The Cancer-Associated Genetic Variant Rs3903072 Modulates Immune Cells in the Tumor Microenvironment

Abstract

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.

Analysis and Interpretation of the Impact of Missense Variants in Cancer

“…Cancer may indeed be considered an adaptive evolutionary process [ 31 , 32 , 33 ], and most works correspondingly focus on the study of somatic mutations [ 16 , 34 ]. As shown by Genome Wide Association Studies (GWAS), many of these cancer-associated genetic variants are not necessarily the cause of the disease, they simply exist into the general picture of the neoplastic disorder and may contribute or not to the evolution of the clinical course of the pathology [ 35 ].…”

ABC-GWAS: Functional Annotation of Estrogen Receptor-Positive Breast Cancer Genetic Variants

“…To identify candidate target genes for each GWAS SNP, we scanned all genes within 4 Mb centered at the SNP by constructing a multivariate linear regression model with the expression level of each gene as the response variable and the genotype of the GWAS SNP and the copy number (CN) of the gene as predictors (Zhang et al, 2018b;Zhang Y. et al, 2019). The processed gene expression levels in RSEM units were transformed as log 2 (RSEM + 1).…”

“…Most studies investigating breast cancer GWAS variants have so far focused only on eQTL analysis to find genes correlated with a variant genotype, while only few have pursued a systematic analysis of causal variants and target genes through chromatin structure and TFs ( Cowper-Sal lari et al, 2012 ; French et al, 2013 ; Li et al, 2013 ; Ghoussaini et al, 2014 , 2016 ; Darabi et al, 2015 ; Dunning et al, 2016 ; Michailidou et al, 2017 ; Zhang et al, 2018b ; Zhang Y. et al, 2019 ). This paper presents ABC-GWAS, an interactive database containing our comprehensive analysis of 70 manually curated estrogen receptor-positive (ER+) breast cancer GWAS loci and 23 additional ER+ breast cancer loci from a recent fine mapping study ( Fachal et al, 2020 ).…”

Allele-specific expression: applications in cancer and technical considerations

“…At the somatic mutation level, a significant fraction of tumors have at least one somatically acquired-oncogenic mutation displaying allelic imbalance. Furthermore, recent evidence shows that germline regulatory variants can influence tissue immune infiltration [ 66 ], response to immunotherapy [ 67 ], and gene regulation in tumor-infiltrating lymphocytes only [ 68 ]. This suggests that future studies of ASE in both cancer tissues and immune cells may reveal additional insights into mechanisms of cancer development and response to therapy, and potentially even in predicting autoimmunity side effects to treatment [ 69 ].…”