Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
复制标题
DOI：
10.1016/j.ajhg.2008.02.008
复制
发表时间：
2008-04-01
影响因子：
9.8
通讯作者：
Easton, Douglas F.
中科院分区：
文献类型：
--
作者：
Antoniou, Antonis C.;Spurdle, Amanda B.;Easton, Douglas F.
BRCA1和BRCA2的种系突变会导致乳腺癌的高风险。然而，有证据表明，这些风险会受到家庭中聚集的其他遗传或环境因素的影响。最近的一项全基因组关联研究表明，FGFR2 （rs2981582）、TNRC9 （rs3803662）和MAP3K1 （rs889312）中的常见等位基因单核苷酸多态性（snp）与普通人群乳腺癌风险增加有关。为了研究这些位点是否也与BRCA1和BRCA2突变携带者的乳腺癌风险相关，我们在23项研究的10,358个突变携带者样本中对这些snp进行了基因分型。SNP rs2981582和rs889312的次要等位基因分别与BRCA2突变携带者的乳腺癌风险增加相关（每等位基因风险比[HR] = 1.32, 95% CI: 1.20-1.45, p（趋势）= 1.7 x 10(-8), HR = 1.12, 95% CI: 1.02-1.24， p趋势= 0.02），但与BRCA1突变携带者无关。rs3803662与BRCA1和BRCA2突变携带者的乳腺癌风险增加相关（每等位基因HR = 1.13, 95% CI: 1.06-1.20，在BRCA1和BRCA2组合中P-trend = 5 × 10(-5)）。这些基因座似乎与BRCA2突变携带者的乳腺癌风险倍增相互作用。FGFR2和MAP3K1 snp在BRCA1和BRCA2携带者之间的作用差异指出了BRCA1和BRCA2乳腺癌肿瘤的生物学差异，并证实了BRCA1突变携带者乳腺癌的不同性质。
Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, P-trend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, P-trend = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.