Gain of function in somatic TP53 mutations is associated with immune‐rich breast tumors and changes in tumor‐associated macrophages

• Type of Material: Article
• Authors: Michael Behring, University of Alabama Birmingham; Ana I. Vazquez, Michigan State University; Xiangqin Cui, Emory University; Marguerite R. Irvin, University of Alabama Birmingham; Akinyemi I. Ojesina, University of Alabama Birmingham; Sumit Agarwal, University of Alabama Birmingham; Upender Manne, University of Alabama Birmingham; Sadeep Shrestha, University of Alabama Birmingham
• Language: English
• Date: 2019-12-01
• Publisher: Wiley Periodicals Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/mgg3.1001
• Title of Journal or Parent Work: Molecular Genetics & Genomic Medicine
• Volume: 7
• Issue: 12
• Start Page: 1
• End Page: 9
• Grant/Funding Information: NIH U54‐CA118948 (Manne), Cancer Research Experiences for Students (CaRES) Program at UAB; 5R25CA76023 (Behring), NIH T32‐CA04788 (Behring).
• Keywords: tumor-invasive lymphocytes; TP53 gain of function; breast cancer; tumor-associated macrophages
• Research Categories: Health Sciences, Epidemiology; Health Sciences, Oncology; Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Background Somatic mutations in TP53 are present in 20%–30% of all breast tumors. While there are numerous population‐based analyses of TP53, yet none have examined the relationship between somatic mutations in TP53 and tumor invasive immune cells. Methods Clinical and genetic data from 601 women drawn from The Cancer Genome Atlas (TCGA) were used to test the association between somatic TP53 mutation and immune‐rich or immune‐poor tumor status; determined using the CIBERSORT‐based gene expression signature of 22 immune cell types. Our validation dataset, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), used a pathologist‐determined measure of lymphocyte infiltration. Results Within TP53‐mutated samples, a mutation at codon p.R175H was shown to be present at higher frequency in immune‐rich tumors. In validation analysis, any somatic mutation in TP53 was associated with immune‐rich status, and the mutation at p.R175H had a significant association with tumor‐invasive lymphocytes. TCGA‐only analysis of invasive immune cell type identified an increase in M0 macrophages associated with p.R175H. Conclusions These findings suggest that TP53 somatic mutations, particularly at codon p.R175H, are enriched in tumors with infiltrating immune cells. Our results confirm recent research showing inflammation‐related gain of function in specific TP53 mutations.