A single nucleotide polymorphism in the 5' untranslated region of RAD51 and risk of cancer among BRCA1/2 mutation carriers.
RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.
Wang
W W
WW
Laboratory of Population Genetics, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Spurdle
A B
AB
Kolachana
P
P
Bove
B
B
Modan
B
B
Ebbers
S M
SM
Suthers
G
G
Tucker
M A
MA
Kaufman
D J
DJ
Doody
M M
MM
Tarone
R E
RE
Daly
M
M
Levavi
H
H
Pierce
H
H
Chetrit
A
A
Yechezkel
G H
GH
Chenevix-Trench
G
G
Offit
K
K
Godwin
A K
AK
Struewing
J P
JP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic; D051135:Rad51 Recombinase; D014157:Transcription Factors / Q000235:genetics; D014481:United States
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase