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. 2015 Jan;24(1):308-16.
doi: 10.1158/1055-9965.EPI-14-0532. Epub 2014 Oct 21.

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Paolo Peterlongo  1 , Jenny Chang-Claude  2 , Kirsten B Moysich  3 , Anja Rudolph  2 , Rita K Schmutzler  4 , Jacques Simard  5 , Penny Soucy  5 , Rosalind A Eeles  6 , Douglas F Easton  7 , Ute Hamann  8 , Stefan Wilkening  9 , Bowang Chen  10 , Matti A Rookus  11 , Marjanka K Schmidt  12 , Frederieke H van der Baan  11 , Amanda B Spurdle  13 , Logan C Walker  14 , Felicity Lose  13 , Ana-Teresa Maia  15 , Marco Montagna  16 , Laura Matricardi  16 , Jan Lubinski  17 , Anna Jakubowska  17 , Encarna B Gómez Garcia  18 , Olufunmilayo I Olopade  19 , Robert L Nussbaum  20 , Katherine L Nathanson  21 , Susan M Domchek  21 , Timothy R Rebbeck  22 , Banu K Arun  23 , Beth Y Karlan  24 , Sandra Orsulic  24 , Jenny Lester  24 , Wendy K Chung  25 , Alex Miron  26 , Melissa C Southey  27 , David E Goldgar  28 , Saundra S Buys  29 , Ramunas Janavicius  30 , Cecilia M Dorfling  31 , Elizabeth J van Rensburg  31 , Yuan Chun Ding  32 , Susan L Neuhausen  32 , Thomas V O Hansen  33 , Anne-Marie Gerdes  34 , Bent Ejlertsen  35 , Lars Jønson  33 , Ana Osorio  36 , Cristina Martínez-Bouzas  37 , Javier Benitez  38 , Edye E Conway  39 , Kathleen R Blazer  40 , Jeffrey N Weitzel  41 , Siranoush Manoukian  42 , Bernard Peissel  42 , Daniela Zaffaroni  42 , Giulietta Scuvera  42 , Monica Barile  43 , Filomena Ficarazzi  44 , Frederique Mariette  44 , Stefano Fortuzzi  44 , Alessandra Viel  45 , Giuseppe Giannini  46 , Laura Papi  47 , Aline Martayan  48 , Maria Grazia Tibiletti  49 , Paolo Radice  50 , Athanassios Vratimos  51 , Florentia Fostira  51 , Judy E Garber  52 , Alan Donaldson  53 , Carole Brewer  54 , Claire Foo  55 , D Gareth R Evans  56 , Debra Frost  7 , Diana Eccles  57 , Angela Brady  58 , Jackie Cook  59 , Marc Tischkowitz  60 , Julian Adlard  61 , Julian Barwell  62 , Lisa Walker  63 , Louise Izatt  64 , Lucy E Side  65 , M John Kennedy  66 , Mark T Rogers  67 , Mary E Porteous  68 , Patrick J Morrison  69 , Radka Platte  7 , Rosemarie Davidson  70 , Shirley V Hodgson  71 , Steve Ellis  7 , Trevor Cole  72 ; EMBRACE; Andrew K Godwin  73 , Kathleen Claes  74 , Tom Van Maerken  74 , Alfons Meindl  75 , Andrea Gehrig  76 , Christian Sutter  77 , Christoph Engel  78 , Dieter Niederacher  79 , Doris Steinemann  80 , Hansjoerg Plendl  81 , Karin Kast  82 , Kerstin Rhiem  83 , Nina Ditsch  84 , Norbert Arnold  85 , Raymonda Varon-Mateeva  86 , Barbara Wappenschmidt  83 , Shan Wang-Gohrke  87 , Brigitte Bressac-de Paillerets  88 , Bruno Buecher  89 , Capucine Delnatte  90 , Claude Houdayer  91 , Dominique Stoppa-Lyonnet  92 , Francesca Damiola  93 , Isabelle Coupier  94 , Laure Barjhoux  95 , Laurence Venat-Bouvet  96 , Lisa Golmard  89 , Nadia Boutry-Kryza  97 , Olga M Sinilnikova  98 , Olivier Caron  99 , Pascal Pujol  100 , Sylvie Mazoyer  93 , Muriel Belotti  89 ; GEMO Study Collaborators; Marion Piedmonte  101 , Michael L Friedlander  102 , Gustavo C Rodriguez  103 , Larry J Copeland  104 , Miguel de la Hoya  105 , Pedro Perez Segura  106 , Heli Nevanlinna  107 , Kristiina Aittomäki  108 , Theo A M van Os  109 , Hanne E J Meijers-Heijboer  110 , Annemarie H van der Hout  111 , Maaike P G Vreeswijk  112 , Nicoline Hoogerbrugge  113 , Margreet G E M Ausems  114 , Helena C van Doorn  115 , J Margriet Collée  116 ; HEBON; Edith Olah  117 , Orland Diez  118 , Ignacio Blanco  119 , Conxi Lazaro  120 , Joan Brunet  121 , Lidia Feliubadalo  122 , Cezary Cybulski  17 , Jacek Gronwald  17 , Katarzyna Durda  17 , Katarzyna Jaworska-Bieniek  17 , Grzegorz Sukiennicki  17 , Adalgeir Arason  123 , Jocelyne Chiquette  124 , Manuel R Teixeira  125 , Curtis Olswold  126 , Fergus J Couch  127 , Noralane M Lindor  128 , Xianshu Wang  129 , Csilla I Szabo  130 , Kenneth Offit  131 , Marina Corines  132 , Lauren Jacobs  132 , Mark E Robson  131 , Liying Zhang  133 , Vijai Joseph  131 , Andreas Berger  134 , Christian F Singer  134 , Christine Rappaport  134 , Daphne Geschwantler Kaulich  134 , Georg Pfeiler  134 , Muy-Kheng M Tea  134 , Catherine M Phelan  135 , Mark H Greene  136 , Phuong L Mai  136 , Gad Rennert  137 , Anna Marie Mulligan  138 , Gord Glendon  139 , Sandrine Tchatchou  140 , Irene L Andrulis  141 , Amanda Ewart Toland  142 , Anders Bojesen  143 , Inge Sokilde Pedersen  144 , Mads Thomassen  145 , Uffe Birk Jensen  146 , Yael Laitman  147 , Johanna Rantala  148 , Anna von Wachenfeldt  149 , Hans Ehrencrona  150 , Marie Stenmark Askmalm  151 , Åke Borg  152 , Karoline B Kuchenbaecker  7 , Lesley McGuffog  7 , Daniel Barrowdale  7 , Sue Healey  13 , Andrew Lee  7 , Paul D P Pharoah  153 , Georgia Chenevix-Trench  13 ; KConFab Investigators; Antonis C Antoniou  7 , Eitan Friedman  154
Affiliations

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

Paolo Peterlongo et al. Cancer Epidemiol Biomarkers Prev. 2015 Jan.

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.

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Conflict of interest statement

Disclosure of potential conflict of interest: All authors declare that they have no conflicts of interest.

References

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