EMBO Molecular Medicine (Aug 2018)
Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer
- Johanna Kondelin,
- Kari Salokas,
- Lilli Saarinen,
- Kristian Ovaska,
- Heli Rauanheimo,
- Roosa‐Maria Plaketti,
- Jiri Hamberg,
- Xiaonan Liu,
- Leena Yadav,
- Alexandra E Gylfe,
- Tatiana Cajuso,
- Ulrika A Hänninen,
- Kimmo Palin,
- Heikki Ristolainen,
- Riku Katainen,
- Eevi Kaasinen,
- Tomas Tanskanen,
- Mervi Aavikko,
- Minna Taipale,
- Jussi Taipale,
- Laura Renkonen‐Sinisalo,
- Anna Lepistö,
- Selja Koskensalo,
- Jan Böhm,
- Jukka‐Pekka Mecklin,
- Halit Ongen,
- Emmanouil T Dermitzakis,
- Outi Kilpivaara,
- Pia Vahteristo,
- Mikko Turunen,
- Sampsa Hautaniemi,
- Sari Tuupanen,
- Auli Karhu,
- Niko Välimäki,
- Markku Varjosalo,
- Esa Pitkänen,
- Lauri A Aaltonen
Affiliations
- Johanna Kondelin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Kari Salokas
- Institute of Biotechnology, University of Helsinki
- Lilli Saarinen
- Genome‐Scale Biology Research Program, Research Programs Unit, University of Helsinki
- Kristian Ovaska
- Genome‐Scale Biology Research Program, Research Programs Unit, University of Helsinki
- Heli Rauanheimo
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Roosa‐Maria Plaketti
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Jiri Hamberg
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Xiaonan Liu
- Institute of Biotechnology, University of Helsinki
- Leena Yadav
- Institute of Biotechnology, University of Helsinki
- Alexandra E Gylfe
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Tatiana Cajuso
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Ulrika A Hänninen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Kimmo Palin
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Heikki Ristolainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Riku Katainen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Eevi Kaasinen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Tomas Tanskanen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Mervi Aavikko
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Minna Taipale
- Division of Functional Genomics, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet
- Jussi Taipale
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Laura Renkonen‐Sinisalo
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa
- Anna Lepistö
- Department of Surgery, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa
- Selja Koskensalo
- The HUCH Gastrointestinal Clinic, Helsinki University Central Hospital
- Jan Böhm
- Department of Pathology, Jyväskylä Central Hospital
- Jukka‐Pekka Mecklin
- Department of Surgery, Jyväskylä Central Hospital, University of Eastern Finland
- Halit Ongen
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Emmanouil T Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School
- Outi Kilpivaara
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Pia Vahteristo
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Mikko Turunen
- Genome‐Scale Biology Research Program, Research Programs Unit, University of Helsinki
- Sampsa Hautaniemi
- Genome‐Scale Biology Research Program, Research Programs Unit, University of Helsinki
- Sari Tuupanen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Auli Karhu
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Niko Välimäki
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Markku Varjosalo
- Institute of Biotechnology, University of Helsinki
- Esa Pitkänen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- Lauri A Aaltonen
- Medicum/Department of Medical and Clinical Genetics, University of Helsinki
- DOI
- https://doi.org/10.15252/emmm.201708552
- Journal volume & issue
-
Vol. 10,
no. 9
pp. 1 – 20
Abstract
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.
Keywords
