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. Taipale & 17 others L. 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

Abstract

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
Volume10
Issue number9
Number of pages20
ISSN1757-4676
DOIs
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

Cite this

@article{b07f612a02b4450f9f1ce7b0fef4f987,
title = "Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer",
abstract = "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. {\circledC} 2018 The Authors. Published under the terms of the CC BY 4.0 license",
keywords = "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",
author = "J. Kondelin and K. Salokas and L. Saarinen and K. Ovaska and H. Rauanheimo and R.-M. Plaketti and J. Hamberg and X. Liu and L. Yadav and A.E. Gylfe and T. Cajuso and U.A. H{\"a}nninen and K. Palin and H. Ristolainen and R. Katainen and E. Kaasinen and T. Tanskanen and M. Aavikko and M. Taipale and J. Taipale and L. Renkonen-Sinisalo and A. Lepist{\"o} and S. Koskensalo and J. B{\"o}hm and J.-P. Mecklin and H. Ongen and E.T. Dermitzakis and O. Kilpivaara and P. Vahteristo and M. Turunen and S. Hautaniemi and S. Tuupanen and A. Karhu and N. V{\"a}lim{\"a}ki and M. Varjosalo and E. Pitk{\"a}nen and L.A. Aaltonen",
year = "2018",
doi = "10.15252/emmm.201708552",
language = "English",
volume = "10",
journal = "EMBO molecular medicine",
issn = "1757-4676",
publisher = "Wiley",
number = "9",

}

TY - JOUR

T1 - Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

AU - Kondelin, J.

AU - Salokas, K.

AU - Saarinen, L.

AU - Ovaska, K.

AU - Rauanheimo, H.

AU - Plaketti, R.-M.

AU - Hamberg, J.

AU - Liu, X.

AU - Yadav, L.

AU - Gylfe, A.E.

AU - Cajuso, T.

AU - Hänninen, U.A.

AU - Palin, K.

AU - Ristolainen, H.

AU - Katainen, R.

AU - Kaasinen, E.

AU - Tanskanen, T.

AU - Aavikko, M.

AU - Taipale, M.

AU - Taipale, J.

AU - Renkonen-Sinisalo, L.

AU - Lepistö, A.

AU - Koskensalo, S.

AU - Böhm, J.

AU - Mecklin, J.-P.

AU - Ongen, H.

AU - Dermitzakis, E.T.

AU - Kilpivaara, O.

AU - Vahteristo, P.

AU - Turunen, M.

AU - Hautaniemi, S.

AU - Tuupanen, S.

AU - Karhu, A.

AU - Välimäki, N.

AU - Varjosalo, M.

AU - Pitkänen, E.

AU - Aaltonen, L.A.

PY - 2018

Y1 - 2018

N2 - 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

AB - 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

KW - Article

KW - cancer cell

KW - clinical evaluation

KW - colony formation

KW - colorectal cancer

KW - controlled study

KW - gene expression

KW - gene frequency

KW - gene interaction

KW - gene replication

KW - genetic analysis

KW - genetic code

KW - genetic identification

KW - human

KW - human cell

KW - human tissue

KW - microsatellite instability

KW - mutator gene

KW - point mutation

KW - priority journal

KW - R105W gene

KW - single nucleotide polymorphism

KW - SMARCB1 gene

KW - STK38L gene

KW - tumor-related gene

KW - validation process

KW - whole exome sequencing

KW - wild type

KW - 3111 Biomedicine

KW - 1184 Genetics, developmental biology, physiology

KW - 3122 Cancers

U2 - 10.15252/emmm.201708552

DO - 10.15252/emmm.201708552

M3 - Article

VL - 10

JO - EMBO molecular medicine

JF - EMBO molecular medicine

SN - 1757-4676

IS - 9

M1 - e8552

ER -