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

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 indi...

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Autores principales: Wu, Jiande, Mamidi, Tarun Karthik Kumar, Zhang, Lu, Hicks, Chindo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466377/
https://www.ncbi.nlm.nih.gov/pubmed/30909550
http://dx.doi.org/10.3390/ijerph16061055
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author Wu, Jiande
Mamidi, Tarun Karthik Kumar
Zhang, Lu
Hicks, Chindo
author_facet Wu, Jiande
Mamidi, Tarun Karthik Kumar
Zhang, Lu
Hicks, Chindo
author_sort Wu, Jiande
collection PubMed
description 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.
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spelling pubmed-64663772019-04-22 Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer Wu, Jiande Mamidi, Tarun Karthik Kumar Zhang, Lu Hicks, Chindo Int J Environ Res Public Health Article 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. MDPI 2019-03-23 2019-03 /pmc/articles/PMC6466377/ /pubmed/30909550 http://dx.doi.org/10.3390/ijerph16061055 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Jiande
Mamidi, Tarun Karthik Kumar
Zhang, Lu
Hicks, Chindo
Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer
title Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer
title_full Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer
title_fullStr Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer
title_full_unstemmed Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer
title_short Integrating Germline and Somatic Mutation Information for the Discovery of Biomarkers in Triple-Negative Breast Cancer
title_sort integrating germline and somatic mutation information for the discovery of biomarkers in triple-negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466377/
https://www.ncbi.nlm.nih.gov/pubmed/30909550
http://dx.doi.org/10.3390/ijerph16061055
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