Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Paolo Peterlongo*, Jenny Chang-Claude, Kirsten B. Moysich, Anja Rudolph, Rita K. Schmutzler, Jacques Simard, Penny Soucy, Rosalind A. Eeles, Douglas F. Easton, Ute Hamann, Stefan Wilkening, Bowang Chen, Matti A. Rookus, MarjankaK. Schmidt, Frederieke H. van der Baan, Amanda B. Spurdle, Logan C. Walker, Felicity Lose, Ana-Teresa Maia, Marco MontagnaLaura Matricardi, Jan Lubinski, Anna Jakubowska, Encarna B. Gomez Garcia, Olufunmilayo I. Olopade, Robert L. Nussbaum, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Beth Y. Karlan, Sandra Orsulic, Jenny Lester, Wendy K. Chung, Alex Miron, Melissa C. Southey, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Yuan Chun Ding, Susan L. Neuhausen, Thomas V. O. Hansen, Anne-Marie Gerdes, Bent Ejlertsen, Annemarie H. van der Hout, EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)

Abstract

Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.

Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.

Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.

Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. (C)2014 AACR.

Original languageEnglish
Pages (from-to)308-316
Number of pages9
JournalCANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
Volume24
Issue number1
DOIs
Publication statusPublished - Jan-2015

Keywords

  • ASSOCIATION

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