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 compr...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201708552 |
| _version_ | 1797285703262928896 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Johanna Kondelin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T18:07:04Z |
| format | Article |
| id | doaj.art-ef342cd752574cf1b549cf1e60ecdf37 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:07:04Z |
| publishDate | 2018-09-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj.art-ef342cd752574cf1b549cf1e60ecdf372024-03-02T09:04:15ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-09-01109n/an/a10.15252/emmm.201708552Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancerJohanna Kondelin0Kari Salokas1Lilli Saarinen2Kristian Ovaska3Heli Rauanheimo4Roosa‐Maria Plaketti5Jiri Hamberg6Xiaonan Liu7Leena Yadav8Alexandra E Gylfe9Tatiana Cajuso10Ulrika A Hänninen11Kimmo Palin12Heikki Ristolainen13Riku Katainen14Eevi Kaasinen15Tomas Tanskanen16Mervi Aavikko17Minna Taipale18Jussi Taipale19Laura Renkonen‐Sinisalo20Anna Lepistö21Selja Koskensalo22Jan Böhm23Jukka‐Pekka Mecklin24Halit Ongen25Emmanouil T Dermitzakis26Outi Kilpivaara27Pia Vahteristo28Mikko Turunen29Sampsa Hautaniemi30Sari Tuupanen31Auli Karhu32Niko Välimäki33Markku Varjosalo34Esa Pitkänen35Lauri A Aaltonen36Medicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandInstitute of Biotechnology University of Helsinki Helsinki FinlandGenome‐Scale Biology Research Program Research Programs Unit University of Helsinki Helsinki FinlandGenome‐Scale Biology Research Program Research Programs Unit University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandInstitute of Biotechnology University of Helsinki Helsinki FinlandInstitute of Biotechnology University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandDivision of Functional Genomics Department of Medical Biochemistry and Biophysics (MBB) Karolinska Institutet Stockholm SwedenMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandDepartment of Surgery Helsinki University Central Hospital Hospital District of Helsinki and Uusimaa Helsinki FinlandDepartment of Surgery Helsinki University Central Hospital Hospital District of Helsinki and Uusimaa Helsinki FinlandThe HUCH Gastrointestinal Clinic Helsinki University Central Hospital Helsinki FinlandDepartment of Pathology Jyväskylä Central Hospital Jyväskylä FinlandDepartment of Surgery Jyväskylä Central Hospital University of Eastern Finland Jyväskylä FinlandDepartment of Genetic Medicine and Development University of Geneva Medical School Geneva SwitzerlandDepartment of Genetic Medicine and Development University of Geneva Medical School Geneva SwitzerlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandGenome‐Scale Biology Research Program Research Programs Unit University of Helsinki Helsinki FinlandGenome‐Scale Biology Research Program Research Programs Unit University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandInstitute of Biotechnology University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandMedicum/Department of Medical and Clinical Genetics University of Helsinki Helsinki FinlandAbstract 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.https://doi.org/10.15252/emmm.201708552cancer geneticscolorectal cancermicrosatellite instability |
| spellingShingle | 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 Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer EMBO Molecular Medicine cancer genetics colorectal cancer microsatellite instability |
| title | Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer |
| title_full | Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer |
| title_fullStr | Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer |
| title_full_unstemmed | Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer |
| title_short | Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer |
| title_sort | comprehensive evaluation of coding region point mutations in microsatellite unstable colorectal cancer |
| topic | cancer genetics colorectal cancer microsatellite instability |
| url | https://doi.org/10.15252/emmm.201708552 |
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