The Functional Impact of Alternative Splicing in Cancer

Abstract

Alternative splicing changes are frequently observed in cancer and are starting to be recognized as important signatures for tumor progression and therapy. However, their functional impact and relevance to tumorigenesis remain mostly unknown. We carried out a systematic analysis to characterize the potential functional consequences of alternative splicing changes in thousands of tumor samples. This analysis revealed that a subset of alternative splicing changes affect protein domain families that are frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer-related pathways. Moreover, there was a negative correlation between the number of these alternative splicing changes in a sample and the number of somatic mutations in drivers. We propose that a subset of the alternative splicing changes observed in tumors may represent independent oncogenic processes that could be relevant to explain the functional transformations in cancer, and some of them could potentially be considered alternative splicing drivers (AS drivers).

A Coiled‐Coil Domain Containing 50 Splice Variant Is Modulated by Serine/Arginine‐Rich Splicing Factor 3 and Promotes Hepatocellular Carcinoma in Mice by the Ras Signaling Pathway

“…Alternative splicing generates different mature mRNAs from a single gene through selection of different exons to increase transcriptome and proteome diversity . Aberrant alternative splicing events are commonly observed in cancer cells and contribute to tumor progression . Cancer‐specific mRNA transcripts, produced by interactions between cellular splicing factors and pre‐mRNAs, may result in either activation of oncogenes or inactivation of tumor‐suppressor genes, eventually leading to tumor invasion and metastasis .…”

A novel splice variant of LOXL2 promotes progression of human papillomavirus–negative head and neck squamous cell carcinoma

“…For example, to the best of our knowledge, the TCGA study was one of the most comprehensive genomic characterizations of HNSCC, in which multiple, frequently mutated genes such as CDKN2A, TP53, FAT1, and AJUBA were identified predominantly in HPV-negative tumors. 9 The genome-wide mapping of alternative splicing variants also has been identified in a variety of tumors, including gastric, prostate, and breast cancer as well as other tumors. Therefore, in the current study, we used functional studies and demonstrated the role of a novel splice variant of LOXL2 in HPV-negative HNSCC progression.…”

“…[2][3][4] Among patients with HNSCC, human papillomavirus (HPV)negative HNSCC has demonstrated a worse response to treatment and a poorer prognosis compared with HPV-positive HNSCC. 7,8 Given the importance of ASEs in regulating gene expression, the role of alternative splicing in tumorigenesis has attracted considerable interest, 9,10 and many cancer-related genes are considered to have functional diversity due to alternative splicing. In humans, it is estimated that >95% of multiexonic genes are alternatively spliced, which largely expands the complexity and diversity of human genes.…”

Mutations in spliceosome genes and therapeutic opportunities in myeloid malignancies

“…As with many other essential cellular processes, cancer cells have co‐opted alternative splicing to promote their survival and response to therapy. Many studies have revealed global dysregulation of splicing in cancer . For example, synonymous mutations occurring in consensus splice sites can alter intron recognition leading to intron retention and tumor suppressor inactivation .…”