Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

J. Kondelin, K. Salokas, L. Saarinen, K. Ovaska, H. Rauanheimo, R.-M. Plaketti, J. Hamberg, X. Liu, L. Yadav, A.E. Gylfe, T. Cajuso, U.A. Hänninen, K. Palin, H. Ristolainen, R. Katainen, E. Kaasinen, T. Tanskanen, M. Aavikko, M. Taipale, J. TaipaleL. Renkonen-Sinisalo, A. Lepistö, S. Koskensalo, J. Böhm, J.-P. Mecklin, H. Ongen, E.T. Dermitzakis, O. Kilpivaara, P. Vahteristo, M. Turunen, S. Hautaniemi, S. Tuupanen, A. Karhu, N. Välimäki, M. Varjosalo, E. Pitkänen, L.A. Aaltonen

Research output: Contribution to journalArticleScientificpeer-review


Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 license
Original languageEnglish
Article numbere8552
JournalEMBO molecular medicine
Issue number9
Number of pages20
Publication statusPublished - 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • Article
  • cancer cell
  • clinical evaluation
  • colony formation
  • colorectal cancer
  • controlled study
  • gene expression
  • gene frequency
  • gene interaction
  • gene replication
  • genetic analysis
  • genetic code
  • genetic identification
  • human
  • human cell
  • human tissue
  • microsatellite instability
  • mutator gene
  • point mutation
  • priority journal
  • R105W gene
  • single nucleotide polymorphism
  • SMARCB1 gene
  • STK38L gene
  • tumor-related gene
  • validation process
  • whole exome sequencing
  • wild type
  • 3111 Biomedicine
  • 1184 Genetics, developmental biology, physiology
  • 3122 Cancers

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