@article{20010d0fc6bf42d498c09f6df8f62afb,
title = "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{\textquoteright} 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.",
keywords = "Breast cancer, Functional characterization, GWAS, Immune cells, Noncoding variant, Tumor microenvironment",
author = "Yi Zhang and Mohith Manjunath and Jialu Yan and Baur, {Brittany A.} and Shilu Zhang and Sushmita Roy and Song, {Jun S.}",
note = "Funding Information: This manuscript has been released as a preprint at https://www. biorxiv.org/content/10.1101/493171v1 (Zhang et al., 2018a). The results appearing here are in part based upon the data generated by the TCGA Research Network (http://cancergenome.nih.gov/, dbGaP accession number phs000424.v6.p1 on 05/06/2016) and the GTEx Project, supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. We acknowledge the ENCODE consortium that generated the datasets used in the manuscript. Funding Information: YZ, MM, JY and JS were supported by the NIH 1U54GM114838 grant, awarded by National Institute of General Medical Sciences (NIGMS) through funds provided by the trans-NIH (National Institutes of Health) Big Data to Knowledge (BD2K) initiative, the National Brain Tumor Society and NIH R01CA163336. BB, SZ, and SR were supported by the NIH BD2K grant U54 AI117924 and Vilas Fellowship; BB was also supported by the Genomic Sciences Training Program (NHGRI 5T32HG002760). Publisher Copyright: Copyright {\textcopyright} 2019 Zhang, Manjunath, Yan, Baur, Zhang, Roy and Song. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.",
year = "2019",
doi = "10.3389/fgene.2019.00754",
language = "English (US)",
volume = "10",
journal = "Frontiers in Genetics",
issn = "1664-8021",
publisher = "Frontiers Media S. A.",
number = "JUL",
}