评估与低外显率乳腺癌风险 SNP 相关基因中的罕见变异在乳腺癌易感性中的作用。
Evaluating the breast cancer predisposition role of rare variants in genes associated with low-penetrance breast cancer risk SNPs.
机构信息
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
出版信息
Breast Cancer Res. 2018 Jan 9;20(1):3. doi: 10.1186/s13058-017-0929-z.
BACKGROUND
Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk.
METHODS
The coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population. Rare (minor allele frequency ≤ 0.001 in the Exome Aggregation Consortium and Exome Variant Server databases) loss-of-function (LoF) and missense variants were studied.
RESULTS
LoF variants were rare in both the cases and control participants across all the candidate genes, with only 38 different LoF variants observed in a total of 39 carriers. For the majority of genes (n = 36), no LoF variants were detected in either the case or control cohorts. No individual gene showed a significant excess of LoF or missense variants in the cases compared with control participants. Among all candidate genes as a group, the total number of carriers with LoF variants was higher in the cases than in the control participants (26 cases and 13 control participants), as was the total number of carriers with missense variants (406 versus 353), but neither reached statistical significance (p = 0.077 and p = 0.512, respectively). The genes contributing most of the excess of LoF variants in the cases included TET2, NRIP1, RAD51B and SNX32 (12 cases versus 2 control participants), whereas ZNF283 and CASP8 contributed largely to the excess of missense variants (25 cases versus 8 control participants).
CONCLUSIONS
Our data suggest that rare LoF and missense variants in genes associated with low-penetrance breast cancer risk SNPs may contribute some additional risk, but as a group these genes are unlikely to be major contributors to breast cancer heritability.
背景
全基因组关联研究（GWAS）已经确定了许多与乳腺癌风险小幅度增加相关的单核苷酸多态性（SNP）。迄今为止的研究表明，一些 SNP 改变了相关基因的表达，这可能介导了风险修饰。在此基础上，我们假设其中一些基因可能富含与更高乳腺癌风险相关的罕见编码变异。
方法
对 56 个基因的编码区域和外显子-内含子边界进行测序，这些基因要么被 GWAS 提出是 SNP 的调节靶点，要么位于与风险 SNP 距离 < 500 kb 的位置。在先前 BRCA1 和 BRCA2 突变检测结果为阴性的 1043 个家族性乳腺癌家庭的索引病例中以及在澳大利亚人群中 944 个与癌症匹配的无癌对照参与者中进行了测序。研究了罕见的（次要等位基因频率 ≤ 在 Exome Aggregation Consortium 和 Exome Variant Server 数据库中为 0.001）无功能（LoF）和错义变异。
结果
在所有候选基因中，病例和对照参与者的 LoF 变异均很少见，在总共 39 名携带者中仅观察到 38 种不同的 LoF 变异。对于大多数基因（n = 36），在病例或对照队列中均未检测到 LoF 变异。与对照参与者相比，没有单个基因在病例中显示出 LoF 或错义变异的显著过多。在所有候选基因作为一个整体中，携带 LoF 变异的病例数量多于对照参与者（26 例病例和 13 例对照参与者），携带错义变异的病例数量也多于对照参与者（406 例和 353 例），但均未达到统计学意义（p = 0.077 和 p = 0.512，分别）。导致病例中 LoF 变异过多的基因包括 TET2、NRIP1、RAD51B 和 SNX32（12 例病例和 2 例对照参与者），而 ZNF283 和 CASP8 则主要导致错义变异过多（25 例病例和 8 例对照参与者）。
结论
我们的数据表明，与低外显率乳腺癌风险 SNP 相关的基因中的罕见 LoF 和错义变异可能会增加一些额外的风险，但作为一个整体，这些基因不太可能是乳腺癌遗传率的主要贡献者。
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