Characterizing the role of ancestry-specific variants of the Duffy Antigen Receptor for Chemokines (DARC) gene in the breast tumor microenvironment

Document Type

Conference Proceeding

Publication Date

8-1-2018

Publication Title

Mol Cancer Res

Abstract

Chemokines play an important role in cancer, as they direct infiltrating immune cells and mediate angiogenesis, tumor progression, and direct metastasis to distal sites. This work focuses on an atypical chemokine receptor, named the Duffy Antigen Receptor for Chemokines (DARC). DARC is a nonsignaling receptor that can bind two structural classes of inflammatory chemokines, and mainly acts as a regulator of chemokine homeostasis by removing chemokines from circulation when expressed on red blood cells, or moving them from sites of inflammation into circulation to recruit appropriate immune cell types. The purpose of this study is to investigate how polymorphic variants of the DARC gene found across global populations influence ancestry-specific immune responses, and how these changes in the immune response influence the breast tumor microenvironment. A well-studied example of this is a variant restricted to recent decedents of sub-Saharan Africa, known as the Duffy-Null allele. This variant removes expression of DARC from red blood cells, causing those individuals carrying the Duffy-Null allele to lose the ability to sequester chemokines in circulation. In terms of immune response, Duffy-Null status is shown to be predictive of chronic low white blood cell counts observed in individuals of African descent. By using 1000 Genomes Project variant calling data, we have been able to identify additional gene variants restricted to varying global populations. Our initial study is focused on variants found in the regulatory region of the gene, as these variants will likely change how the DARC gene will be expressed. Preliminarily, using data from the Genotype-Tissue Expression project (GTEx), we have been able to show that our DARC gene variants are also tissue-specific expression quantitative trait loci, showing significant changes in tissue-specific gene expression in association with our variants of interest. By studying these variants with panels of human breast cell lines, ancestry-specific cell lines, and human tissue, we will be able to identify these ancestry-specific changes in immune response, and resulting breast tumor microenvironment.

Volume

16

Issue

Supplement 8

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