Abstract
Prostate cancer (PCa) is the most common diagnosed malignancy and the second leading cause of cancer-related deaths among men in the USA. Advances in high-throughput genotyping and next generation sequencing technologies have enabled discovery of germline genetic susceptibility variants and somatic mutations acquired during tumor formation. Emerging evidence indicates that germline variations may interact with somatic events in carcinogenesis. However, the possible oncogenic interactions and cooperation between germline and somatic variation and their role in aggressive PCa remain largely unexplored. Here we investigated the possible oncogenic interactions and cooperation between genes containing germline variation from genome-wide association studies (GWAS) and genes containing somatic mutations from tumor genomes of 305 men with aggressive tumors and 52 control samples from The Cancer Genome Atlas (TCGA). Network and pathway analysis were performed to identify molecular networks and biological pathways enriched for germline and somatic mutations. The analysis revealed 90 functionally related genes containing both germline and somatic mutations. Transcriptome analysis revealed a 61-gene signature containing both germline and somatic mutations. Network analysis revealed molecular networks of functionally related genes and biological pathways including P53, STAT3, NKX3-1, KLK3, and Androgen receptor signaling pathways enriched for germline and somatic mutations. The results show that integrative analysis is a powerful approach to uncovering the possible oncogenic interactions and cooperation between germline and somatic mutations and understanding the broader biological context in which they operate in aggressive PCa.
Highlights
Despite remarkable progress in patient screening using the prostate specific antigen (PSA) and improved patient care, prostate cancer (PCa) remains a major public health problem [1, 2]
Advances in high-throughput genotyping and reduction in genotyping costs have enabled discovery of genetic variants, primarily single nucleotide polymorphisms (SNPs) called germline mutations associated with an increased risk of developing PCa using genome-wide association studies GWAS [5]
Our analysis reveals that oncogenic interactions and cooperation between germline and somatic mutations likely occurs through molecular networks and biological pathways
Summary
Despite remarkable progress in patient screening using the prostate specific antigen (PSA) and improved patient care, prostate cancer (PCa) remains a major public health problem [1, 2]. There is an urgent need for the discovery of molecular markers for early detection of aggressive PCa. Advances in high-throughput genotyping and reduction in genotyping costs have enabled discovery of genetic variants, primarily single nucleotide polymorphisms (SNPs) called germline mutations associated with an increased risk of developing PCa using genome-wide association studies GWAS [5]. Seibert et al developed and validated a polygenic hazard score to guide screening for aggressive PCa [7] Despite this remarkable success, establishing the link between genetic predisposition and tumorigenesis remains a challenge.
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