Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China.
Cancer Med. 2018 Aug;7(8):3912-3920. doi: 10.1002/cam4.1612. Epub 2018 Jun 20.
Genome-wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions. Besides, we performed a pathway enrichment analysis to find common-enrich pathways of cancer driver genes and susceptibility genes. Finally, on the basis of the gastric cancer samples and data from TCGA STAD project, we evaluated the associations between susceptibility loci and somatic alterations. Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes (P = .05). The susceptibility genes and driver genes were commonly enriched in 8 biological pathways. Gastric cancer susceptibility locus of rs2285947 was associated with truncation mutation within Signaling by PDGF pathway (OR = 0.26, 95%CI: 0.12-0.55, P = 3.93 × 10 ). The rs1679709 was connected with COSMIC Signature15 (P = .026). Moreover, rs1679709 was also associated with copy number values of RFC4 which is related to Signature15. These results provide evidence for the relationship between germline variants and somatic alterations, which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development.
全基因组关联研究已经确定了胃癌中的几个种系变异。同时，测序研究也描述了在胃癌发生过程中广泛出现的体细胞改变。然而，胃癌中种系变异和体细胞改变之间的关系仍不清楚。基于以前的研究和公开可用的数据库，确定了 11 个胃癌易感性位点和 276 个驱动基因。进行了富集分析，以检测驱动基因是否富集在易感性区域。此外，我们还进行了通路富集分析，以找到癌症驱动基因和易感性基因的常见富集通路。最后，基于胃癌样本和 TCGA STAD 项目的数据，我们评估了易感性位点与体细胞改变之间的关联。富集分析表明，胃癌易感性基因比所有基因更有可能富集在驱动基因中（P =.05）。易感性基因和驱动基因通常在 8 个生物学途径中富集。胃癌易感性位点 rs2285947 与 PDGF 通路信号转导中的截断突变相关（OR = 0.26，95%CI：0.12-0.55，P = 3.93 × 10）。rs1679709 与 COSMIC Signature15 相关（P =.026）。此外，rs1679709 还与与 Signature15 相关的 RFC4 的拷贝数值相关。这些结果为种系变异与体细胞改变之间的关系提供了证据，有助于理解种系变异与体细胞改变在胃癌发生发展中的相互作用机制。
