PT  - JOURNAL ARTICLE
AU  - Yi Zhang
AU  - Mohith Manjunath
AU  - Jialu Yan
AU  - Brittany A. Baur
AU  - Shilu Zhang
AU  - Sushmita Roy
AU  - Jun S. Song
TI  - Can cancer GWAS variants modulate immune cells in the tumor microenvironment?
AID  - 10.1101/493171
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 493171
4099  - http://biorxiv.org/content/early/2018/12/13/493171.short
4100  - http://biorxiv.org/content/early/2018/12/13/493171.full
AB  - Genome-wide association studies (GWAS) have hitherto identified several genetic 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 non-coding GWAS SNPs by 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 might 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.