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1. Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting

Author

Xavier Pivot, Alexey Georgievitch Manikhas, Volodymyr Shamrai, Giorgi Dzagnidze, Hwoei Fen Soo Hoo, Viriya Kaewkangsadan, Fausto Petrelli, Cristian Villanueva, Jamie Kim, Sumita Pradhan, Litha Jaison, Peggy Feyaerts, Leonard Kaufman, Marie-Paule Derde, Filip Deforce, and David G. Cox

Subjects
Trastuzumab, Biosimilar, HD201, Breast cancer, Neoadjuvant, HER2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. Methods In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan–Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. Results The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3–38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28–89.52) and 84.9% (95% CI: 79.54–88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63–1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90–97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45–97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. Conclusions This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. Trial registration ClinicalTrials.gov identifier: NCT03013504.

Published
2023
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2. Outcome of lung oligometastatic patients treated with stereotactic body irradiation

Author

Guillaume Virbel, David G. Cox, Anne Olland, Pierre-Emmanuel Falcoz, Clara Le Fevre, Roland Schott, Delphine Antoni, and Georges Noel

Subjects
lung, metastases, oligometastatic, stereotactic body radiotherapy, SBRT, SABR, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

PurposeThe oligometastatic stage is an intermediate stage of cancer between the localized stage and polymetastatic stage. The prognosis of patients in this stage also appears to be intermediate. Lung stereotactic body radiotherapy is a possible tool for treating oligometastatic lung sites. The objective of our study was to evaluate the clinical outcomes in terms of local control, progression-free survival, overall survival, and toxicity of SBRT in oligometastatic patients with lung metastases from any solid primary tumor.Materials and methodsClinical records of consecutive lung oligometastatic patients treated between January 2010 and December 2020 for lung SBRT at 60 Gy in 3- or 8-fraction schedules and a controlled primary tumor were retrospectively analyzed.ResultsAfter a median follow-up of 20.3 months, local failure occurred for 14 lesions, 57 patients experienced lung progression, and 64 patients experienced disease progression. Overall survival rates at 1 and 2 years were 85.6 and 69.7%, respectively. Fifty-two patients experienced radiation pneumonitis, but only 2 patients were symptomatic and presented grade 2 late pneumonitis. No grade 3-4 toxicity was observed. ECOG 0 was the only prognostic factor for overall survival (HR = 3.5; 95% CI 3.2-3.8; p < 0.01).ConclusionSBRT with a 60-Gy schedule in 8 fractions is an effective and well-tolerated treatment for patients with lung oligometastases from any solid primary tumor.

Published
2022
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3. Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Author

Amy Moore, Eleanor Kane, Zhaoming Wang, Orestis A. Panagiotou, Lauren R. Teras, Alain Monnereau, Nicole Wong Doo, Mitchell J. Machiela, Christine F. Skibola, Susan L. Slager, Gilles Salles, Nicola J. Camp, Paige M. Bracci, Alexandra Nieters, Roel C. H. Vermeulen, Joseph Vijai, Karin E. Smedby, Yawei Zhang, Claire M. Vajdic, Wendy Cozen, John J. Spinelli, Henrik Hjalgrim, Graham G. Giles, Brian K. Link, Jacqueline Clavel, Alan A. Arslan, Mark P. Purdue, Lesley F. Tinker, Demetrius Albanes, Giovanni M. Ferri, Thomas M. Habermann, Hans-Olov Adami, Nikolaus Becker, Yolanda Benavente, Simonetta Bisanzi, Paolo Boffetta, Paul Brennan, Angela R. Brooks-Wilson, Federico Canzian, Lucia Conde, David G. Cox, Karen Curtin, Lenka Foretova, Susan M. Gapstur, Hervé Ghesquières, Martha Glenn, Bengt Glimelius, Rebecca D. Jackson, Qing Lan, Mark Liebow, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Roger L. Milne, Thierry J. Molina, Lindsay M. Morton, Kari E. North, Kenneth Offit, Marina Padoan, Alpa V. Patel, Sara Piro, Vignesh Ravichandran, Elio Riboli, Silvia de Sanjose, Richard K. Severson, Melissa C. Southey, Anthony Staines, Carolyn Stewart, Ruth C. Travis, Elisabete Weiderpass, Stephanie Weinstein, Tongzhang Zheng, Stephen J. Chanock, Nilanjan Chatterjee, Nathaniel Rothman, Brenda M. Birmann, James R. Cerhan, and Sonja I. Berndt

Subjects
non-Hodgkin lymphoma, height, genetics, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00–1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01–1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.

Published
2020
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4. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Mitchell J. Machiela, Thomas G. P. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Andreas E. Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, and Olivier Delattre

Subjects
Science
Abstract

Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Published
2018
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5. A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus

Author

Lenha Mobuchon, Aude Battistella, Claire Bardel, Ghislaine Scelo, Alexia Renoud, Alexandre Houy, Nathalie Cassoux, Maud Milder, Géraldine Cancel-Tassin, Olivier Cussenot, Olivier Delattre, Céline Besse, Anne Boland, Jean-François Deleuze, David G. Cox, and Marc-Henri Stern

Subjects
Medicine, Genetics, QH426-470
Abstract

Cancer: Risk allele identified for melanoma of the eye Researchers have discovered an important genetic risk variant linked to uveal melanoma, a rare malignant tumor of the eye. Marc-Henri Stern from Institut Curie in Paris, France, and colleagues compared more than 860,000 single DNA variants covering the entire genome, from the genomes of 259 people with uveal melanoma and 401 healthy controls, all of whom were of European ancestry. The researchers found that a series of closely linked gene variants on the short arm of chromosome 5 were significantly more common in the melanoma patients. They confirmed the association between this genomic region and disease risk in an independent cohort of 276 cancer cases and 184 controls. Expression analyses showed that the CLPTM1L gene contained in this region was more expressed in people with the risk variants, pointing to CLPTM1L playing a role in tumor development.

Published
2017
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6. Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort

Author

Xavier Pivot, Gilles Romieu, Pierre Fumoleau, Maria Rios, Hervé Bonnefoi, Thomas Bachelot, Patrick Soulié, Christelle Jouannaud, Hugues Bourgeois, Thierry Petit, Isabelle Tennevet, David Assouline, Marie-Christine Mathieu, Jean-Philippe Jacquin, Sandrine Lavau-Denes, Ariane Darut-Jouve, Jean-Marc Ferrero, Carole Tarpin, Christelle Lévy, Valérie Delecroix, Véronique Trillet-Lenoir, Oana Cojocarasu, Jérôme Meunier, Jean-Yves Pierga, Cécile Agostini, Pierre Kerbrat, Céline Faure-Mercier, Hélène Blanché, Mourad Sahbatou, Anne Boland, Delphine Bacq, Céline Besse, Fabien Calvo, Alexia Renaud, Jean-François Deleuze, Iris Pauporté, Gilles Thomas, and David G. Cox

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Genetics: heredity does not explain HER2 expression A large gene-finding study failed to identify any hereditary factors linked to HER2 expression among women with breast cancer. A team in France led by Xavier Pivot from the University Hospital Center of Besançon, France, analyzed more than 500,000 single DNA letters from a cohort of 8703 patients with breast cancer, 3230 of whom had tumors with high expression of human epidermal growth factor receptor 2 (HER2) and are thus treated with for anti-HER2 targeted therapies. The researchers searched for DNA variants associated with HER2 status, but none reached the threshold for statistical significance. The findings reveal a high level of genetic diversity in women with HER2-positive breast cancer and suggest that HER2 amplification may have more to do with the intrinsic nature of the tumor than with the genetics of the patient.

Published
2017
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7. Supplemental Table from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang

Abstract

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

Published
2023
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8. Supplementary notes from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author

Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin

Abstract

Supplementary acknowledgments.

Published
2023
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9. Data from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang

Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Published
2023
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10. Data from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author

Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin

Abstract

Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).Results: We observed no significant association between genetic variants and prostate cancer survival.Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.

Published
2023
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11. Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

Author

Dimitrios Trichopoulos, Anne Tjonneland, Michael J. Thun, Gilles Thomas, Daniel O. Stram, V. Wendy Setiawan, Elio Riboli, Malcolm C. Pike, Petra H. Peeters, Carmen Navarro, William Modi, Jakob Linseisen, Loic LeMarchand, Peter Kraft, Laurence N. Kolonel, David Hunter, Joel N. Hirschhorn, Richard B. Hayes, Susan E. Hankinson, Christopher A. Haiman, Matthew L. Freedman, W. Ryan Diver, Graham Colditz, Francoise Clavel-Chapelon, Stephen J. Chanock, Eugenia E. Calle, Noel P. Burtt, Julie E. Buring, Sheila Bingham, Franco Berrino, Goran Berglund, David Altshuler, Demetrius Albanes, Brian E. Henderson, Rudolf Kaaks, Sholom Wacholder, Howard M. Cann, David G. Cox, and Heather Spencer Feigelson

Abstract

Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

Published
2023
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12. Supplementary Methods and Tables 1-4 from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

Author

Regina G. Ziegler, Sholom Wacholder, Dimitrios Trichopoulos, Ruth Travis, Anne Tjonneland, Elio Riboli, Malcolm C. Pike, Petra H. Peeters, Salvatore Panico, Eiliv Lund, Per Lenner, Loïc Le Marchand, Laurence N. Kolonel, Rudolf Kaaks, David J. Hunter, Robert Hoover, Joel N. Hirschhorn, Brian E. Henderson, Richard B. Hayes, Susan E. Hankinson, Heather Spencer Feigelson, David G. Cox, Graham A. Colditz, Françoise Clavel-Chapelon, Stephen Chanock, Eugenia E. Calle, Noël Burtt, Julie Buring, Heiner Boeing, Eva Ardanaz, David Altshuler, Demetrius Albanes, Michael J. Thun, Gilles Thomas, Alison M. Dunning, Daniel O. Stram, V. Wendy Setiawan, Laure Dossus, and Christopher A. Haiman

Abstract

Supplementary Methods and Tables 1-4 from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

Published
2023
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13. Data from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

Author

Regina G. Ziegler, Sholom Wacholder, Dimitrios Trichopoulos, Ruth Travis, Anne Tjonneland, Elio Riboli, Malcolm C. Pike, Petra H. Peeters, Salvatore Panico, Eiliv Lund, Per Lenner, Loïc Le Marchand, Laurence N. Kolonel, Rudolf Kaaks, David J. Hunter, Robert Hoover, Joel N. Hirschhorn, Brian E. Henderson, Richard B. Hayes, Susan E. Hankinson, Heather Spencer Feigelson, David G. Cox, Graham A. Colditz, Françoise Clavel-Chapelon, Stephen Chanock, Eugenia E. Calle, Noël Burtt, Julie Buring, Heiner Boeing, Eva Ardanaz, David Altshuler, Demetrius Albanes, Michael J. Thun, Gilles Thomas, Alison M. Dunning, Daniel O. Stram, V. Wendy Setiawan, Laure Dossus, and Christopher A. Haiman

Abstract

The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (≥5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5′ region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 × 10−15]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer. [Cancer Res 2007;67(5):1893–7]

Published
2023
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14. Efficacity of Deep Inspiration Breath Hold and Intensity-Modulated Radiotherapy in Preventing Perfusion Defect for Left Sided Breast Cancer (EDIPE): A Prospective Cohort Study Protocol

Author

Jordan Eber, Cyrille Blondet, Martin Schmitt, David G. Cox, Claire Vit, Clara Le Fèvre, Delphine Antoni, Fabrice Hubele, and Georges Noel

Subjects
Cancer Research, Oncology
Abstract

Breast radiotherapy can lead to radiation-induced cardiac disease, particularly in left breast cancers. Recent studies have shown that subclinical cardiac lesions, such as myocardial perfusion deficits, may occur early after radiotherapy. The primary method for irradiating breast cancer, known as opposite tangential field radiotherapy, can cause the anterior interventricular coronary artery to receive a high dose of radiation during left breast irradiation. To explore alternative approaches that could reduce the risk of myocardial perfusion defects in patients with left breast cancer, we plan to conduct a prospective single-center study using a combination of deep inspiration breath hold radiotherapy and intensity modulated radiation therapy. The study will use stress and, if necessary, resting myocardial scintigraphy to assess myocardial perfusion. The trial aims to show that reducing the cardiac dose with these techniques can prevent the appearance of early (3-month) and medium-term (6- and 12-month) perfusion disorders.

Published
2023
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15. Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes

Author

Joseph Vijai, Henrik Hjalgrim, Roger L. Milne, Simonetta Bisanzi, Rebecca D. Jackson, Graham G. Giles, Mark Liebow, John J. Spinelli, Stephanie J. Weinstein, Wendy Cozen, Susan M. Gapstur, Michael Dean, Paolo Boffetta, Pierluigi Cocco, Paige M. Bracci, Nicola J. Camp, Amy Moore, Herve Ghesquieres, Federico Canzian, James McKay, Thomas M. Habermann, Nikolaus Becker, Kari E. North, Demetrius Albanes, Alain Monnereau, Marc Maynadié, Lesley F. Tinker, Christine F. Skibola, Vignesh Ravichandran, Susan L. Slager, Karin E. Smedby, Ruth C. Travis, Jacqueline Clavel, Lucia Miligi, Melissa C. Southey, Mary Carrington, Claire M. Vajdic, Karen Curtin, David G. Cox, Roel Vermeulen, Elio Riboli, Eleanor Kane, Weiyin Zhou, Nathaniel Rothman, Mitchell J. Machiela, Yolanda Benavente, Alan A. Arslan, Meredith Yeager, Paul Brennan, Tongzhang Zheng, Elisabete Weiderpass, Moara Machado, Qing Lan, Alpa V. Patel, James R. Cerhan, Sonja I. Berndt, Neil E. Caporaso, Silvia de Sanjosé, Stephen J. Chanock, Nicole Wong Doo, Lauren R. Teras, Sara Piro, Lenka Foretova, Chi Gao, Gilles Salles, Immaculata De Vivo, Alexandra Nieters, Bengt Glimelius, Sophia S. Wang, Richard K. Severson, Mads Melbye, Hans-Olov Adami, Yawei Zhang, Carolyn Stewart, Lucia Conde, Brenda M. Birmann, Angela Brooks-Wilson, Thierry Jo Molina, Kenneth Offit, Brian K. Link, Martha Glenn, Anthony Staines, Moore, Amy, Machiela, Mitchell J, Machado, Moara, Wang, Sophia S, Kane, Eleanor, Slager, Susan L, Zhou, Weiyin, Carrington, Mary, Lan, Qing, Milne, Roger L, Birmann, Brenda M, Adami, Hans-Olov, Albanes, Demetriu, Arslan, Alan A, Becker, Nikolau, Benavente, Yolanda, Bisanzi, Simonetta, Boffetta, Paolo, Bracci, Paige M, Brennan, Paul, Brooks-Wilson, Angela R, Canzian, Federico, Caporaso, Neil, Clavel, Jacqueline, Cocco, Pierluigi, Conde, Lucia, Cox, David G, Cozen, Wendy, Curtin, Karen, De Vivo, Immaculata, de Sanjose, Silvia, Foretova, Lenka, Gapstur, Susan M, Ghesquières, Hervè, Giles, Graham G, Glenn, Martha, Glimelius, Bengt, Gao, Chi, Habermann, Thomas M, Hjalgrim, Henrik, Jackson, Rebecca D, Liebow, Mark, Link, Brian K, Maynadie, Marc, McKay, Jame, Melbye, Mad, Miligi, Lucia, Molina, Thierry J, Monnereau, Alain, Nieters, Alexandra, North, Kari E, Offit, Kenneth, Patel, Alpa V, Piro, Sara, Ravichandran, Vignesh, Riboli, Elio, Salles, Gille, Severson, Richard K, Skibola, Christine F, Smedby, Karin E, Southey, Melissa C, Spinelli, John J, Staines, Anthony, Stewart, Carolyn, Teras, Lauren R, Tinker, Lesley F, Travis, Ruth C, Vajdic, Claire M, Vermeulen, Roel C H, Vijai, Joseph, Weiderpass, Elisabete, Weinstein, Stephanie, Doo, Nicole Wong, Zhang, Yawei, Zheng, Tongzhang, Chanock, Stephen J, Rothman, Nathaniel, Cerhan, James R, Dean, Michael, Camp, Nicola J, Yeager, Meredith, and Berndt, Sonja I

Subjects
Genetics, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Follicular lymphoma, Single-nucleotide polymorphism, Runs of Homozygosity, Biology, medicine.disease, marginal zone lymphoma, Article, follicular lymphoma, immune system diseases, hemic and lymphatic diseases, Genetic variation, medicine, chronic lymphocytic leukemia, homozygosity, Diffuse large B-cell lymphoma, Inbreeding, Non-Hodgkin lymphoma, Genetic association
Abstract

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Published
2021
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16. Analysis of the StoRM cohort reveals physical activity to be associated with survival in metastatic breast cancer

Author

Christine M. Friedenreich, Thomas Bachelot, C. Roemer-Becuwe, Sophie Abadie-Lacourtoisie, Céline Segura-Ferlay, Jean-Philippe Jacquin, E. Jacquet, Loic Chaigneau, Frédérique Penault-Llorca, H. Orfeuvre, Jean-Marc Ferrero, Christelle Jouannaud, David G. Cox, Lidia Delrieu, Pierre-Etienne Heudel, Monica Arnedos, N Quenel-Tueux, William Jacot, Isabelle Moullet, Gilles Romieu, Olivier Tredan, Maria Rios, Ellen Blanc, Olivia Febvey-Combes, CHU Grenoble, Université Joseph Fourier, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER

Subjects
Oncology, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], lcsh:Medicine, Triple Negative Breast Neoplasms, Body Mass Index, Breast cancer, 0302 clinical medicine, Surveys and Questionnaires, Prospective Studies, 030212 general & internal medicine, Neoplasm Metastasis, lcsh:Science, Prospective cohort study, education.field_of_study, Multidisciplinary, Anthropometry, Middle Aged, Prognosis, Metastatic breast cancer, 3. Good health, Survival Rate, Treatment Outcome, Data Interpretation, Statistical, 030220 oncology & carcinogenesis, Cohort, Female, medicine.medical_specialty, Population, Breast Neoplasms, Subgroup analysis, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, education, Exercise, Survival rate, Aged, Proportional Hazards Models, business.industry, lcsh:R, medicine.disease, Physical activity level, Multivariate Analysis, lcsh:Q, business
Abstract

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07–0.70, p = 0.01 and HR 0.38; 95% CI 0.15–0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

Published
2020
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17. Efficacy of HD201 vs Referent Trastuzumab in Patients With ERBB2-Positive Breast Cancer Treated in the Neoadjuvant Setting

Author

Xavier, Pivot, M A, Georgievich, Volodymyr, Shamrai, Giorgi, Dzagnidze, Hwoei Fen, Soo Hoo, Viriya, Kaewkangsadan, Fausto, Petrelli, Cristian, Villanueva, Lipatov O, Nikolaevich, Jocelyn, Hii, Jamie, Kim, Sumita, Pradhan, Litha, Jaison, Peggy, Feyaerts, Leonard, Kaufman, Marie-Paule, Derde, Ghislain M C, Bonamy, Filip, Deforce, and David G, Cox

Subjects
Adult, Aged, 80 and over, Cancer Research, Receptor, ErbB-2, Correction, Antineoplastic Agents, Breast Neoplasms, Middle Aged, Trastuzumab, Neoadjuvant Therapy, Oncology, Humans, Female, Aged
Abstract

The drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab.To compare the efficacy of HD201 with referent trastuzumab.This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up.Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab.The primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity.A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at -3.8% (95% CI, -12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively.The results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile.ClinicalTrials.gov Identifier: NCT03013504.

Published
2022
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18. Encoding of 3D Head Orienting Movements in Primary Visual Cortex

Author

Steffen B. E. Wolff, Javier Masís, David G. Cox, and Grigori Guitchounts

Subjects
0303 health sciences, Movement (music), Efference copy, Sensory system, Visual processing, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Visual cortex, Orientation (mental), medicine, Premovement neuronal activity, Psychology, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology, Motor cortex
Abstract

Animals actively sample from the sensory world by generating complex patterns of movement that evolve in three dimensions. At least some of these movements have been shown to influence neural codes in sensory areas. For example, in primary visual cortex (V1), locomotion-related neural activity influences sensory gain, encodes running speed, and predicts the direction of visual flow. As most experiments exploring movement-related modulation of V1 have been performed in head-fixed animals, it remains unclear whether or how the naturalistic movements used to interact with sensory stimuli– like head orienting–influence visual processing. Here we show that 3D head orienting movements modulate V1 neuronal activity in a direction-specific manner that also depends on the presence or absence of light. We identify two largely independent populations of movement-direction-tuned neurons that support this modulation, one of which is direction-tuned in the dark and the other in the light. Finally, we demonstrate that V1 gains access to a motor efference copy related to orientation from secondary motor cortex, which has been shown to control head orienting movements. These results suggest a mechanism through which sensory signals generated by purposeful movement can be distinguished from those arising in the outside world, and reveal a pervasive role of 3D movement in shaping sensory cortical dynamics.

Published
2020
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19. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Author

Sakina Zaidi, Didier Surdez, Javier Alonso, Gregory T. Armstrong, Gaëlle Pierron, Nadège Corradini, Nathaniel Rothman, Markus Metzler, Valérie Laurence, Kathleen Wyatt, Kristine Jones, Heinrich Kovar, Brian D. Carter, Eve Lapouble, Weiyin Zhou, Leslie L. Robison, Rebeca Alba Rubio, Thomas Kirchner, Wendy M. Leisenring, David G. Cox, Manuela Krumbholz, Lisa Mirabello, Smita Bhatia, Olivier Delattre, Casey L. Dagnall, Lindsay M. Morton, Neal D. Freedman, Stéphanie Reynaud, Stelly Ballet, Udo Kontny, Thomas Meitinger, Sandrine Grossetête-Lalami, Robert N. Hoover, Shu-Hong Lin, Ana Patiño-García, Joshua N. Sampson, Margaret A. Tucker, Laurie Burdett, Olivier Mirabeau, Perrine Marec Bérard, Mitchell J. Machiela, Jeremy A. Miller, Stephen J. Chanock, Thomas G. P. Grunewald, Jennifer Kriebel, Jean Michon, Meredith Yeager, Uta Dirksen, Wolfgang Hartmann, Andreas E. Kulozik, Javed Khan, Konstantin Strauch, Franck Tirode, Eric Karlins, Anna González-Neira, Michelle Manning, NIH - National Cancer Institute (NCI) (Estados Unidos), Agence Nationale de la Recherche (Francia), Unión Europea. Comisión Europea. 7 Programa Marco, Deutsche Forschungsgemeinschaft (Alemania), Instituto de Salud Carlos III, Comunidad Foral de Navarra (España), National Cancer Institute (United States), Agence Nationale de la Recherche (France), 7º Programa Marco - Comisión Europea, Deutsche Forschungsgemeinschaft, Instituto de Salud Carlos III - ISCIII, and Gobierno de Navarra

Subjects
0301 basic medicine, Heredity, Epidemiology, Medizin, Genome-wide association study, Linkage Disequilibrium, 0302 clinical medicine, Medizinische Fakultät, Medicine and Health Sciences, Odds Ratio, Genetics, Multidisciplinary, Cancer Risk Factors, Prostate Cancer, Prostate Diseases, Sarcoma, Genomics, Genetic Mapping, Oncology, 030220 oncology & carcinogenesis, Medicine, Research Article, Urology, Science, Ewing Sarcoma, Locus (genetics), Variant Genotypes, Sarcoma, Ewing, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic variation, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Alleles, Genetic association, Colorectal Cancer, Haplotype, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Genetic Variation, Human Genetics, Genome Analysis, Minor allele frequency, Genitourinary Tract Tumors, 030104 developmental biology, Germ Cells, Genetic Loci, Medical Risk Factors, Chromosome 20, Genome-Wide Association Study
Abstract

PLOS ONE 15(9), e0237792 (2020). doi:10.1371/journal.pone.0237792, Published by PLOS, San Francisco, California, US

Published
2020
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20. Transmission of breast cancer polygenic risk based on single nucleotide polymorphisms

Author

Xavier Pivot, David G. Cox, Julie Henry, Pierre-Etienne Heudel, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Triangle : action, discours, pensée politique et économique (TRIANGLE), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Centre Paul Strauss, CRLCC Paul Strauss, Centre National de la Recherche Scientifique (CNRS)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Risk, 0301 basic medicine, Multifactorial Inheritance, media_common.quotation_subject, education, Population, Mothers, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Risk Assessment, Nuclear Family, 03 medical and health sciences, breast cancer, 0302 clinical medicine, Breast cancer, Humans, Medicine, Genetic Predisposition to Disease, Nuclear family, Allele frequency, Alleles, media_common, Daughter, education.field_of_study, Framingham Risk Score, business.industry, [SHS.PHIL]Humanities and Social Sciences/Philosophy, General Medicine, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Surgery, business, Risk assessment, Demography
Abstract

Aim The goal of the present study was to further refine how polygenic risk scores may be used in a large population and to quantify the transmission of risk score through generations. Methods Allele frequencies from the 1000 Genomes data for 159 single nucleotide polymorphisms associated with breast cancer risk were used. A breast cancer risk score was calculated among 100,000 people. Choosing two “parents” and the alleles they transmit at random, 100,000 “daughters” were simulated. The population was divided by deciles of risk score. Comparing mean risk score in the mother and daughter populations provided information regarding the general relationship at a population level. By examining the distribution of daughter's risk score within each decile of maternal risk score, the transmission was evaluated at the subject level. Results Mean values of risk score were 85.1 (St Dev = 7.5) and 85.0 (St Dev = 7.5) for the populations of mothers and daughters, respectively (mean absolute difference = 0.02, p = 0.48). When examining the transmission of risk score from mothers to daughters in specific deciles of risk, statistically significant differences were observed in all deciles (ranged between 0.001 and Conclusion The relationship at the subject level will not provide information regarding prevention and screening of offspring based on the knowledge of parents' risk score alone. The present results show that risk estimation by polygenic risk scores is personal, and evaluation of risk score is required for each individual.

Published
2018
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21. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Ana Patiño-García, Thomas G. P. Grunewald, David G. Cox, Lindsay M. Morton, Michelle Manning, Sandrine Grossetête-Lalami, Gaëlle Pierron, Nadège Corradini, Stephen J. Chanock, Kathleen Wyatt, Udo Kontny, Gregory T. Armstrong, Jean Michon, Sakina Zaidi, Didier Surdez, Wolfgang Hartmann, Heinrich Kovar, Olivier Delattre, Jennifer Kriebel, Nathalie Gaspar, Perrine Marec Bérard, Valérie Laurence, Casey L. Dagnall, Thomas Kirchner, Stéphanie Reynaud, Uta Dirksen, Nathaniel Rothman, Konstantin Strauch, Margaret A. Tucker, Lisa Mirabello, Smita Bhatia, Markus Metzler, Laurie Burdett, Neal D. Freedman, Rebeca Alba Rubio, Franck Tirode, Andreas E. Kulozik, Meredith Yeager, Kristine Jones, Javier Alonso, Stelly Ballet, Olivier Mirabeau, Eve Lapouble, Robert N. Hoover, Weiyin Zhou, Wendy M. Leisenring, Leslie L. Robison, Piero Picci, Javed Khan, Thomas Meitinger, Anna González-Neira, Eric Karlins, Mitchell J. Machiela, Unión Europea, TIRODE, Franck, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unité de Génétique Somatique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research (FNLCR), Unité de Génétique Somatique [Institut Curie, Paris], Children’s Cancer Research Institute [Vienna, Austria], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Cancer Control [Memphis, TN, USA], Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA], Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA], University Children's Hospital of Heidelberg [Heidelberg, Germany], Research Unit of Molecular Biology [Neuherberg, Germany], Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen = Uniklinikum Erlangen, Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Genetic Epidemiology [Neuherberg, Germany], Chair of Genetic Epidemiology [Munich, Germany] (IBE), Institute of Pathology [Munich, Germany], University Children's Hospital of Essen [Essen, Germany], This work was supported by the Intramural Research Program of the U.S. NationalCancer Institute and the Intramural Research Program of the American Cancer Society.This work was supported by grants from the Institut Curie, the Inserm, the LigueNationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs programand Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the AgenceNationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supportedby FP7 grant 'EURO EWING Consortium' No. 602856 and the following associations:Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M lavie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin andthe Société Française de lutte contre les Cancers et les leucémies de l’Enfant et del’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultätder LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellentwithin the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the WilhelmSander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 andDKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). Wethank the following clinicians for providing samples used in this study: C. Alenda, F.Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D.Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles,V. Gandemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L.Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O.Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard,G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G.Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A.Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet,M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre,M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L.Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. This work was supported by the Instituto de SaludCarlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa deAlex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y OncologíaPediátricas. The Childhood Cancer Survivor Study is supported by the NationalCancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding forgenotyping from the Intramural Research Program of the National Institutes ofHealth, National Cancer Institute. The KORA study was initiated and financed by theHelmholtz Zentrum München—German Research Center for Environmental Health,which is funded by the German Federal Ministry of Education and Research (BMBF) andby the State of Bavaria. Furthermore, KORA research was supported within the MunichCenter of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part ofLMUinnovativ, Helmholtz-Zentrum München (HZM), University Hospital Erlangen [Germany], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Candidate gene, Oncogene Proteins, Fusion, Medizin, General Physics and Astronomy, Genome-wide association study, Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science, Genetics, Multidisciplinary, Nuclear Proteins, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality Control, Risk, Genotype, Science, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Genetic Predisposition to Disease, Allele, Alleles, Cell Proliferation, Homeodomain Proteins, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Zebrafish Proteins, Pediatric cancer, 030104 developmental biology, Expression quantitative trait loci, lcsh:Q, RNA-Binding Protein EWS, Transcription Factors, Genome-Wide Association Study
Abstract

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Published
2018
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22. HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Roel Vermeulen, Paulo Bofetta, Nicole Wong Doo, Mark P. Purdue, Eleanor Kane, Gilles Salles, Bengt Glimelius, Christine F. Skibola, Tongzhang Zheng, Graham G. Giles, Scott Davis, Pierluigi Cocco, Karin E. Smedby, Melissa C. Southey, Alexandra Nieters, Elizabeth A. Holly, Corrado Magnani, Paul Brennan, Stephanie J. Lax, David G. Cox, Lindsay M. Morton, Nikolaus Becker, Qing Lan, Elio Riboli, Herve Ghesquieres, Rudolph Kaaks, Jennifer Turner, Martha S. Linet, Anne Kricker, Stephanie J. Weinstein, Christopher R. Flowers, Alain Monnereau, Silvia de Sanjosé, Mary Carrington, John J. Spinelli, Patricia Hartge, Nathaniel Rothman, Yolanda Benavente, Susan L. Slager, Martha Glenn, Richard K. Severson, Ora Paltiel, Yawei Zhang, Ruth C. Travis, Demetrius Albanes, Nicola J. Camp, Paige M. Bracci, Jacqueline Clavel, James R. Cerhan, Marc Maynadié, Maria Grazia Ennas, Marie Hélène Delfau-Larue, Peter Kraft, Henrik Hjalgrim, Roger L. Milne, Alan A. Arslan, Jacob Musinsky, Martyn T. Smith, Anthony Staines, Lauren R. Teras, Jenna M. Voutsinas, Lenka Foretova, Sophia S. Wang, Hans-Olov Adami, Andrew L. Feldman, Wendy Cozen, Angela Brooks-Wilson, Kenneth Offit, Brian K. Link, Brenda M. Birmann, Sonja I. Berndt, Stephen J. Chanock, James McKay, Dennis D. Weisenburger, Claire M. Vajdic, Giancarlo Latte, Karen Curtin, W. Ryan Diver, Mads Melbye, Lucia Conde, Elizabeth E. Brown, Joseph Vijai, Eve Roman, Wang, Sophia S., Carrington, Mary, Berndt, Sonja I., Slager, Susan L., Bracci, Paige M., Voutsinas, Jenna, Cerhan, James R., Smedby, Karin E., Hjalgrim, Henrik, Vijai, Joseph, Morton, Lindsay M., Vermeulen, Roel, Paltiel, Ora, Vajdic, Claire M., Linet, Martha S., Nieters, Alexandra, de Sanjose, Silvia, Cozen, Wendy, Brown, Elizabeth E., Turner, Jennifer, Spinelli, John J., Zheng, Tongzhang, Birmann, Brenda M., Flowers, Christopher R., Becker, Nikolau, Holly, Elizabeth A., Kane, Eleanor, Weisenburger, Denni, Maynadie, Marc, Cocco, Pierluigi, Albanes, Demetriu, Weinstein, Stephanie J., Teras, Lauren R., Diver, W. Ryan, Lax, Stephanie J., Travis, Ruth C., Kaaks, Rudolph, Riboli, Elio, Benavente, Yolanda, Brennan, Paul, McKay, Jame, Delfau-Larue, Marie-Hélène, Link, Brian K., Magnani, Corrado, Ennas, Maria Grazia, Latte, Giancarlo, Feldman, Andrew L., Doo, Nicole Wong, Giles, Graham G., Southey, Melissa C., Milne, Roger L., Offit, Kenneth, Musinsky, Jacob, Arslan, Alan A., Purdue, Mark P., Adami, Hans-Olov, Melbye, Mad, Glimelius, Bengt, Conde, Lucia, Camp, Nicola J., Glenn, Martha, Curtin, Karen, Clavel, Jacqueline, Monnereau, Alain, Cox, David G., Ghesquières, Hervé, Salles, Gille, Boffetta, Paolo, Foretova, Lenka, Staines, Anthony, Davis, Scott, Severson, Richard K., Lan, Qing, Brooks-Wilson, Angela, Smith, Martyn T., Roman, Eve, Kricker, Anne, Zhang, Yawei, Kraft, Peter, Chanock, Stephen J., Rothman, Nathaniel, Hartge, Patricia, and Skibola, Christine F.

Subjects
Male, 0301 basic medicine, Heterozygote, Cancer Research, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Chronic lymphocytic leukemia, EPIDEMIOLOGIC RESEARCH, Genome-wide association study, Human leukocyte antigen, Biology, CLASSIFICATION, ANTIGENS, Article, Genetic Heterogeneity, 03 medical and health sciences, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, INTERLYMPH, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, GENOME-WIDE ASSOCIATION, Allele, HLA Complex, Science & Technology, Hematology, CHRONIC LYMPHOCYTIC-LEUKEMIA, Genetic heterogeneity, Lymphoma, Non-Hodgkin, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, HETEROZYGOTE ADVANTAGE, medicine.disease, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, Case-Control Studies, Immunology, B-VIRUS INFECTION, Female, Life Sciences & Biomedicine, NEOPLASMS, Genome-Wide Association Study
Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Published
2018
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23. 319P A propensity score weighted study comparing two versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

Author

H. Bischoff, C. Pflumio, C. Bigot, C. Fischbach, Xavier Pivot, P. Coliat, M. Alt, D. Karouby, M. Kalish Weindling, David G. Cox, L. Bender, L. Pierard, F. Moinard, Thierry Petit, P. Trensz, Jean-Emmanuel Kurtz, and Martin Demarchi

Subjects
Oncology, medicine.medical_specialty, Regimen, business.industry, Internal medicine, Propensity score matching, medicine, Hematology, medicine.disease, business, Metastatic breast cancer, Pegylated Liposomal Doxorubicin
Published
2021
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24. 286P Outcome of patients with HER2-positive brain metastatic breast cancer: A 10-year retrospective study

Author

Jean-Emmanuel Kurtz, C. Lefevre, Thierry Petit, Xavier Pivot, P. Trensz, L. Bender, M. Alt, C. Bigot, Georges Noël, David G. Cox, C. Fischbach, L. Pierard, Martin Demarchi, M. Kalish Weindling, I. Chambrelant, H. Bischoff, and C. Pflumio

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, Medicine, Retrospective cohort study, Hematology, business, medicine.disease, Outcome (game theory), Metastatic breast cancer
Published
2021
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25. LBA11 Individual patient data meta-analysis of 5 non-inferiority RCTs of reduced duration single agent adjuvant trastuzumab in the treatment of HER2 positive early breast cancer

Author

Xavier Pivot, David G. Cox, C. Faure-Mercier, Jacinta Abraham, Janet A. Dunn, V. Georgoulias, Roberto D'Amico, Heikki Joensuu, Valentina Guarneri, Pierfranco Conte, Helena M. Earl, Marc Debled, Louise Hiller, David Miles, T. Huttunen, Andrew M Wardley, Henrik Lindman, David Cameron, Judith Fraser, and Gilles Romieu

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Hematology, Patient data, Non inferiority, Trastuzumab, Meta-analysis, Internal medicine, medicine, Single agent, Duration (project management), business, Adjuvant, Early breast cancer, medicine.drug
Published
2021
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26. Hands-on engagement online: using a randomised control trial to estimate the impact of an at-home lab kit on student attitudes and achievement in a MOOC

Author

David G. Cox, Casey J Smith, S. Zahra Atiq, Casey Lynn Haney, and Jennifer DeBoer

Subjects
Self-efficacy, Medical education, Online learning, 05 social sciences, Control (management), Distance education, General Engineering, 050301 education, 06 humanities and the arts, 0603 philosophy, ethics and religion, Electronic learning, Education, law.invention, Randomized controlled trial, law, Engineering education, Pedagogy, 060301 applied ethics, Psychology, 0503 education
Abstract

A shortcoming of Massive Open Online Courses (MOOCs) is the lack of substantive integration of hands-on activities into online classrooms. We conducted a randomised control trial (RCT) in a MOOC wh...

Published
2017
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27. Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort

Author

R. Tumino, Marco Matejcic, J. R. Quirós, Anne Zeleniuch-Jacquotte, Marc J. Gunter, Björn Gylling, Elisabete Weiderpass, Pagona Lagiou, Genevieve Buckland, Salvatore Panico, Flavie Perrier, C. Ricci, Renée T. Fortner, Fulvio Ricceri, Pilar Amiano, Inge Huybrechts, Veronique Chajes, Mathilde His, Claire Cadeau, Petra H.M. Peeters, Isabelle Romieu, M-D Chirlaque, Timothy J. Key, Vassiliki Benetou, Antonia Trichopoulou, David G. Cox, Elio Riboli, M. C. Boutron-Ruault, Rudolf Kaaks, Sabina Sieri, D. Palli, María José Sánchez, Aurelio Barricarte, Carine Biessy, H. Bas Bueno-de-Mesquita, J. D. De Batlle, H. Boeing, C. H. van Gils, and Guri Skeie

Subjects
0301 basic medicine, Oncology, Gynecology, Cancer Research, medicine.medical_specialty, business.industry, Follow up studies, Case-control study, EPIC, medicine.disease, 03 medical and health sciences, B vitamins, 030104 developmental biology, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, Epidemiology, Cohort, medicine, Vitamin B12, business
Abstract

Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vit ...

Published
2017
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28. Determinants of folate and vitamin B12 plasma levels in the French E3N-EPIC cohort

Author

Marco Matejcic, Amina Amadou, Isabelle Romieu, Veronique Chajes, Françoise Clavel-Chapelon, Guy Fagherazzi, David G. Cox, Hortensia Moreno-Macías, Jordi de Batlle, and Nadia Slimani

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Nutritional Status, Medicine (miscellaneous), Folic Acid Deficiency, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Folic Acid, 0302 clinical medicine, Internal medicine, Genotype, Humans, Medicine, Genetic Predisposition to Disease, Prospective Studies, 030212 general & internal medicine, Vitamin B12, Risk factor, Genetic Association Studies, Methylenetetrahydrofolate Reductase (NADPH2), 030109 nutrition & dietetics, Nutrition and Dietetics, biology, business.industry, Vitamin B 12 Deficiency, Hormone replacement therapy (menopause), Plasma levels, Middle Aged, Diet, Vitamin B 12, B vitamins, Endocrinology, Amino Acid Substitution, Biochemistry, Case-Control Studies, Methylenetetrahydrofolate reductase, Cohort, biology.protein, Patient Compliance, Female, France, Self Report, Diet, Healthy, business, Biomarkers
Abstract

Impaired B vitamin status has been identified as a risk factor for major chronic diseases. This study aims at examining the determinants of plasma folate and vitamin B12 concentrations, considering lifestyle factors and MTHFR polymorphisms. A total of 988 women aged 40–65 years from the French E3N cohort were investigated. Intakes of folate and vitamin B12 were assessed using food frequency questionnaires, and plasma concentrations were measured by microbiological assay. Dietary scores were computed to summarize folate and vitamin B12 dietary sources. MTHFR-C677T and MTHFR-A1298C were determined by Kaspar assay. Pearson’s partial correlation coefficients and multivariable linear regression models were used to assess correlations between main determinants and plasma folate and vitamin B12 levels. The partial correlation coefficient between dietary intakes and plasma folate was 0.19 (p value

Published
2016
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29. Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes

Author

Paul Brennan, M. G. Ennas, Qing Lan, Sasha Bernatsky, Alan A. Arslan, Peter Kraft, Lohith Madireddy, Roel Vermeulen, Kenan Onel, Graham G. Giles, John J. Spinelli, Eleanor Kane, Bengt Glimelius, Alexandra Nieters, David V. Conti, Christine F. Skibola, Pouya Khankhanian, Amy Moore, Ruth C. Travis, Mads Melbye, Sonja I. Berndt, Mark Liebow, Lauren R. Teras, Pierluigi Cocco, Lennox Din, Alain Monnereau, Mark P. Purdue, Lenka Foretova, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Wendy Cozen, Kenneth Offit, Demetrius Albanes, Anne J. Novak, Melissa C. Southey, Paolo Boffetta, Nicola J. Camp, James R. Cerhan, Rudolph Kaaks, Silvia de Sanjosé, Karen Curtin, Sophia S. Wang, James McKay, Nicole Wong Doo, Hans-Olov Adami, Tongzhang Zheng, Claire M. Vajdic, Nisha Pradhan, Giacomo Muzi, Gilles Salles, Nathaniel Rothman, Yolanda Benavente, Marc Maynadié, Brian K. Link, Delphine Casabonne, Hervé Ghesquières, Joseph Vijai, Karin E. Smedby, Paige M. Bracci, David G. Cox, Brenda M. Birmann, Lucia Miligi, Carolyn Stewart, Lucia Conde, Leonid Padyukov, Eve Roman, Richard K. Severson, Jorge R. Oksenberg, Immaculata De Vivo, Yawei Zhang, Corrado Magnani, Jacqueline Clavel, Lindsay M. Morton, Corinne Haioun, Jonathan N. Hofmann, Karen H. Costenbader, Pierre-Antoine Gourraud, Mohammad Sheikh, Stephanie J. Weinstein, Susan L. Slager, Paolo Vineis, Nikitha Kosaraju, Zachary Taub, Henrik Hjalgrim, Roger L. Milne, Morris Din, Martha Glenn, Nikolaus Becker, Timothy J. Vyse, Thomas M. Mack, Anthony Staines, Department of Medicine, Clinical Epidemiology, McGill University Health Center [Montreal] (MUHC), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Emory University [Atlanta, GA], Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, International Agency for Cancer Research (IACR), Department of Public Health, Vientiane Municipality, Registre des hémopathies malignes de Côte d'Or, Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, GRAPHOS - IFROSS Recherche, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Faculty of Medicine, Section of Rheumatology, Imperial College London, Karolinska Institutet [Stockholm], Epidémiologie environnementale des cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Uppsala Universitet [Uppsala], Carver College of Medicine, University of Iowa, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Cancer Epidemiology and Genetics, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Health Sciences, University of York [York, UK], Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), University of Melbourne, Centre Léon Bérard [Lyon], Mayo Clinic [Rochester], Occupational and Environmental Epidemiology Branch [Bethesda, Maryland], Division of Cancer Epidemiology and Genetics [Bethesda, Maryland], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), Memorial Sloane Kettering Cancer Center [New York], Huntsman Cancer Institute, Clinical Genetics Service, ISPO - Cancer Prevention and Research Institute, Unit of Environmental and Occupational Epidemiology, Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], B.B. Brodie Department of Neuroscience, Department of Pathology, Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unit of Environment Cancer Epidemiology, IARC, University of Torino and CPO-Piemonte, Università degli studi di Torino (UNITO), Department of Epidemiology, Harvard School of Public Health, Wayne State University [Detroit], Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Cancer Epidemiology Centre, Cancer Council Victoria, Cancer Epidemiology Unit, University of Oxford [Oxford], De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Catalan Institute of Oncology (ICO), Department of Neurology [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Norris Comprehensive Cancer Center, Masaryk University [Brno] (MUNI), Università degli studi di Torino = University of Turin (UNITO), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Imperial College London, University of Oxford, Din L., Sheikh M., Kosaraju N., Smedby K.E., Bernatsky S., Berndt S.I., Skibola C.F., Nieters A., Wang S., McKay J.D., Cocco P., Maynadie M., Foretova L., Staines A., Mack T.M., de Sanjose S., Vyse T.J., Padyukov L., Monnereau A., Arslan A.A., Moore A., Brooks-Wilson A.R., Novak A.J., Glimelius B., Birmann B.M., Link B.K., Stewart C., Vajdic C.M., Haioun C., Magnani C., Conti D.V., Cox D.G., Casabonne D., Albanes D., Kane E., Roman E., Muzi G., Salles G., Giles G.G., Adami H.-O., Ghesquieres H., De Vivo I., Clavel J., Cerhan J.R., Spinelli J.J., Hofmann J., Vijai J., Curtin K., Costenbader K.H., Onel K., Offit K., Teras L.R., Morton L., Conde L., Miligi L., Melbye M., Ennas M.G., Liebow M., Purdue M.P., Glenn M., Southey M.C., Din M., Rothman N., Camp N.J., Wong Doo N., Becker N., Pradhan N., Bracci P.M., Boffetta P., Vineis P., Brennan P., Kraft P., Lan Q., Severson R.K., Vermeulen R.C.H., Milne R.L., Kaaks R., Travis R.C., Weinstein S.J., Chanock S.J., Ansell S.M., Slager S.L., Zheng T., Zhang Y., Benavente Y., Taub Z., Madireddy L., Gourraud P.-A., Oksenberg J.R., Cozen W., Hjalgrim H., Khankhanian P., and Le Bihan, Sylvie

Subjects
Oncology, Male, Multifactorial Inheritance, Lymphoma, Epidemiology, Chronic lymphocytic leukemia, Follicular lymphoma, Genome-wide association study, Disease, Neurodegenerative, meta-analysi, immune system diseases, HLA Antigens, Risk Factors, hemic and lymphatic diseases, 2.1 Biological and endogenous factors, HLA Antigen, Aetiology, Genetics (clinical), Cancer, Allele, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Lymphoma, Non-Hodgkin, non-Hodgkin lymphoma, 030305 genetics & heredity, Single Nucleotide, Hematology, Middle Aged, 3. Good health, Public Health and Health Services, Female, Human, medicine.medical_specialty, autoimmune disease, genome-wide association study, meta-analysis, Alleles, Autoimmune Diseases, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Non-Hodgkin, Article, 03 medical and health sciences, Rare Diseases, Internal medicine, Genetic variation, medicine, Genetics, Polymorphism, 030304 developmental biology, Autoimmune disease, business.industry, Multiple sclerosis, Risk Factor, Arthritis, Inflammatory and immune system, Human Genome, medicine.disease, Brain Disorders, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Published
2019
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30. Triton: an intermediate language and compiler for tiled neural network computations

Author

David G. Cox, Hsiang-Tsung Kung, and Philippe Tillet

Subjects
Artificial neural network, business.industry, Programming language, Computer science, Deep learning, computer.software_genre, Matrix multiplication, CUDA, Software portability, High-level programming language, Leverage (statistics), Compiler, Artificial intelligence, business, computer
Abstract

The validation and deployment of novel research ideas in the field of Deep Learning is often limited by the availability of efficient compute kernels for certain basic primitives. In particular, operations that cannot leverage existing vendor libraries (e.g., cuBLAS, cuDNN) are at risk of facing poor device utilization unless custom implementations are written by experts – usually at the expense of portability. For this reason, the development of new programming abstractions for specifying custom Deep Learning workloads at a minimal performance cost has become crucial. We present Triton, a language and compiler centered around the concept of tile, i.e., statically shaped multi-dimensional sub-arrays. Our approach revolves around (1) a C-based language and an LLVM-based intermediate representation (IR) for expressing tensor programs in terms of operations on parametric tile variables and (2) a set of novel tile-level optimization passes for compiling these programs into efficient GPU code. We demonstrate how Triton can be used to build portable implementations of matrix multiplication and convolution kernels on par with hand-tuned vendor libraries (cuBLAS / cuDNN), or for efficiently implementing recent research ideas such as shift convolutions.

Published
2019
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31. 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
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32. Abstract P1-08-06: SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping

Author

Ellen Blanc, N Quenel-Tueux, Thierry Petit, Sophie Abadie-Lacourtoisie, Monica Arnedos, David G. Cox, J.P. Jacquin, Frédérique Penault-Llorca, Emilie Lavergne, Olivier Tredan, P-E Heudel, Isabelle Moullet, H. Orfeuvre, Thomas Bachelot, Gilles Romieu, Loic Chaigneau, Maria Rios, C. Roemer-Becuwe, Christelle Jouannaud, and J-M Ferrero

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Bone metastasis, Retrospective cohort study, medicine.disease, Metastatic breast cancer, Surgery, Clinical trial, Breast cancer, Trastuzumab, Internal medicine, Epidemiology, medicine, business, medicine.drug
Abstract

Background: Due to better molecular classification and new treatment options, epidemiology and prognosis of mBC is rapidly changing. Clinical data extracted from randomized studies are only relevant to specific subpopulations and retrospective studies are prone to selection bias. SToRM is a prospective clinical trial that aims to create a cohort of 1500 mBC patients, with the ultimate goal of identifying germ line polymorphisms associated with prognosis of breast cancer (BC) and response to treatment in the metastatic phase. Material and methods: Any newly (within 1 year) diagnosed mBC patients were eligible. Whole blood samples were drawn and germline DNA extracted for genetic analysis. Extensive epidemiologic data, disease history from primary diagnosis to metastatic spread, pathological characteristics and ER, PR and HER2 status were collected. Patients are prospectively followed until death. Genotyping using the HumanCoreExome chipset from Illumina is currently underway and will be completed in early summer 2015. Results: 1502 patients were included from March 2012 to May 2014 from 71 French institutions. Median age at metastatic relapse was 60 years (range 26-93). Median time from primary diagnosis to metastatic relapse was 30 months (range 0-473) with 24% of patients already metastatic at initial diagnosis. 78% of patients were ER+, 18% were HER2+ and only 16% were triple negative. Molecular subtype classification derived from pathological data following St Gallen consensus recommendations is presented below: n (%)Luminal A like261 (22.2%)Luminal B like HER2 negative476 (40.5%)Luminal B like HER2 positive134 (11.4%)HER2 positive non Luminal (ER-)111 (9.5%)Triple negative193 (16.4%)Missing data327 64% of the patients had received previous adjuvant treatment, among which 81% received adjuvant chemotherapy and 9% trastuzumab. At metastatic relapse, loco-regional progression, liver, lung and bone metastasis were documented in 301 (20%), 494 (33%), 410 (27%) and 1017 (68%) patients respectively. 313 patients (21%) had bone only metastatic disease. First line treatment included: chemotherapy (71%), endocrine therapy (50%) and anti-HER2 treatments (17%). Survival data will be presented at the meeting. Conclusion: Despite a theoretically better prognosis and widespread use of adjuvant hormonal treatment, ER+/HER2- breast cancer still account for more than 60% of mBC. The proportion of patients with HER2+ disease (18%) and triple negative disease (16%) is consistent with percentages observed in early BC populations. In comparison with a cohort of "cured", localized cancer, such as the SIGNAL/PHARE study, GWAS analysis will allow for the identification of genetic polymorphisms correlated with treatment resistance. Fundamentally, such variants will provide insight into the molecular mechanisms responsible for host-genetic influence on BC progression. From a clinical perspective, genetic variants that predispose to metastatic disease can serve as stratification variables in future clinical trials, particularly as the development of new treatment options for resistant BC is needed. Citation Format: Bachelot T, Lavergne E, Romieu G, Rios M, Heudel P-E, Roemer-Becuwe C, Jouannaud C, Tredan O, Chaigneau L, Arnedos M, Orfeuvre H, Petit T, Quenel-Tueux N, Jacquin J-P, Ferrero J-M, Moullet I, Abadie-Lacourtoisie S, Penault-Llorca F, Blanc E, Cox D. SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-06.

Published
2016
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33. Treatment Patterns and Clinical Outcomes in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors Treated in the Community Practice Setting in the United States

Author

Beloo Mirakhur, Jennifer Frytak, A. Scott Paulson, Susan Pitman Lowenthal, Patricia S. Fox, Fadi Braiteh, Marley Boyd, Xiaolong Jiao, Sonia Pulgar, and David G. Cox

Subjects
Adult, Male, medicine.medical_specialty, Abdominal pain, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Octreotide, Neuroendocrine tumors, Overweight, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Intestinal Neoplasms, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Neoplasm Metastasis, Aged, Retrospective Studies, Aged, 80 and over, Chemotherapy, Hepatology, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Primary tumor, Survival Analysis, United States, Pancreatic Neoplasms, Neuroendocrine Tumors, 030220 oncology & carcinogenesis, Female, medicine.symptom, business, Somatostatin, medicine.drug
Abstract

OBJECTIVE This study was conducted to understand treatment patterns and clinical outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients treated in a large community oncology network. METHODS This retrospective study used the McKesson Specialty Health/US Oncology Network iKnowMed electronic health record database with supplemental chart review. Eligibility criteria included a metastatic neuroendocrine tumor diagnosis between January 1, 2008, and to December 31, 2012; at least 2 US Oncology Network visits; and age at least 18 years. Follow-up was through October 31, 2014. RESULTS Among the 229 patients identified, median age was 64.0 years, 52.4% were male, 69.4% were white, and 62.9% were overweight/obese. Primary tumor sites included small bowel (47.6%), pancreas (31.4%), and stomach/colorectum (21.0%). There were 16.2% under observation without treatment, 52.4% received only somatostatin analogs (SSAs), and 31.4% received chemotherapy/targeted therapy during treatment. In the first-line setting (n = 192), 77% received SSAs, 12% received chemotherapy, and 10.9% received targeted therapy. Fifty percent of patients receiving octreotide had a relative dose intensity of less than 85%, and 16.7% received above-label dose. Toxicities of SSAs included diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median overall survival from diagnosis was 68.0 months (95% confidence interval, 57.1 to not reached). CONCLUSIONS Most metastatic gastroenteropancreatic neuroendocrine tumor patients received systemic treatment with SSAs. Patient treatment used an individualized dosing approach. Overall survival and toxicity were consistent with the published literature.

Published
2017

34. 'Half Bacchanalian, Half Devout': White Intellectuals, Black Folk Culture, and the 'Negro Problem'

Author

David G. Cox

Subjects
History, White (horse), Folklore, media_common.quotation_subject, Gender studies, Racial politics, Politics, White supremacy, Local color, Aesthetics, Sociology, Ideology, Folk culture, media_common
Abstract

In the wake of the Civil War, white Americans generated an unprecedented amount of writing about the songs, stories, and “superstitions” of black southerners. This interest was not purely esthetic. In the late nineteenth century, folk culture was commonly conceptualized as a gauge of racial character and potential; in consequence, discourse on black folklore was entangled with the debate on the social and political place of African Americans. A number of scholars have noted the ways in which white supremacy was bulwarked by the work of folklorists, ethnologists, local color writers, and other intellectuals. The variety and contingency of this discourse on race, however, has sometimes been obscured, giving the impression of a static and monolithic racial ideology. Ideas about black folk culture shifted over time, shaped by a range of racial attitudes encompassing a liberal emphasis on uplift, a conservative commitment to stasis, and a radical insistence on regression. Moreover, the racial politics of intel...

Published
2015
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35. Impact of Body Mass Index, Age, Prostate Volume, and Genetic Polymorphisms on Prostate-specific Antigen Levels in a Control Population

Author

N. Koutlidis, Abdel-Rahmène Azzouzi, C. Gaffory, Geraldine Cancel-Tassin, Morgan Rouprêt, Luc Cormier, Olivier Cussenot, David G. Cox, Pierre Bigot, Antoine Valeri, Jean-Nicolas Cornu, Georges Fournier, V. Ondet, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Urologie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Chirurgie Urologique (BREST - Urologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Service d'urologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie urologique [CHU de Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), and Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Risk, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, diagnosis, Urology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Context (language use), urologic and male genital diseases, Polymorphism, Single Nucleotide, Body Mass Index, Mitochondrial Proteins, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, blood, Prostate, Internal medicine, medicine, Genetic predisposition, Humans, Receptor, Fibroblast Growth Factor, Type 2, Cation Transport Proteins, 2. Zero hunger, Gynecology, business.industry, Age Factors, Prostatic Secretory Proteins, Organ Size, Prostate-Specific Antigen, medicine.disease, 3. Good health, Prostate-specific antigen, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Kallikreins, pathology, France, T-Box Domain Proteins, business, Body mass index
Abstract

International audience; Prostate-specific antigen (PSA) is still the cornerstone of prostate cancer (PCa) screening and diagnosis in both research and current clinical practice. Inaccuracy of PSA is partly due to the influence of a number of genetic, clinical, and biological factors modifying PSA blood levels. In the present study, we detailed the respective influence of each factor among age, body mass index (BMI), prostate volume, and five single-nucleotide polymorphisms-rs10788160 (10q26), rs10993994 (10q11), rs11067228 (12q24), rs17632542 (19q13.33), and rs2928679 (8p21)-on PSA values in a cohort of 1374 men without PCa. Our results show that genetic factors, when risk variants are combined, influence PSA levels with an effect size similar to that of BMI. Taken together, the respective correlations of clinical parameters and genetic parameters would make it possible to correct and adjust PSA values more effectively in each individual. These results establish the basis to understand and implement a more personalised approach for the interpretation of PSA blood levels in the context of PCa screening and diagnosis. PATIENT SUMMARY: Prostate-specific antigen (PSA) values in an individual may vary according to genetic predisposition. The effect size of this variation can be significant, comparable with those resulting from clinical characteristics. Personalised PSA testing should take this into account

Published
2016
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36. Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Author

Mariagrazia Zucca, Thomas M. Habermann, Lauren R. Teras, Joseph Vijai, Lenka Foretova, Simon Crouch, Anneclaire J. De Roos, Jacqueline Clavel, Lindsay M. Morton, Melissa C. Southey, W. Ryan Diver, Patrick M. Gaffney, James McKay, Eve Roman, Sophia S. Wang, Mark P. Purdue, Hans-Olov Adami, Gilles Salles, Jarmo Virtamo, Yan W. Asmann, Angela Brooks-Wilson, Thierry Jo Molina, Andrew D. Zelenetz, Ahmet Dogan, Kenneth Offit, Peter Kraft, Gianluca Severi, Zhaoming Wang, Tongzhang Zheng, Sonja I. Berndt, Brian K. Link, Sasha Bernatsky, Theodore R. Holford, Emanuele Angelucci, Paige M. Bracci, Martyn T. Smith, Stephen J. Chanock, Brenda M. Birmann, Hervé Ghesquières, Stephen M. Ansell, Paolo Vineis, Mads Melbye, Kari E. North, Jenny Turner, Jacques Riby, Charles E. Lawrence, Alain Monnereau, Nikolaus Becker, Lucia Conde, James R. Cerhan, Susan L. Slager, Demetrius Albanes, Henrik Hjalgrim, Hervé Tilly, Héctor A. Velásquez García, Rebecca D. Jackson, Ann E. Clarke, Elizabeth A. Holly, Robert J. Klein, Paolo Boffetta, Mark Liebow, Karin E. Smedby, Marco Rais, David G. Cox, Patricia Hartge, Rosalind Ramsey-Goldman, Rachel S. Kelly, Lesley F. Tinker, Christine F. Skibola, Wendy Cozen, Tracy Lightfoot, Anne J. Novak, Heiner Boeing, Roel Vermeulen, Claire M. Vajdic, Bengt Glimelius, Kimberly A. Bertrand, Marc Maynadie, Eleanor Kane, Nathaniel Rothman, Yolanda Benavente, Paul Brennan, Anne Tjønneland, John J. Spinelli, Qing Lan, Anne Kricker, Alex Smith, Anthony Staines, Graham G. Giles, Carrie A. Thompson, Thomas E. Witzig, Stephanie J. Weinstein, Karen H. Cotenbader, Corinne Haioun, Anne Zeleniuch-Jacquotte, Simonetta Di Lollo, Alexandra Nieters, Rudolph Kaaks, Silvia de Sanjosé, Richard K. Severson, Yawei Zhang, Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Oklahoma Medical Research Foundation, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Bourgogne Franche-Comté ( UBFC ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), University of Calgary, Bernatsky, S. and García, H.A.V. and Spinelli, J.J. and Gaffney, P. and Smedby, K.E. and Ramsey-Goldman, R. and Wang, S.S. and Adami, H.-O. and Albanes, D. and Angelucci, E. and Ansell, S.M. and WAsmann, Y. and Becker, N. and Benavente, Y. and Berndt, S.I. and Bertrand, K.A. and Birmann, B.M. and Boeing, H. and Boffetta, P. and Bracci, P.M. and Brennan, P. and Brooks-Wilson, A.R. and Cerhan, J.R. and Chanock, S.J. and Clavel, J. and Conde, L. and Cotenbader, K.H. and Cox, D.G. and Cozen, W. and Crouch, S. and De Roos, A.J. and De Sanjose, S. and Di Lollo, S. and Diver, W.R. and Dogan, A. and Foretova, L. and Ghesquières, H. and Giles, G.G. and Glimelius, B. and Habermann, T.M. and Haioun, C. and Hartge, P. and Hjalgrim, H. and Holford, T.R. and Holly, E.A. and Jackson, R.D. and Kaaks, R. and Kane, E. and Kelly, R.S. and Klein, R.J. and Kraft, P. and Kricker, A. and Lan, Q. and Lawrence, C. and Liebow, M. and Lightfoot, T. and Link, B.K. and Maynadie, M. and McKay, J. and Melbye, M. and Molina, T.J. and Monnereau, A. and Morton, L.M. and Nieters, A. and North, K.E. and Novak, A.J. and Offit, K. and Purdue, M.P. and Rais, M. and Riby, J. and Roman, E. and Rothman, N. and Salles, G. and Severi, G. and Severson, R.K. and Skibola, C.F. and Slager, S.L. and Smith, A. and Smith, M.T. and Southey, M.C. and Staines, A. and Teras, L.R. and Thompson, C.A. and Tilly, H. and Tinker, L.F. and Tjonneland, A. and Turner, J. and Vajdic, C.M. and Vermeulen, R.C.H. and Vijai, J. and Vineis, P. and Virtamo, J. and Wang, Z. and Weinstein, S. and Witzig, T.E. and Zelenetz, A. and Zeleniuch-Jacquotte, A. and Zhang, Y. and Zheng, T. and Zucca, M. and Clarke, A.E., McGill University Health Center [Montreal] (MUHC), Oklahoma Medical Research Foundation (OMRF), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, and dIRAS RA-I&I RA

Subjects
Oncology, medicine.medical_specialty, Immunology, Single-nucleotide polymorphism, Genome-wide association study, [SDV.CAN]Life Sciences [q-bio]/Cancer, lymphoma, Human leukocyte antigen, Bioinformatics, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, SNP, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, General Medicine, medicine.disease, Systemic lupus, Lupus Nephritis, Risk of diffuse large B-cell lymphoma, 3. Good health, Lymphoma, 030220 oncology & carcinogenesis, business, Diffuse large B-cell lymphoma, IRF5, malignancy
Abstract

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genomewide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE. © 2017 BMJ Publishing Group. All rights reserved.

Published
2017
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37. Input-aware auto-tuning of compute-bound HPC kernels

Author

David G. Cox and Philippe Tillet

Subjects
020203 distributed computing, Computer science, business.industry, Parameterized complexity, 02 engineering and technology, Parallel computing, Pascal (programming language), Square matrix, Matrix multiplication, CUDA, Software, Template, 020204 information systems, 0202 electrical engineering, electronic engineering, information engineering, business, computer, computer.programming_language
Abstract

Efficient implementations of HPC applications for parallel architectures generally rely on external software packages (e.g., BLAS, LAPACK, CUDNN). While these libraries provide highly optimized routines for certain characteristics of inputs (e.g., square matrices), they generally do not retain optimal performance across the wide range of problems encountered in practice. In this paper, we present an input-aware auto-tuning framework for matrix multiplications and convolutions, ISAAC, which uses predictive modeling techniques to drive highly parameterized PTX code templates towards not only hardware-, but also application-specific kernels. Numerical experiments on the NVIDIA Maxwell and Pascal architectures show up to 3x performance gains over both cuBLAS and cuDNN after only a few hours of auto-tuning.

Published
2017
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38. A new era for treatment development in HER2-positive breast cancer

Author

Xavier Pivot and David G. Cox

Subjects
Oncology, medicine.medical_specialty, Pyridines, medicine.medical_treatment, MEDLINE, Breast Neoplasms, Antibodies, Monoclonal, Humanized, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Trastuzumab, HER2 Positive Breast Cancer, Internal medicine, medicine, Humans, 030212 general & internal medicine, Fulvestrant, Neoadjuvant therapy, biology, business.industry, Treatment development, Neoadjuvant Therapy, 030220 oncology & carcinogenesis, Monoclonal, biology.protein, Antibody, business, medicine.drug
Published
2017

39. A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability

Author

David G. Cox, Daniel Birnbaum, Qing Wang, Pascal Finetti, Frédéric Hollande, Emmanuelle Despras, François Bertucci, Emmanuelle Ruiz, Joël Lachuer, Christelle Chassot, Frédérique Fauvet, Pierre Saintigny, Roxane M. Pommier, Julie Caramel, Arnaud M. Vigneron, Anne Wierinckx, Nina Radosevic-Robin, Frédérique Penault-Llorca, Emmanuelle Charafe-Jauffret, Julien Wicinski, Emilie Thomas, Mojgan Devouassoux-Shisheboran, Stéphane Ansieau, Christiane Pinatel, Olivier Cabaud, Alain Puisieux, Anne-Pierre Morel, Jean-Luc Jauffret, Valérie Combaret, Jérôme Guitton, Caroline Moyret-Lalle, Agnès Tissier, Christophe Ginestier, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomo-Pathologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Synergie Lyon Cancer [Lyon], Laboratoire de Génétique de la Radiosensibilité (LGR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), clinique Phenicia, Service d'Oncologie Médicale, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), ProfileXpert, Université de Lyon, Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Melbourne, Cancérologie expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Arts et Métiers ParisTech d'Angers - Procédés Matériaux Durabilité ( LAMPA - PMD ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Oncologie Moléculaire, Oncovirologie et Biothérapies, Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Laboratoire de Génétique de la Radiosensibilité ( LGR ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire de Toxicologie ( ISPB ), Université de Lyon-Université de Lyon, Hunan Institute of Science and Technology, Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Equipe 6, Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), equipe 2, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -labex DEVweCAN, Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Synergie Lyon Cancer [Lyon], Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Genome instability, Pathology, Cellular differentiation, [SDV]Life Sciences [q-bio], Fluorescent Antibody Technique, medicine.disease_cause, Malignant transformation, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, Inbred NOD, Chromosome instability, Aged, 80 and over, Stem Cells, Cell Differentiation, General Medicine, Middle Aged, Flow Cytometry, 3. Good health, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Female, Stem cell, Adult, Chromatin Immunoprecipitation, medicine.medical_specialty, Adolescent, DNA damage, Immunoblotting, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, Genomic Instability, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Epithelial–mesenchymal transition, Mammary Glands, Human, Aged, Gene Expression Profiling, Carcinoma, Zinc Finger E-box-Binding Homeobox 1, Epithelial Cells, Sequence Analysis, DNA, 030104 developmental biology, Tissue Array Analysis, Methionine Sulfoxide Reductases, Cancer research, Tumor Suppressor Protein p53, Reactive Oxygen Species, Carcinogenesis, DNA Damage
Abstract

International audience; Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.

Published
2017
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40. Infomax-ICA using Hessian-free optimization

Author

Philippe Tillet, Hsiang-Tsung Kung, and David G. Cox

Subjects
Hessian matrix, Hyperparameter, Mathematical optimization, Computer science, MathematicsofComputing_NUMERICALANALYSIS, 020206 networking & telecommunications, 02 engineering and technology, Blind signal separation, Independent component analysis, symbols.namesake, ComputingMethodologies_PATTERNRECOGNITION, Rate of convergence, 0202 electrical engineering, electronic engineering, information engineering, symbols, 020201 artificial intelligence & image processing, Infomax, Newton's method, Algorithm
Abstract

We present HF-ICA, a second-order “Hessian-free” algorithm for Infomax-ICA. Our approach achieves asymptotically quadratic convergence while retaining the memory footprint of first-order methods. Without any hyperparameter tuning, we show better convergence properties than both other approximate Newton-type methods and finely-tuned stochastic Natural Gradient Descent on EEG and fMRI data. A portable, multi-threaded and vectorized C++ implementation is made publicly available along with MATLAB and Python interfaces.

Published
2017
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41. Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort

Author

Maria Rios, Alexia Renaud, Valérie Delecroix, Oana Cojocarasu, Céline Besse, Fabien Calvo, Mourad Sahbatou, Véronique Trillet-Lenoir, Ariane Darut-Jouve, Sandrine Lavau-Denes, Patrick Soulié, Hélène Blanché, Hervé Bonnefoi, Marie-Christine Mathieu, Céline Faure-Mercier, David G. Cox, Jean-Yves Pierga, Christelle Jouannaud, Thierry Petit, Jean-Marc Ferrero, Pierre Kerbrat, Christelle Levy, Carole Tarpin, Thomas Bachelot, Jérôme Meunier, Anne Boland, David Assouline, Gilles Romieu, Jean-François Deleuze, Cécile Agostini, Gilles Thomas, Isabelle Tennevet, Delphine Bacq, Jean-Philippe Jacquin, Iris Pauporté, Pierre Fumoleau, Xavier Pivot, and Hugues Bourgeois

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, medicine.medical_treatment, Population, Single-nucleotide polymorphism, 010402 general chemistry, 01 natural sciences, Article, Targeted therapy, 03 medical and health sciences, Breast cancer, Internal medicine, Genotype, Medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, skin and connective tissue diseases, education, neoplasms, Genotyping, Exome, RC254-282, education.field_of_study, integumentary system, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Odds ratio, medicine.disease, 0104 chemical sciences, 030104 developmental biology, business
Abstract

Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case–case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and k-means were then used to characterize the ancestry of the participants. A random sample of subjects from the main “European” cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2–positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients., Genetics: heredity does not explain HER2 expression A large gene-finding study failed to identify any hereditary factors linked to HER2 expression among women with breast cancer. A team in France led by Xavier Pivot from the University Hospital Center of Besançon, France, analyzed more than 500,000 single DNA letters from a cohort of 8703 patients with breast cancer, 3230 of whom had tumors with high expression of human epidermal growth factor receptor 2 (HER2) and are thus treated with for anti-HER2 targeted therapies. The researchers searched for DNA variants associated with HER2 status, but none reached the threshold for statistical significance. The findings reveal a high level of genetic diversity in women with HER2-positive breast cancer and suggest that HER2 amplification may have more to do with the intrinsic nature of the tumor than with the genetics of the patient.

Published
2017

42. 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
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43. The genetics of breast cancer susceptibility — Polymorphism and the prospect of their use in a clinical setting

Author

David G. Cox

Subjects
Genetics, business.industry, Complex disease, Genetic variants, Cancer, Disease, medicine.disease, Minor allele frequency, Breast cancer, Oncology, Polymorphism (computer science), Genetic predisposition, Medicine, business
Abstract

Susceptibility is defined as “the quality or state of being open to, subject to or non-resistant to stimuli, influences and agents”. The concept of genetic susceptibility simply implies that our genes predispose us, or increase the probability of us developing certain traits during the course of our lifetime. When we talk about susceptibility, it is important to remember that cancer is a complex disease, with numerous risk factors and development mechanisms. To assess the susceptibility of developing the disease, all risk factors need to be taken into consideration. In this paper, we will be investigating how common genetic variants (minor allele frequency ~5% or greater) associated with the risk of breast cancer have been identified and the issues that need to be overcome before these variants can be used medically to improve the prospects of preventing breast cancer.

Published
2014
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44. Genome-wide association studies and the clinic: a focus on breast cancer

Author

David G. Cox, Amelie S. Veron, and Sophie Blein

Subjects
Clinical Biochemistry, Breast Neoplasms, Genome-wide association study, Single-nucleotide polymorphism, Disease, Bioinformatics, Polymorphism, Single Nucleotide, Breast cancer screening, Breast cancer, Risk Factors, Drug Discovery, Biomarkers, Tumor, medicine, Humans, SNP, Genetic Predisposition to Disease, skin and connective tissue diseases, medicine.diagnostic_test, business.industry, Biochemistry (medical), Cancer, medicine.disease, Genetic epidemiology, Female, business, Genome-Wide Association Study
Abstract

Breast cancer is the most frequently diagnosed cancer among women worldwide, and has long been considered to be a genetic disease. A wide range of genetic variants, both rare mutations and more common variants, have been shown to influence breast cancer risk. In particular, recent studies have identified a number of common genetic variants, or single nucleotide polymorphisms, that are associated with breast cancer risk. In this review, we will briefly present the genetic epidemiology of breast cancer, genome-wide association study technology and how this technology may influence breast cancer screening in the clinic.

Published
2014
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45. Active and passive cigarette smoking and breast cancer risk: Results from the EPIC cohort

Author

María José Sánchez, Elisabete Weiderpass, Inger T. Gram, Kim Overvad, Rudolf Kaaks, Tonje Braaten, Antonia Trichopoulou, Pagona Lagiou, Alice Vilier, Jonas Manjer, Maria Sarantopoulou, Salma Butt, Eivind Bjerkaas, Petra H.M. Peeters, Pilar Amiano, H. Bas Bueno-de-Mesquita, Nicholas J. Wareham, Rosario Tumino, Ruth C. Travis, Kay-Tee Khaw, Fränzel J.B. Van Duijnhoven, Annika Steffen, Teresa Norat, Sabina Rinaldi, Anja Olsen, Paolo Vineis, Valerie McCormack, Timothy J. Key, Béatrice Fervers, Franco Berrino, Virginia Menéndez, Antonio Agudo, Isabelle Romieu, Marie-Christine Boutron-Ruault, Aurelio Barricarte, Amalia Mattiello, Marieke F. Bakker, Anne Tjønneland, Laure Dossus, David G. Cox, Elio Riboli, Heiner Boeing, María José Tormo, Domenico Palli, Jenny Chang-Claude, and Françoise Clavel-Chapelon

Subjects
Gynecology, Cancer Research, medicine.medical_specialty, Passive smoking, Obstetrics, business.industry, Hazard ratio, medicine.disease_cause, medicine.disease, European Prospective Investigation into Cancer and Nutrition, Menopause, Breast cancer, Oncology, Cohort, medicine, Menarche, business, Cohort study
Abstract

Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack-years and a dose-response relationship with increasing pack-years of smoking between menarche and first full-term pregnancy (FFTP). Studies with comprehensive quantitative life-time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05–1.28], 1.14 [1.04–1.25] and 1.10 [1.01–1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack-years from menarche to FFTP (1.73 [1.29–2.32] for every increase of 20 pack-years) while pack-years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34–0.82 for every increase of 20 pack-years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious.

Published
2014
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46. [Erratum to: 'Breast cancer screening: On our way to the future' [Bull. Cancer 103 (2016) 753-763]]

Author

Suzette, Delaloge, Thomas, Bachelot, François-Clément, Bidard, Marc, Espie, Etienne, Brain, Hervé, Bonnefoi, Joseph, Gligorov, Florence, Dalenc, Anne-Claire, Hardy-Bessard, David, Azria, Jean-Philippe, Jacquin, Jérôme, Lemonnier, William, Jacot, Anthony, Goncalves, Charles, Coutant, Gérard, Ganem, Thierry, Petit, Frédérique, Penault-Llorca, Marc, Debled, Mario, Campone, Christelle, Levy, Bruno, Coudert, Alain, Lortholary, Laurence, Venat-Bouvet, Julien, Grenier, Hugues, Bourgeois, Bernard, Asselain, Johanna, Arvis, Martine, Castro, Anne, Tardivon, David G, Cox, Patrick, Arveux, Corinne, Balleyguier, Fabrice, André, and Roman, Rouzier

Published
2016

47. Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes

Author

Carole Tarpin, Sophie Paget-Bailly, Xavier Pivot, David Assouline, Maria Rios, Isabelle Tennevet, Gilles Romieu, Jean-Marc Ferrero, Céline Faure-Mercier, Pierre Fumoleau, Jean-François Deleuze, David G. Cox, Hélène Blanché, Marie-Christine Mathieu, Thierry Petit, Christelle Jouannaud, Hugues Bourgeois, Oana Cojocarasu, Thomas Bachelot, Elsa Curtit, Jérôme Meunier, Ariane Darut-Jouve, Delphine Bacq, Jean-Yves Pierga, Sandrine Lavau-Denes, Iris Pauporté, Valérie Delecroix, Christelle Levy, Patrick Soulié, Pierre Kerbrat, Véronique Trillet-Lenoir, Anne Boland, Hervé Bonnefoi, Mourad Sahbatou, Gilles Thomas, Jean-Philippe Jacquin, Julie Henriques, Céline Besse, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Unité de Méthodologie et de Qualité de Vie en Cancérologie (UMQVC), Institut Régional Fédératif du Cancer (IRFC)-Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Pôle cancérologie (CHRU Besançon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Département d’Oncologie Médicale [Vandoeuvre Les Nancy], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), Département d'oncologie médicale, Institut Bergonié [Bordeaux], Département de Cancérologie Médicale [Lyon], Centre Léon Bérard : Centre Régional de Lutte Contre le Cancer Lyon Rhône-Alpes, Service Oncologie Médicale [Angers], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), Service Oncologie Médicale [Reims], Institut Jean Godinot [Reims], Centre Jean Bernard [Institut Inter-régional de Cancérologie - Le Mans], Service d’Oncologie Médicale [Strasbourg], Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Département d'oncologie médicale [Rouen], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service Oncologie Médicale [Grenoble], Institut Daniel Hollard [Grenoble], Pathologie mammaire, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service Oncologie Médicale [Saint Priest en Jarez], Institut de Cancérologie Lucien Neuwirth [Saint Priest en Jarez], Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Centre d'oncologie et de radiothérapie du parc [Dijon], Département Oncologie Médicale [Nice], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA), Département d’Oncologie Médicale [Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Oncologie Médicale [Caen], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service Oncologie Médicale [Saint-Nazaire] (Pôle Mutualiste), Centre Etienne Dolet [Saint-Nazaire], Service d’Oncologie Médicale [CHU Lyon Sud], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d’Onco-Hématologie et Médecine interne [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service d’Oncologie médicale [Orleans], Centre Hospitalier Régional d'Orléans (CHRO), Département d'Oncologie Médicale [Paris], Institut Curie [Paris], Service d'Oncologie Médicale [Rennes], CRLCC Eugène Marquis (CRLCC), Direction de la Recherche [Boulogne-Billancourt], Institut National du Cancer [Boulogne Billancourt] (INC), Centre de Ressources Biologiques [Paris], Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain [Paris] (CEPH), Centre de Ressources Biologiques [Evry], Centre National du Génotypage [Evry], Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work has fully been funded by the sponsor of the study, l’Institut National du Cancer, France (INCa)., Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Service d'Oncologie Médicale [Besançon], Centre Hospitalier Régional Universitaire Hôpital Jean Minjoz [Besançon], Unité de Méthodologie et de Qualité de Vie en Cancérologie ( UMQVC ), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC ( CEF2P / CARCINO ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université Bourgogne Franche-Comté ( UBFC ) -Université de Franche-Comté ( UFC ) -Pôle cancérologie (CHU Besançon), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Institut Régional Fédératif du Cancer ( IRFC ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Institut de Cancérologie de Lorraine - Alexis Vautrin ( ICL ), Institut Bergonié - CRLCC Bordeaux, UNICANCER - Institut de cancérologie de l'Ouest - Paul Papin [Angers], Centre Jean Bernard [Le Mans], Clinique Victor Hugo [Le Mans], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen ( CLCC Henri Becquerel ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre d’oncologie et de radiothérapie du Parc [Dijon], Clinique Drévon [Dijon], UNICANCER - Centre Antoine Lacassagne [Nice], Institut Paoli-Calmettes [Marseille], Centre Régional de Lutte contre le Cancer François Baclesse ( CRLC François Baclesse ), Service Oncologie Médicale [Saint-Nazaire] ( Pôle Mutualiste ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre Hospitalier Le Mans, Centre Hospitalier Régional d'Orléans ( CHR ), Institut Curie (Paris), CRLCC Eugène Marquis ( CRLCC ), Institut National du Cancer [Boulogne Billancourt] ( INC ), Centre d’Etudes du Polymorphisme Humain [Paris], Institut de recherche en cancérologie de Montpellier ( IRCM ), Université Montpellier 1 ( UM1 ) -CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut Régional Fédératif du Cancer (IRFC), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), BMC, BMC, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut Régional Fédératif du Cancer (IRFC), Polyclinique du Parc - Clinique Drevon [Dijon], Université Côte d'Azur (UCA)-UNICANCER-Université Côte d'Azur (UCA)-UNICANCER, and UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)

Subjects
0301 basic medicine, Oncology, [SDV]Life Sciences [q-bio], Metastasis, Cohort Studies, 0302 clinical medicine, Breast cancer, Neoplasm Metastasis, Prospective cohort study, Estrogen Receptor Status, Genetic variant, Randomized Controlled Trials as Topic, Aged, 80 and over, Framingham Risk Score, Middle Aged, Prognosis, Tumor Burden, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cohort, Female, Research Article, Adult, medicine.medical_specialty, Genotype, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Young Adult, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Aged, Neoplasm Staging, [ SDV ] Life Sciences [q-bio], business.industry, Cancer, medicine.disease, Survival Analysis, Single nucleotide polymorphism, 030104 developmental biology, Clinical Trials, Phase III as Topic, Risk score, Neoplasm Grading, business
Abstract

Background Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer. Methods A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS. Results The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1–97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival. Conclusions In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients’ outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis. Trial registration PHARE cohort: NCT00381901, Sept. 26, 2006 – SIGNAL cohort: INCa RECF1098, Jan. 28, 2009 Electronic supplementary material The online version of this article (doi:10.1186/s13058-017-0888-4) contains supplementary material, which is available to authorized users.

Published
2016
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48. Prognosis value of a genetic score based on germline genetic variants in a prospective cohort of early triple-negative breast cancer patients

Author

Xavier Pivot, Laetitia Gambotti, Marc Debled, Thomas Bachelot, Claire Garnier-Tixidre, Patrick Soulié, Hélène Blanché, Christelle Jouannaud, Gilles Romieu, Ariane Darut-Jouve, Sylvain Ladoire, David G. Cox, Sophie Paget-Bailly, Elsa Curtit, Jean-François Deleuze, Céline Faure-Mercier, Thierry Petit, Julie Henriques, Maria Rios, and Jean-Philippe Jacquin

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Heterogeneous group, business.industry, Internal medicine, medicine, Genetic variants, Prospective cohort study, business, Triple-negative breast cancer, Germline
Abstract

1529 Background: Triple-negative breast cancers (TNBC) are a heterogeneous group of tumors with poor outcome. In this study, the association between germline genetic variants and invasive disease-free survival (iDFS) was analyzed in TNBC patients. Methods: A genome wide-association study (GWAS) aimed to identify variants (single nucleotide polymorphisms – SNPs) associated with prognosis in 1121 patients with TNBC in the SIGNAL prospective cohort. Associations between gene variants and iDFS were assessed in univariate Cox regression models. Variants were combined in a score to identify risk categories. A prognostic model based on breast cancer stage and genetic variants was estimated using a multivariate Cox regression. Interaction between stage and genetic score was tested. Discrimination of the model was assessed by the Harrell’s C statistic and internal validity by bootstrap method. Results: The characteristics of the 1121 patients were representative of a population with early TNBC. Four SNPs on chromosomes 9 and 2 were found significantly associated to iDFS in univariate Cox models. Homozygous status for the most frequent allele was associated with poorer iDFS for two SNPs and this status was present in 50% and 57% of the population. For the two other SNPs, the most frequent allele was associated with more favorable iDFS. Three prognostic categories were derived from the genetic score. The following table presents the results from the multivariate Cox model including genetic score and disease stage. Clinical trial information: RECF1098. Conclusions: In a prospective cohort of 1121 patients with early TNBC, 4 genetic variants (SNPs) were associated with iDFS. A score involving SNPs provided similar prognostic indications as breast cancer stages. A search assessing the function and the role of the involved genes is ongoing.[Table: see text]

Published
2019
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49. Therogenetics: transferring GWAS technology to the clinic

Author

David G. Cox, Thomas Bachelot, Pierre-Etienne Heudel, and Olivier Tredan

Subjects
business.industry, Health, Toxicology and Mutagenesis, Breast tumours, MEDLINE, Breast Neoplasms, Genome-wide association study, Disease, Toxicology, medicine.disease, Bioinformatics, Germline, Metastasis, Breast cancer, Germline mutation, Genetics, medicine, Humans, Female, Genetic Predisposition to Disease, Neoplasm Metastasis, business, Germ-Line Mutation, Genetics (clinical), Genome-Wide Association Study
Abstract

Molecular characteristics of breast tumours have been used for the last decades to guide clinicians in treating this devastating disease. More recent information has led to further refinement of molecular characteristics of breast tumours, and subsequent indications for specific treatments. However, evidence exists that factors independent of the primary tumour type, potentially germline genetics, may influence progression to metastasis. In this review, we expose some of this evidence, and propose tools needed to overcome current limitations to the identification of specific germline variants that influence risk of metastases in breast cancer patients.

Published
2015
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50. Association betweenTP53R249S mutation and polymorphisms inTP53intron 1 in hepatocellular carcinoma

Author

Marlin D. Friesen, Sandra Ortiz-Cuaran, Suleeporn Sangrajrang, Thiravud Khuhaprema, Geoffroy Durand, Stephanie Villar, John D. Groopman, David G. Cox, Simona Ognjanovic, Pierre Hainaut, Amelie Chabrier, and Florence Le Calvez-Kelm

Subjects
Genetics, Cancer Research, Linkage disequilibrium, Mutation rate, Exon, Haplotype, Intron, SNP, Locus (genetics), Single-nucleotide polymorphism, Biology, Molecular biology
Abstract

Over 100 single nucleotide polymorphisms (SNP) are validated in the TP53 tumor suppressor gene. They define haplotypes, which may differ in their activities. Therefore, mutation in cancer may occur at different rates depending upon haplotypes. However, these associations may be masked by differences in mutations types and causes of mutagenesis. We have analyzed the associations between 19 SNPs spanning the TP53 locus and a single specific aflatoxin-induced TP53 mutation (R249S) in 85 in hepatocellular carcinoma cases and 132 controls from Thailand. An association with R249S mutation (P = 0.007) was observed for a combination of two SNPs (rs17882227 and rs8064946) in a linkage disequilibrium block extending from upstream of exon 1 to the first half of intron 1. This domain contains two coding sequences overlapping with TP53 (WRAP53 and Hp53int1) suggesting that sequences in TP53 intron 1 encode transcripts that may modulate R249S mutation rate in HCC.

Published
2013
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