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A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered

Angela N Brooks1, Peter S Choi1, Luc de Waal1

  • 1Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.

Plos One
|February 6, 2014
PubMed

Insights

Somatic mutations in the splicing factor U2AF1 drive consistent splicing alterations across lung adenocarcinoma and acute myeloid leukemia. These U2AF1 mutations impact 3' splice site recognition, affecting key cancer genes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genomics

Background:

  • Recurrent somatic mutations in U2AF1 (U2AF35) are found in various cancers.
  • The precise impact of these U2AF1 mutations on the cancer transcriptome remains incompletely understood.

Purpose of the Study:

  • To identify and characterize splicing alterations associated with U2AF1 mutations in distinct cancer types.
  • To investigate the functional consequence of U2AF1 mutations on splice site selection.

Main Methods:

  • Analysis of DNA and RNA sequencing data from The Cancer Genome Atlas (TCGA) for lung adenocarcinoma and acute myeloid leukemia (AML).
  • Identification of splicing alterations significantly associated with U2AF1 mutations.
  • Functional validation using cell line experiments (HeLa, 293T) expressing U2AF1 S34F mutant.
  • Assessment of 3' splice site sequence preferences.

Main Results:

  • Identified 131 and 369 significant splicing alterations in lung adenocarcinoma and AML, respectively, linked to U2AF1 mutations.
  • Discovered 30 splicing alterations common to both cancer types, including in Cancer Gene Census genes CTNNB1, CHCHD7, and PICALM.
  • Demonstrated that U2AF1 S34F/Y mutations alter 3' splice site recognition, favoring CAG over UAG sequences.

Conclusions:

  • U2AF1 mutations consistently induce specific splicing alterations in distinct cancer types.
  • These findings highlight U2AF1's role in cancer transcriptome regulation and identify potential therapeutic targets.

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