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MonoSeq Variant Caller Reveals Novel Mononucleotide Run Indel Mutations in Tumors with Defective DNA Mismatch Repair.

Authors
  • Walker, Christopher J1
  • Miranda, Mario A1
  • O'Hern, Matthew J1
  • Blachly, James S2
  • Moyer, Cassandra L1
  • Ivanovich, Jennifer3
  • Kroll, Karl W4
  • Eisfeld, Ann-Kathrin4
  • Sapp, Caroline E1
  • Mutch, David G5
  • Cohn, David E1
  • Bundschuh, Ralf6
  • Goodfellow, Paul J7
  • 1 James Comprehensive Cancer Center and the Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH.
  • 2 James Comprehensive Cancer Center and the Department of Internal Medicine, Ohio State University, Columbus, Ohio.
  • 3 Siteman Cancer Center and the Department of Surgery, Washington University School of Medicine, St. Louis, MO.
  • 4 James Comprehensive Cancer Center, Ohio State University, Columbus, OH.
  • 5 Siteman Cancer Center and the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO.
  • 6 Department of Physics, Department of Chemistry and Biochemistry, Department of Internal Medicine, Ohio State University, Columbus, OH.
  • 7 James Comprehensive Cancer Center and the Department of Obstetrics and Gynecology, Ohio State University, Columbus, OH. [email protected]
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Oct 01, 2016
Volume
37
Issue
10
Pages
1004–1012
Identifiers
DOI: 10.1002/humu.23036
PMID: 27346418
Source
Medline
Keywords
License
Unknown

Abstract

Next-generation sequencing has revolutionized cancer genetics, but accurately detecting mutations in repetitive DNA sequences, especially mononucleotide runs, remains a challenge. This is a particular concern for tumors with defective mismatch repair (MMR) that accumulate strand-slippage mutations. We developed MonoSeq to improve indel mutation detection in mononucleotide runs, and used MonoSeq to investigate strand-slippage mutations in endometrial cancers, a tumor type that has frequent loss of MMR. We performed extensive Sanger sequencing to validate both clonal and subclonal MonoSeq mutation calls. Eighty-one regions containing mononucleotide runs were sequenced in 540 primary endometrial cancers (223 with defective MMR). Our analyses revealed that the overall mutation rate in MMR-deficient tumors was 20-30-fold higher than in MMR-normal tumors. MonoSeq analysis identified several previously unreported mutations, including a novel hotspot in an A7 run in the terminal exon of ARID5B.The ARID5B indel mutations were seen in both MMR-deficient and MMR-normal tumors, suggesting biologic selection. The analysis of tumor mRNAs revealed the presence of mutant transcripts that could result in translation of neopeptides. Improved detection of mononucleotide run strand-slippage mutations has clear implications for comprehensive mutation detection in tumors with defective MMR. Indel frameshift mutations and the resultant antigenic peptides could help guide immunotherapy strategies.

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