Table_2_The Cancer-Associated Genetic Variant Rs3903072 Modulates Immune Cells in the Tumor Microenvironment.xlsx

Genome-wide association studies (GWAS) have hitherto identified several germline variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized. Recent studies have begun to uncover the regulatory potential of noncoding GWAS SNPs using epigenetic information in corresponding cancer cell types and matched normal tissues. However, this approach does not explore the potential effect of risk germline variants on other important cell types that constitute the microenvironment of tumor or its precursor. This paper presents evidence that the breast-cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor-infiltrating lymphocytes. CTSW is a candidate tumor-suppressor gene, with expression highly specific to immune cells and also positively correlated with breast cancer patient survival. Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3’ end of CTSW through three-dimensional chromatin interaction. Our work thus poses the possibility that a cancer-associated genetic variant could regulate a gene not only in the cell of cancer origin but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.

全基因组关联分析（Genome-wide association studies, GWAS）迄今已鉴定出若干与癌症易感性相关的生殖系变异，但这些风险调节因子的分子功能在很大程度上仍未被阐明。近期研究开始借助对应癌细胞类型及匹配正常组织中的表观遗传信息，揭示非编码GWAS单核苷酸多态性（single nucleotide polymorphisms, SNPs）的调控潜能。然而，该方法并未探究风险生殖系变异对构成肿瘤或其前驱体微环境的其他重要细胞类型的潜在影响。本研究提供证据表明，乳腺癌相关变异rs3903072可在肿瘤浸润淋巴细胞中调控CTSW基因的表达。CTSW是一种候选抑癌基因，其表达具有高度的免疫细胞特异性，且与乳腺癌患者生存率呈正相关。整合分析显示，淋巴细胞中一处与GWAS相关的增强子内存在推定的致病变异，该增强子通过三维染色质相互作用与CTSW基因的3'端形成染色质环。综上，本研究提示癌症相关遗传变异的调控靶点不仅可位于癌症起源细胞中，也可位于微环境的免疫细胞内，进而调控T淋巴细胞与自然杀伤细胞介导的免疫监视，影响早期肿瘤起始细胞的清除。