Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Abstract

SUMMARY Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

Oncogenic splicing abnormalities induced by DEAD‐Box Helicase 56 amplification in colorectal cancer

“…The expression of WEE1 is suppressed in colon cancer and non‐small cell lung cancer . Interestingly, the expression of some tumor suppressor genes, such as LKB1 and KLF6 , was controlled by splicing alterations . In the present study, we showed that WEE1 expression is also altered through alternative splicing by DDX56 overexpression.…”

“…RNA splicing enables the production of multiple mRNA species by alternative splicing of exons, which are found in nearly 95% of mammalian genes, to generate tissue‐ and species‐specific differentiation patterns . Deregulated or abnormal splicing is often observed in various malignancies, including colorectal cancer (CRC), which is one of the most common malignant tumors worldwide . Furthermore, splicing abnormality has recently been recognized as an important mechanism for regulating the expression of cancer‐related genes …”

Hsa‐miR‐139‐5p is a prognostic thyroid cancer marker involved in HNRNPF‐mediated alternative splicing

“…It has been reported to mediate the alternative splicing of multiple genes involved in different cancer‐related processes, such as the epithelial to mesenchymal transition and resistance to therapy . Recent reports have shown that the activity of alternative splicing regulators is recurrently altered in cancer, and this affects transcripts balance of key genes involved in cancer‐related pathways …”

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

“…Interestingly, an M110I mutation corresponding to the n5127 M157I mutation in C. elegans UAF-1 [35] was identified in a case of uterine corpus endometrial carcinoma. Mutations in the U2AF large subunit gene and the splicing factor one gene ( sfa-1 ) have also been proposed to be potential cancer drivers based on a comprehensive analysis of the mutation profiles of over 400 splicing factors in various cancers [65]. …”