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.
Candidate genetic modifiers for breast and ovarian cancer risk inBRCA1andBRCA2 mutation carriers / Peterlongo, P; Chang Claude, J; Moysich, Kb; Rudolph, A; Schmutzler, Rk; Simard, J; Soucy, P; Eeles, Ra; Easton, Df; Hamann, U; Wilkening, S; Chen, B; Rookus, Ma; Schmidt, Mk; van der Baan, Fh; Spurdle, Ab; Walker, Lc; Lose, F; Maia, At; Montagna, M; Matricardi, L; Lubinski, J; Jakubowska, A; Gómez Garcia, Eb; Olopade, Oi; Nussbaum, Rl; Nathanson, Kl; Domchek, Sm; Rebbeck, Tr; Arun, Bk; Karlan, By; Orsulic, S; Lester, J; Chung, Wk; Miron, A; Southey, Mc; Goldgar, De; Buys, Ss; Janavicius, R; Dorfling, Cm; van Rensburg, Ej; Ding, Yc; Neuhausen, Sl; Hansen, Tv; Gerdes, Am; Ejlertsen, B; Jønson, L; Osorio, A; Martínez Bouzas, C; Benitez, J; Conway, Ee; Blazer, Kr; Weitzel, Jn; Manoukian, S; Peissel, B; Zaffaroni, D; Scuvera, G; Barile, M; Ficarazzi, F; Mariette, F; Fortuzzi, S; Viel, A; Giannini, Giuseppe; Papi, L; Martayan, A; Tibiletti, Mg; Radice, P; Vratimos, A; Fostira, F; Garber, Je; Donaldson, A; Brewer, C; Foo, C; Evans, Dg; Frost, D; Eccles, D; Brady, A; Cook, J; Tischkowitz, M; Adlard, J; Barwell, J; Walker, L; Izatt, L; Side, Le; Kennedy, Mj; Rogers, Mt; Porteous, Me; Morrison, Pj; Platte, R; Davidson, R; Hodgson, Sv; Ellis, S; Cole, T; Embrace, ; Godwin, Ak; Claes, K; Van Maerken, T; Meindl, A; Gehrig, A; Sutter, C; Engel, C; Niederacher, D; Steinemann, D; Plendl, H; Kast, K; Rhiem, K; Ditsch, N; Arnold, N; Varon Mateeva, R; Wappenschmidt, B; Wang Gohrke, S; Bressac de Paillerets, B; Buecher, B; Delnatte, C; Houdayer, C; Stoppa Lyonnet, D; Damiola, F; Coupier, I; Barjhoux, L; Venat Bouvet, L; Golmard, L; Boutry Kryza, N; Sinilnikova, Om; Caron, O; Pujol, P; Mazoyer, S; Belotti, M; GEMO Study, Collaborators; Piedmonte, M; Friedlander, Ml; Rodriguez, Gc; Copeland, Lj; de la Hoya, M; Segura, Pp; Nevanlinna, H; Aittomäki, K; van Os, Ta; Meijers Heijboer, He; van der Hout, Ah; Vreeswijk, Mp; Hoogerbrugge, N; Ausems, Mg; van Doorn, Hc; Collée, Jm; Hebon, ; Olah, E; Diez, O; Blanco, I; Lazaro, C; Brunet, J; Feliubadalo, L; Cybulski, C; Gronwald, J; Durda, K; Jaworska Bieniek, K; Sukiennicki, G; Arason, A; Chiquette, J; Teixeira, Mr; Olswold, C; Couch, Fj; Lindor, Nm; Wang, X; Szabo, Ci; Offit, K; Corines, M; Jacobs, L; Robson, Me; Zhang, L; Joseph, V; Berger, A; Singer, Cf; Rappaport, C; Kaulich, Dg; Pfeiler, G; Tea, Mk; Phelan, Cm; Greene, Mh; Mai, Pl; Rennert, G; Mulligan, Am; Glendon, G; Tchatchou, S; Andrulis, Il; Toland, Ae; Bojesen, A; Pedersen, Is; Thomassen, M; Jensen, Ub; Laitman, Y; Rantala, J; von Wachenfeldt, A; Ehrencrona, H; Askmalm, Ms; Borg, Å; Kuchenbaecker, Kb; Mcguffog, L; Barrowdale, D; Healey, S; Lee, A; Pharoah, Pd; Chenevix Trench, G; Kconfab, Investigators; Antoniou, Ac; Friedman, E.. - In: CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION. - ISSN 1055-9965. - STAMPA. - 24:1(2015), pp. 308-316. [10.1158/1055-9965.EPI-14-0532]
Candidate genetic modifiers for breast and ovarian cancer risk inBRCA1andBRCA2 mutation carriers
GIANNINI, Giuseppe;
2015
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.| File | Dimensione | Formato | |
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