Abstract
Defective DNA repair may contribute to early age and late stage at time of diagnosis and mutations in critical tumor suppressor genes, such as
TP53
in breast cancer. Using DNA samples from 436 breast cancer cases (374 Caucasians and 62 African-Americans), we tested these associations with 18 non-synonymous single-nucleotide polymorphisms (nsSNPs) in four DNA repair pathways: (i) base excision repair:
ADPRT V762A
,
APE1 D148E
,
XRCC1 R194W/
R280H/
R399Q
and
POLD1 R119H
; (ii) double-strand break repair:
NBS1 E185Q
and
XRCC3 T241M
; (iii) mismatch repair:
MLH1 I219V
,
MSH3 R940Q/
T1036A
and
MSH6 G39E
and (iv) nucleotide excision repair:
ERCC2 D312N/
K751Q
,
ERCC4 R415Q
,
ERCC5 D1104H
and
XPC A499V/K939Q
. Younger age at diagnosis (<50) was associated with
ERCC2 312 DN/NN
genotypes [odds ratio (OR) = 1.76; 95% confidence interval (CI) = 1.10, 2.81] and NBS1 185 QQ genotype (OR = 3.09; 95% CI = 1.47, 6.49). The
XPC 939 QQ
genotype was associated with
TP53
mutations (OR = 5.80; 95% CI = 2.23, 15.09). There was a significant trend associating younger age at diagnosis (<50) with increasing numbers of risk genotypes for
ERCC2 312 DN/NN
,
MSH6 39 EE
and
NBS1 185 QQ
(
P
trend
< 0.001). A similar significant trend was also observed associating
TP53
mutations with increasing numbers of risk genotypes for
XRCC1 399 QQ
,
XPC 939 QQ
,
ERCC4 415 QQ
and
XPC 499 AA
(
P
trend
< 0.001). Our pilot data suggest that nsSNPs of multiple DNA repair pathways are associated with younger age at diagnosis and
TP53
mutations in breast cancer and larger studies are warranted to further evaluate these associations.
