Dataset Information

Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.

ABSTRACT: Background:Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer. Methods:We addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations. Results:The investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC. Conclusions:The results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.

SUBMITTER: Wu J

PROVIDER: S-EPMC7364202 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.

Wu Jiande J Mamidi Tarun K K TKK Zhang Lu L Hicks Chindo C

International journal of genomics 20200706

<h4>Background</h4>Breast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. ...[more]

PMID: 32724790

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Project 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.

Project description:Background:A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. Materials and Methods:We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. Results:We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. Conclusion:The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

Dataset Information

Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.

Publications

Delineation of the Germline and Somatic Mutation Interaction Landscape in Triple-Negative and Non-Triple-Negative Breast Cancer.

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