Genomic Epidemiology Group, German Cancer Research Center (Deutsches Krebsforschungszentrum; DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
J Natl Cancer Inst. 2011 Aug 17;103(16):1252-63. doi: 10.1093/jnci/djr265. Epub 2011 Jul 26.
Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer.
To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided.
We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 × 10(-3) -3.96 × 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028).
This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.
最近，几项全基因组关联研究已经确定了乳腺癌的各种遗传易感性位点。相对较少的是这些位点与乳腺癌的既定风险因素之间可能存在的相互作用。
为了评估单核苷酸多态性（SNP）与既定风险因素之间的相互作用，我们前瞻性地从国家癌症研究所的乳腺癌和前列腺癌队列联盟（BPC3）内嵌套的 8576 例乳腺癌病例和 11892 例对照中收集 DNA 样本和问卷调查数据。我们对 17 个种系 SNP（FGFR2-rs2981582、FGFR2-rs3750817、TNRC9-rs3803662、2q35-rs13387042、MAP3K1-rs889312、8q24-rs13281615、CASP8-rs1045485、LSP1-rs3817198、COL1A1-rs2075555、COX11-rs6504950、RNF146-rs2180341、6q25-rs2046210、SLC4A7-rs4973768、NOTCH2-rs11249433、5p12-rs4415084、5p12-rs10941679、RAD51L1-rs999737）进行了基因分型，并通过逻辑回归估计了比值比，以确认先前报道的与乳腺癌风险相关的关联。我们进行了似然比检验，以评估 17 个 SNP 与 9 个既定风险因素（初潮年龄、产次、绝经年龄、激素替代疗法使用、家族史、身高、体重指数、吸烟状况和饮酒量）之间的相互作用，并对 153 次检验进行了多重检验校正（调整后的 P 值阈值=0.05/153=3×10(-4))。针对肿瘤分期、雌激素和孕激素受体状态以及诊断时年龄等亚组，进行了病例-病例比较，以确定多态性的可能差异相关性。所有统计检验均为双侧检验。
我们确认了 14 个 SNP 与乳腺癌风险相关（P(trend)=2.57×10(-3)-3.96×10(-19)）。三个 SNP（LSP1-rs3817198、COL1A1-rs2075555 和 RNF146-rs2180341）与乳腺癌风险无关。在考虑到多次检验后，未发现 17 个 SNP 与 9 个风险因素之间存在统计学显著的相互作用。我们还证实，FGFR2 和 TNRC9 中的 SNP 与雌激素受体阳性乳腺癌的风险增加有关，而与雌激素受体阴性乳腺癌的风险无关（FGFR2-rs2981582 的异质性 P 值=0.0016，TNRC9-rs3803662 的异质性 P 值=0.0053）。SNP 5p12-rs10941679 与孕激素受体阳性乳腺癌的风险增加呈统计学显著相关（异质性 P 值=0.0028）。
本研究不支持已知的常见乳腺癌易感性位点强烈改变既定风险因素与乳腺癌之间关联的假设。
