Comprehensive evaluation of coding region point mutations in microsatellite‐unstable colorectal cancer. Issue 9 (14th August 2018)

• Record Type: Journal Article
• Authors: Kondelin, Johanna; Salokas, Kari; Saarinen, Lilli; Ovaska, Kristian; Rauanheimo, Heli; Plaketti, Roosa‐Maria; Hamberg, Jiri; Liu, Xiaonan; Yadav, Leena; Gylfe, Alexandra E; Cajuso, Tatiana; Hänninen, Ulrika A; Palin, Kimmo; Ristolainen, Heikki; Katainen, Riku; Kaasinen, Eevi; Tanskanen, Tomas; Aavikko, Mervi; Taipale, Minna; Taipale, Jussi; Renkonen‐Sinisalo, Laura; Lepistö, Anna; Koskensalo, Selja; Böhm, Jan; Mecklin, Jukka‐Pekka; Ongen, Halit; Dermitzakis, Emmanouil T; Kilpivaara, Outi; Vahteristo, Pia; Turunen, Mikko; Hautaniemi, Sampsa; Tuupanen, Sari; Karhu, Auli; Välimäki, Niko; Varjosalo, Markku; Pitkänen, Esa; Aaltonen, Lauri A;
• Is Part Of: EMBO molecular medicine. Volume 10:Issue 9(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-08-14
• Subjects: cancer genetics -- colorectal cancer -- microsatellite instability; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201708552
• Languages: English
• ISSNs: 1757-4676

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. Synopsis: To date, only few genes with causative point mutations are known in microsatellite instability in colorectal cancers (MSI CRC), most having been flagged by missense mutation hot spots. This study identifies candidate cancer driving genes based on exome‐wide somatic mutation data from MSI CRC. A ranked list of 57 candidate MSI CRC driver genes is defined. SMARCB1 exhibited altered interactions with several proteins with enrichment of alterations for the pentose phosphate pathway, and increased colony formation in CRC cells. STK38L exhibited altered interaction with several interaction partners, of which many have been previously linked to cancer. Seven novel hot spot containing candidate oncogenes CORIN, KLHL6, PCDHB16, PLEKHG1, PROS1, SPP2, and TROAP are identified. Abstract : To date, only few genes with causative point mutations are known in microsatellite instability in colorectal cancers (MSI CRC), most having been flagged by missense mutation hot spots. This study identifies candidate cancer driving genes based on exome‐wide somatic mutation data from MSI CRC.