Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer

Jiande Wu, Tarun Karthik Kumar Mamidi, Lu Zhang and Chindo Hicks
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Jiande Wu: Department of Genetics and the Bioinformatics and Genomics Program, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar Street, New Orleans, LA 70112, USA
Tarun Karthik Kumar Mamidi: Department of Genetics and the Bioinformatics and Genomics Program, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar Street, New Orleans, LA 70112, USA
Lu Zhang: Louisiana Tumor Registry, Louisiana State University Health Sciences Center, School of Public Health, 2020 Gravier Street, New Orleans, LA 70112, USA
Chindo Hicks: Department of Genetics and the Bioinformatics and Genomics Program, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar Street, New Orleans, LA 70112, USA

IJERPH, 2019, vol. 16, issue 6, 1-16

Abstract: Recent advances in high-throughput genotyping and the recent surge of next generation sequencing of the cancer genomes have enabled discovery of germline mutations associated with an increased risk of developing breast cancer and acquired somatic mutations driving the disease. Emerging evidence indicates that germline mutations may interact with somatic mutations to drive carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic alterations in triple-negative breast cancer (TNBC) have not been characterized. The objective of this study was to investigate the possible oncogenic interactions and cooperation between genes containing germline and somatic mutations in TNBC. Our working hypothesis was that genes containing germline mutations associated with an increased risk developing breast cancer also harbor somatic mutations acquired during tumorigenesis, and that these genes are functionally related. We further hypothesized that TNBC originates from a complex interplay among and between genes containing germline and somatic mutations, and that these complex array of interacting genetic factors affect entire molecular networks and biological pathways which in turn drive the disease. We tested this hypothesis by integrating germline mutation information from genome-wide association studies (GWAS) with somatic mutation information on TNBC from The Cancer Genome Atlas (TCGA) using gene expression data from 110 patients with TNBC and 113 controls. We discovered a signature of 237 functionally related genes containing both germline and somatic mutations. We discovered molecular networks and biological pathways enriched for germline and somatic mutations. The top pathways included the hereditary breast cancer and role of BRCA1 in DNA damage response signaling pathways. In conclusion, this is the first large-scale and comprehensive analysis delineating possible oncogenic interactions and cooperation among and between genes containing germline and somatic mutations in TNBC. Genetic and somatic mutations, along with the genes discovered in this study, will require experimental functional validation in different ethnic populations. Functionally validated genetic and somatic variants will have important implications for the development of novel precision prevention strategies and discovery of prognostic markers in TNBC.

Keywords: germline somatic mutation; interactions cooperation; triple-negative breast cancer (search for similar items in EconPapers)
JEL-codes: I I1 I3 Q Q5 (search for similar items in EconPapers)
Date: 2019
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

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