIONS, Genetic Predisposition to Disease, education, Genetics (clinical), Finland, REPAIR, RISK, Ovarian Neoplasms, education.field_of_study, Haplotype, DNA Helicases, Cancer, medicine.disease, 3. Good health, 030104 developmental biology, SUSCEPTIBILITY GENE, Haplotypes, RAD51C, HELQ, RAD51 PARALOGS, Female, Carcinogenesis
Abstract

Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk. To investigate the role of HELQ in cancer predisposition, we screened the gene for germline variation in 185 Finnish breast or ovarian cancer families and performed haplotype analyses for 1517 breast cancer cases, 308 ovarian cancer cases, and 1234 population controls using five common polymorphisms at the HELQ gene locus. No truncating mutations were identified among the families. One putatively pathogenic missense mutation c.1309A > G was identified but no additional carriers were observed in the subsequent genotyping of 332 familial breast or ovarian cancer patients. Furthermore, the haplotype distribution did not differ between breast or ovarian cancer cases and population controls. Our results indicate that HELQ is not a major breast and ovarian cancer susceptibility gene in the Finnish population. However, we cannot rule out rare risk-variants in the Finnish or other populations and larger datasets are needed to further assess the role of HELQ especially in ovarian cancer predisposition.

Published
2015

31. The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

Author

Douglas F. Easton, William J. Tapper, Robert Luben, Georgia Chenevix-Trench, Jianjun Liu, Melissa C. Southey, Vesa Kataja, Renske Keeman, Diana Eccles, Hans Wildiers, Rainer Fagerholm, Paul D.P. Pharoah, Sara Margolin, Mitul Shah, Diether Lambrechts, Irene L. Andrulis, Agnes Jager, Kristiina Aittomäki, Dario Greco, Annika Lindblom, Per Hall, Arto Mannermaa, Christian R. Loehberg, Barbara Perkins, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Sajjad Rafiq, Marjanka K. Schmidt, Wolfgang Janni, Janet E. Olson, Sofia Khan, Heli Nevanlinna, Peter A. Fasching, Richard M. Weinshilboum, Kamila Czene, Maartje J. Hooning, Montserrat Garcia-Closas, John L. Hopper, kConFab Investigators, Fergus J. Couch, Maria Kabisch, Ute Hamann, Tuomas Heikkinen, Taru A. Muranen, Jenny Chang-Claude, Carl Blomqvist, Clinicum, Department of Obstetrics and Gynecology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Lauri Antti Aaltonen / Principal Investigator, Department of Oncology, HUS Gynecology and Obstetrics, Obstetrics & Gynecology, and Medical Oncology

Subjects
Oncology, PROGNOSIS, medicine.medical_treatment, SUSCEPTIBILITY, Bioinformatics, chemotherapy, Deoxycytidine, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Genotype, Antineoplastic Combined Chemotherapy Protocols, Anthracyclines, Aged, 80 and over, 0303 health sciences, OUTCOMES, Middle Aged, 3. Good health, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Taxoids, cell cycle, ESTROGEN-RECEPTOR-ALPHA, Adult, EXPRESSION, medicine.medical_specialty, LARGE GENE LISTS, Anthracycline, Quantitative Trait Loci, 3122 Cancers, SNP, Single-nucleotide polymorphism, Breast Neoplasms, CELL-LINES, Polymorphism, Single Nucleotide, survival, 03 medical and health sciences, Young Adult, Breast cancer, breast cancer, LUNG-CANCER, SDG 3 - Good Health and Well-being, Internal medicine, REVEALS, medicine, Humans, BRCA2 MUTATIONS, Lung cancer, Survival analysis, 030304 developmental biology, Aged, Chemotherapy, business.industry, medicine.disease, Survival Analysis, Gemcitabine, Multivariate Analysis, business, Genome-Wide Association Study, Priority Research Paper
Abstract

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway. ispartof: Oncotarget vol:6 issue:10 pages:7390-407 ispartof: location:United States status: published

Published
2015

32. Abstract 1322: A meta-analysis of genome-wide association studies identifies novel loci that influence breast cancer prognosis

Author

Andrew Collins, Heli Nevanlinna, Carl Bloomqvist, Lorraine Durcan, Jianjun Liu, John L. Hopper, Dianna Eccles, Peter A. Fasching, Fergus J. Couch, Sofia Khan, Latha Kadalayil, William J. Tapper, and Tom Maishman

Subjects
Cancer Research, Breast cancer, Oncology, Meta-analysis, medicine, Genome-wide association study, Computational biology, Biology, medicine.disease
Abstract

Familial studies were among the first to indicate that breast cancer prognosis has a heritable component. Subsequently many variants associated with prognosis have been identified using a range of techniques including genome-wide association studies (GWAs). Despite these advances, much of the heritability remains unexplained. In young women, breast cancer is characterised by a higher incidence of adverse pathological features, unique tumour gene expression profiles and worse survival. In addition, the association of risk with conventional epidemiological exposures is less clear in women with early onset. We hypothesise that some of these difference between early and late onset could be influenced by germline variation. To identify additional variants that influence breast cancer prognosis we conducted a two stage meta-analysis of four GWAs consisting of 6,042 patients from the UK (POSH), Finland (HEBCS), Germany (SUCCESS-A) and Australia (ABCFS). Cox-regression analyses were used to investigate overall survival (OS, n=1,101 events) and disease-free survival (DFS, n=1,316 events) with correction for oestrogen status (ER). These survival analyses were repeated in a subset of patients with early onset (aged ≤40 at diagnosis, n=2,315 patients, OS n=604 events, DFS n=716 events). Meta-analysis identified two intronic SNPs in ADAMTSL1 that were associated exclusively with early onset DFS, rs715212 (Pmeta=3.54x10-5) and rs10963755 (Pmeta=3.91x10-4) without heterogeneity between cohorts. Multivariable Cox-regression demonstrated that the effect of these SNPs were independent of the classical prognostic factors. Most importantly, rs715212 reached genome-wide significance (Pmultivariate=5.37x10-8) in the multivariate model. ADAMTSL1 encodes a glycoprotein that forms part of the extracellular matrix (ECM) and may function in cell-cell or cell-matrix interactions or may regulate other ADAMTS proteases. Previous studies have shown that ADAMTSL1 is hypermethylated in ER positive breast cancer tumours. Using GTEx to perform eQTL analysis, we found that rs715212 is associated with the expression of several biologically relevant genes AREG (P=0.035), TNF (P=0.015), FASLG (P=0.0031) and EGF (P=0.0018) in breast mammary tissue. Interestingly, separate studies have shown that AREG is overexpressed in ER-positive breast tumours from pre-menopausal women versus post-menopausal women. Furthermore, AREG is differentially expressed between parous and non-parous mammary glands and is persistently downregulated by parity, which suggests it may contribute to the susceptibility of the nulliparous gland to breast cancer. We conclude that rs715212 is associated with an increased risk of disease progression in patients with early onset and speculate that this could be due to an interaction with the expression of AREG. Note: This abstract was not presented at the meeting. Citation Format: Latha Kadalayil, Sofia Khan, Heli Nevanlinna, Peter A. Fasching, Fergus J. Couch, John Hopper, Jianjun Liu, Tom Maishman, Lorraine Durcan, Carl Bloomqvist, Andy Collins, Dianna Eccles, William Tapper. A meta-analysis of genome-wide association studies identifies novel loci that influence breast cancer prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1322. doi:10.1158/1538-7445.AM2017-1322

Published
2017

33. Abstract P6-04-01: Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy

Author

Killian P. O’Brien, Doireann P. Joyce, Kerry Thompson, Peter Dockery, M.J. Kerin, Pierce Lalor, Helen Ingoldsby, Sofia Khan, and Roisin M. Dwyer

Subjects
0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Stromal cell, business.industry, Mesenchymal stem cell, Cell, Cancer, medicine.disease, Microvesicles, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Breast cancer, Oncology, Downregulation and upregulation, microRNA, medicine, Cancer research, business
Abstract

Introduction: Mesenchymal Stem Cells(MSCs) are multipotent stromal cells that are known to engraft into tumours, raising their potential as tumour-targeted delivery vehicles. MSCs secrete tiny vesicles known as exosomes, which contain genetic material including microRNAs, and are effectively taken up by recipient cells. This study aimed to characterise a tumour-suppressing microRNA, miR-379, and engineer MSCs to secrete exosomes enriched with the microRNA. Methods: The mechanism of action of miR-379 In Vivo was determined through lentivirus-mediated upregulation of miR-379 in breast tumours, and analysis of changes in tumour angiogenesis, proliferation and progression. Subsequently, MSCs were engineered with lenti-379 and any impact on MSC migration, proliferation and morphology was assessed. MSC-secreted exosomes were isolated and characterised using Transmission Electron Microscopy(TEM) and Western Blot. The exosomal microRNA content was analysed by RQ-PCR, and transfer between cell populations visualised using confocal microscopy. Results: While elevated miR-379 expression did not impact tumour size In Vivo, an increase in tumour necrosis and decrease in invasion was observed. MSCs were successfully transduced with miR-379, resulting in a distinct change in cell morphology. Despite this, MSC-379 cells maintained inherent tumour-targeted migratory capacity, with no impact on proliferation observed. MSC-379 derived exosomes were 30-120nm in size and expressed the exosome-associated protein CD63. A 5-fold increase in miR-379 was observed in engineered exosomes. Successful transfer of RFP-labelled MSC-derived exosomes to breast cancer cells was visualised using confocal microscopy. Conclusion: Engineering tumour-targeted MSCs to secrete exosomes enriched with miR-379 holds exciting potential as a novel therapy for breast cancer. Citation Format: O'Brien KP, Khan S, Thompson K, Joyce D, Lalor P, Dockery P, Ingoldsby H, Kerin MJ, Dwyer RM. Engineering mesenchymal stem cells(MSCs) to secrete tumour-suppressing exosomes for breast cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-04-01.

Published
2017

34. Identification of inherited genetic variations influencing prognosis in early-onset breast cancer

Author

Jianjun Liu, Fergus J. Couch, Sofia Khan, Andrew Collins, Diana Eccles, Sue Gerty, William J. Tapper, Sajjad Rafiq, Carl Blomqvist, Ioannis Politopoulos, and Heli Nevanlinna

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, Genome-wide association study, Single-nucleotide polymorphism, Breast Neoplasms, Polymorphism, Single Nucleotide, Article, Breast cancer, Internal medicine, Genotype, Medicine, SNP, Humans, Genetic Predisposition to Disease, Age of Onset, Prospective cohort study, Genetic association, business.industry, Genetic Variation, medicine.disease, Prognosis, Female, Age of onset, business
Abstract

Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10−7 was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ≤ 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33–1.96; P = 9.5 × 10−7]. Four further associations at or close to the PBX1, RORα, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10−6). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10−4 and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis. Cancer Res; 73(6); 1883–91. ©2012 AACR.

Published
2013

35. 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

36. Impact of Aspirin on factors associated with breast cancer lymph node metastasis

Author

K. Gilligan, T.I. Barron, B. Moloney, Annette T. Byrne, M.J. Kerin, K. Bennett, K. O’Brien, E. Ramphul, I.S. Miller, Roisin M. Dwyer, and Sofia Khan

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Aspirin, Breast cancer, business.industry, Internal medicine, Medicine, Lymph node metastasis, business, medicine.disease, medicine.drug
Published
2016

37. Abstract 3274: SNP-SNP interaction analyses of NQO1 and NF-κB signaling pathway genes on breast cancer survival and treatment outcome

Author

Carl Blomqvist, Maral Jamshidi, Marjanka K. Schmidt, Heli Nevanlinna, Sofia Khan, Kristiina Aittomäki, and Rainer Fagerholm

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, Anthracycline, business.industry, medicine.medical_treatment, Cancer, Single-nucleotide polymorphism, medicine.disease_cause, medicine.disease, Bioinformatics, Breast cancer, Internal medicine, medicine, Carcinogenesis, Breast carcinoma, business, Genotyping
Abstract

To improve individualized therapy, new prognostic and predictive markers are needed to identify patients with expected poor breast cancer outcome and patients who profit most from a given treatment. NF-κB pathway plays a pervasive role in the pathogenesis of cancer through its implication in distinct hallmarks of tumorigenesis. Previous studies have indicated the role of NF-κB transcription factor in promoting cell survival and resistance to chemotherapy in breast carcinoma. We have previously found that NQO1-rs1800566 predicts poor survival among breast cancer patients, particularly after anthracycline-based adjuvant chemotherapy and in patients with p53-aberrant tumors. We have also reported the inverse relationship between NQO1 protein expression and NF-κB activation. We have here analyzed the interaction of SNPs residing within the NF-κB signaling pathway genes, and NQO1-rs6499255 (tagging NQO1-rs1800566 with r2> 0.90) on breast cancer patient survival and treatment outcome. The panel of markers included the NF-κB pathway SNPs available in a custom Illumina iSelect genotyping array designed for Collaborative Oncological Gene-Environment Study (iCOGS) as well as NQO1-rs6499255. For the SNP-SNP interaction analysis on patient survival we conducted a likelihood ratio test that compares Cox's regression model with and without an interaction term to evaluate whether the interaction model is a better fit for the prognostic data. The results obtained from this study will be reported. Identification of interactive SNPs/genes contribute to the elucidation of the mechanisms underlying complex diseases such as breast cancer. Citation Format: Maral Jamshidi, Rainer Fagerholm, Sofia Khan, Kristiina Aittomäki, Carl Blomqvist, Marjanka K. Schmidt, Heli Nevanlinna, BCAC: Breast Cancer Association Consortium. SNP-SNP interaction analyses of NQO1 and NF-κB signaling pathway genes on breast cancer survival and treatment outcome. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3274. doi:10.1158/1538-7445.AM2014-3274

Published
2014

39. TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer

Author

Manjeet K. Bolla, Carl Blomqvist, Qin Wang, Qi Guo, Melissa C. Southey, Giuseppe Floris, Kristiina Aittomäki, Joe Dennis, Douglas F. Easton, Peter A. Fasching, Sofia Khan, Jenny Chang-Claude, Paul D.P. Pharoah, Jonathan Beesley, Rainer Fagerholm, Diether Lambrechts, Alison M. Dunning, Jianjun Liu, Fiona M. Blows, Päivi Heikkilä, Jonine D. Figueroa, Sabine Behrens, kConFab, Montserrat Garcia-Closas, Irene L. Andrulis, Bernd Holleczek, Aocs Investigators, Maral Jamshidi, Elena Provenzano, Fergus J. Couch, Jani Saarela, Ute Hamann, Michael Lush, Agnes Jager, Renske Keeman, Gord Glendon, Veli-Matti Kosma, Emily Hallberg, Annika Lindblom, Kamila Czene, Matthias W. Beckmann, John L. Hopper, H. Raza Ali, Heli Nevanlinna, Chenevix-Trench G, Maria Kabisch, Arto Mannermaa, Hermann Brenner, Maartje J. Hooning, Marjanka K. Schmidt, Per Hall, Mitul Shah, Sara Margolin, Kyriaki Michailidou, Medical Oncology, School of Medicine / Clinical Medicine, Ali, Raza [0000-0001-7587-0906], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
Adult, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Anthracycline, Quantitative Trait Loci, SNP, Estrogen receptor, Breast Neoplasms, Single-nucleotide polymorphism, Gene mutation, anthracycline, Bioinformatics, Polymorphism, Single Nucleotide, survival, Young Adult, 03 medical and health sciences, breast cancer, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Journal Article, Humans, Anthracyclines, TP53, Survival analysis, Aged, Aged, 80 and over, SKP Cullin F-Box Protein Ligases, Predictive marker, business.industry, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Treatment Outcome, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, business, Research Paper
Abstract

TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes. In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines. If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer., published version, peerReviewed

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40. COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration

Author

Douglas F. Easton, Olga M. Sinilnikova, Jacques Simard, Rosa B. Barkardottir, Mads Thomassen, Bing Jian Feng, Anders Kvist, Thomas Hansen, Francesca Damiola, Javier Benitez, Therese Törngren, Daniel J. Park, Inge Søkilde Pedersen, Jirong Long, Penny Soucy, Rita K. Schmutzler, Sofia Khan, Jeffrey N. Weitzel, Katherine L. Nathanson, Paolo Radice, Ian G. Campbell, Michael R. Dufault, Susan L. Neuhausen, Georgia Chenevix-Trench, T. L. Chris Chan, Paolo Peterlongo, Eric Hahnen, Heli Nevanlinna, San Ming Wang, Sylvie Mazoyer, David J. Hunter, Sean V. Tavtigian, Fabienne Lesueur, Peter Devilee, Yu-Tang Gao, Ava Kwong, Fergus J. Couch, Alfons Meindl, Wei Zheng, Lars Jønson, Martine Dumont, Carrie Snyder, Ella R. Thompson, Kasmintan A. Schrader, Melissa C. Southey, David E. Goldgar, Alison H. Trainer, S. Lindstrom, Mark E. Robson, Florentine Hilbers, Yeong C. Kim, Kenneth Offit, Susan J. Ramus, Tu Nguyen-Dumont, Peter Kraft, Henry T. Lynch, and Vijai Joseph

Subjects
Candidate gene, Letter, Positional cloning, Genetic Linkage, Genome-wide association study, Breast Neoplasms, Biology, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Missing heritability problem, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Exome, 030304 developmental biology, Genetics, 0303 health sciences, Massive parallel sequencing, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Cancer and Oncology, Mutation, Female, Genome-Wide Association Study
Abstract

Linkage analysis, positional cloning, candidate gene muta tion scanning and genome-wide association study approaches have all contributed signifi cantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identifi ed genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered. Th e application of massively parallel sequencing has further demonstrated the complexity of human genetic variation and has raised many challenges for computational and statistical methods for searching for additional breast cancer predisposition genes. Early fi ndings are consistent with previous indications that no single gene is likely to account for a large proportion of the remaining unexplained genetic susceptibility [1,2]. Coordinated international collaboration off ers great potential to advance the discovery of additional breast cancer susceptibility genes by increasing the likelihood of identifying functionally relevant genetic variants in the same genes in multiple families. A new consortium, COMPLEXO (a name chosen to refl ect the complexity of the exome), has been formed to facilitate collaborations between researchers actively applying massively parallel sequencing to understand the genetics of breast and ovarian cancer. Th e consortium has defi ned activities aimed at bringing together data and resources suitable for exome/genome sequencing initiatives and for large case-control-family study resources suitable for validation of candidate susceptibility genes in which rare mutations are associated with high to moderate risk of breast cancer. Th e aim of COMPLEXO is to bring to massively

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