BRCA1 wild-type allele modifies risk of ovarian cancer in carriers of BRCA1 germ-line mutations.
Strong inter- and intrafamilial variation of penetrance of breast and ovarian cancer is observed in BRCA1 mutation carriers. The wild-type copy of the BRCA1 gene is a plausible candidate as a cancer risk modifier given that the residual function corresponding to the intact BRCA1 allele may influence the process of tumor formation in BRCA1 carriers. Indeed, growing evidence is now becoming available on impaired reparation of double-strand DNA breaks in cells heterozygous for BRCA1 mutations, implying an enhanced mutability of BRCA1(+/-) cells. To determine whether certain variant forms of the wild-type BRCA1 allele are implicated in variation of the BRCA1-related cancer risk, their effect was studied in a panel of 591 women with BRCA1 germ-line mutations. We found that BRCA1 carriers with the wild-type BRCA1 copy bearing a common Gly1038 variant were at increased risk of ovarian cancer (hazards ratio, 1.50; 95% confidence interval, 1.03-2.19). The results of our study imply that a quite significant proportion of the interindividual variability in ovarian cancer penetrance in BRCA1 carriers may be explained by a common BRCA1 Gly1038 wild-type allele, given its high frequency (0.27).
Ginolhac
Sophie M
SM
Centre National de la Recherche Scientifique, UMR 5641, Lyon, France.
Gad
Sophie
S
Corbex
Marilys
M
Bressac-De-Paillerets
Brigitte
B
Chompret
Agnès
A
Bignon
Yves-Jean
YJ
Peyrat
Jean-Philippe
JP
Fournier
Joelle
J
Lasset
Christine
C
Giraud
Sophie
S
Muller
Danièle
D
Fricker
Jean-Pierre
JP
Hardouin
Agnès
A
Berthet
Pascaline
P
Maugard
Christine
C
Nogues
Catherine
C
Lidereau
Rosette
R
Longy
Michel
M
Olschwang
Sylviane
S
Toulas
Christine
C
Guimbaud
Rosine
R
Yannoukakos
Drakoulis
D
Szabo
Csilla
C
Durocher
Francine
F
Moisan
Anne-Marie
AM
Simard
Jacques
J
Mazoyer
Sylvie
S
Lynch
Henry T
HT
Goldgar
David
D
Stoppa-Lyonnet
Dominique
D
Lenoir
Gilbert M
GM
Sinilnikova
Olga M
OM
D000328:Adult; D000367:Age Factors; D000483:Alleles; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics; D002170:Canada / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D005787:Gene Frequency / Q000235:genetics; D019398:Genes, BRCA1 / Q000502:physiology; D005819:Genetic Markers / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006115:Greece / Q000453:epidemiology; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics*; D010298:Parity / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D016387:Women's Health
D005819:Genetic Markers