The cancer-associated genetic variant rs3903072 modulates immune cells in the tumor microenvironment

Yi Zhang, Mohith Manjunath, Jialu Yan, Brittany A. Baur, Shilu Zhang, Sushmita Roy, Jun S. Song

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number754
JournalFrontiers in Genetics
Volume10
Issue numberJUL
DOIs
StatePublished - 2019

Keywords

  • Breast cancer
  • Functional characterization
  • GWAS
  • Immune cells
  • Noncoding variant
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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