Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers

Tarun Karthik Kumar Mamidi; Jiande Wu; Chindo Hicks

doi:10.1155/2019/4168784

Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers

J Oncol. 2019 Nov 13:2019:4168784. doi: 10.1155/2019/4168784. eCollection 2019.

Authors

Tarun Karthik Kumar Mamidi¹, Jiande Wu², Chindo Hicks²

Affiliations

¹ Informatics Institute, University of Alabama at Birmingham, School of Medicine, 1720 2nd Avenue South, Birmingham, AL 35294-3412, USA.
² Department of Genetics, Louisiana State University Health Sciences Center, School of Medicine, 533 Bolivar, New Orleans, LA-70112, USA.

Abstract

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.