12p11、12q24、9p21、9q31.2 及 ZNF365 上的常见变异与 BRCA1 和/或 BRCA2 突变携带者的乳腺癌风险相关。
Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers.
机构信息
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK.
出版信息
Breast Cancer Res. 2012 Feb 20;14(1):R33. doi: 10.1186/bcr3121.
INTRODUCTION
Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).
METHODS
To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.
RESULTS
Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).
CONCLUSIONS
The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
简介
已经证实，几种常见的等位基因与 BRCA1 和 BRCA2 突变携带者的乳腺癌和/或卵巢癌风险相关。最近对乳腺癌的全基因组关联研究确定了另外 8 个乳腺癌易感基因座：rs1011970（9p21、CDKN2A/B）、rs10995190（ZNF365）、rs704010（ZMIZ1）、rs2380205（10p15）、rs614367（11q13）、rs1292011（12q24）、rs10771399（12p11 附近的 PTHLH）和 rs865686（9q31.2）。
方法
为了评估这些单核苷酸多态性（SNP）是否与 BRCA1 和 BRCA2 携带者的乳腺癌风险相关，我们对 12599 名 BRCA1 和 7132 名 BRCA2 突变携带者进行了这些 SNP 的基因分型，并在回顾性似然框架内分析了它们与乳腺癌风险的关联。
结果
只有 PTHLH 附近的 SNP rs10771399 与 BRCA1 突变携带者的乳腺癌风险相关（每个等位基因的危险比（HR）=0.87，95%置信区间：0.81 至 0.94，P 趋势=3×10-4）。这种关联仅限于证明或预测导致蛋白表达缺失的突变（HR=0.82，95%置信区间：0.74 至 0.90，P 趋势=3.1×10-5，P 差值=0.03）。有 4 个 SNP 与 BRCA2 突变携带者的乳腺癌风险相关：rs10995190，P 趋势=0.015；rs1011970，P 趋势=0.048；rs865686，2df-P=0.007；rs1292011 2df-P=0.03。rs10771399（PTHLH）主要与 BRCA1 突变携带者的雌激素受体（ER）阴性乳腺癌相关（HR=0.81，95%置信区间：0.74 至 0.90，P 趋势=4×10-5），并且 BRCA2 突变携带者的 ER 阴性乳腺癌也存在边际关联（HR=0.78，95%置信区间：0.62 至 1.00，P 趋势=0.049）。
结论
目前的研究结果，结合先前确定的风险修饰因子，最终将导致更准确的风险预测，并提高对 BRCA1 和 BRCA2 突变携带者疾病病因的理解。
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