Abstract
Determining the functional impact of somatic mutations is crucial to understanding tumorigenesis and metastasis. Recent sequences of several cancers have provided comprehensive lists of somatic mutations across entire genomes, enabling investigation of the functional impact of somatic mutations in non-coding regions. Here, we study somatic mutations in 3′UTRs of genes that have been identified in four cancers and computationally predict how they may alter miRNA targeting, potentially resulting in dysregulation of the expression of the genes harboring these mutations. We find that somatic mutations create or disrupt putative miRNA target sites in the 3′UTRs of many genes, including several genes, such as MITF, EPHA3, TAL1, SCG3, and GSDMA, which have been previously associated with cancer. We also integrate the somatic mutations with germline mutations and results of association studies. Specifically, we identify putative miRNA target sites in the 3′UTRs of BMPR1B, KLK3, and SPRY4 that are disrupted by both somatic and germline mutations and, also, are in linkage disequilibrium blocks with high scoring markers from cancer association studies. The somatic mutation in BMPR1B is located in a target site of miR-125b; germline mutations in this target site have previously been both shown to disrupt regulation of BMPR1B by miR-125b and linked with cancer.
Highlights
The genomes of most adult human cancers contain thousands of somatic mutations [1], and a critical aspect of cancer research is determining which of these somatic mutations have crucial functional impact on biological processes related to tumorigenesis and metastasis [2,3,4]
Patterns of somatic mutations in 39UTRs We collected a total of 610 somatic mutations in 39UTRs from four cancers (SCLC, melanoma, lung, and prostate)
One report investigated the rates of non-coding somatic mutations in multiple myeloma and observed that many non-coding mutations were near coding regions with known somatic hypermutation and that the mutation frequency in somenon-coding regions was greater than that expected by chance [56], but the functional impact of these non-coding mutations was not investigated
Summary
The genomes of most adult human cancers contain thousands of somatic mutations [1], and a critical aspect of cancer research is determining which of these somatic mutations have crucial functional impact on biological processes related to tumorigenesis and metastasis [2,3,4]. One effect of somatic mutations in non-coding regions that has the potential to significantly impact cellular functions associated with cancer is the alteration of microRNA (miRNA) targeting. A somatic mutation in the 39UTR of TNFAIP2, a known target of the PRAM1 oncogene, creates a new miRNA target site that results in a reduction of TNFAIP2 expression in a patient with acute myeloid leukemia [28]. This example illustrates the potential for somatic mutations to alter miRNA targeting and contribute to pathogenesis, but there has, to this point, been limited investigation of somatic mutations located in miRNA target sites
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