Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer.
Johanna KondelinKari SalokasLilli SaarinenKristian OvaskaHeli RauanheimoRoosa-Maria PlakettiJiri HambergXiaonan LiuLeena YadavAlexandra E GylfeTatiana CajusoUlrika A HänninenKimmo PalinHeikki RistolainenRiku KatainenEevi KaasinenTomas TanskanenMervi AavikkoMinna TaipaleJussi TaipaleLaura Renkonen-SinisaloAnna LepistöSelja KoskensaloJan BöhmJukka-Pekka MecklinHalit OngenEmmanouil T DermitzakisOuti KilpivaaraPia VahteristoMikko TurunenSampsa HautaniemiSari TuupanenAuli KarhuNiko VälimäkiMarkku VarjosaloEsa PitkänenLauri A AaltonenPublished in: EMBO molecular medicine (2019)
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.