6533b855fe1ef96bd12b1215
RESEARCH PRODUCT
Contribution of allelic imbalance to colorectal cancer
Aurora TairaEmmanouil T. DermitzakisSandeep Kumar BotlaJussi TaipaleJussi TaipaleJussi TaipalePäivi SuloUlrika A. HänninenBernhard SchmiererRoosa-maria PlakettiKashyap DaveNiko VälimäkiTatiana CajusoTorben F. ØRntoftAnna VähärautioPäivi PihlajamaaMervi AavikkoMaria SokolovaHalit OngenSari TuupanenJohanna KondelinOuti KilpivaaraAnna LepistöKornelia GladyszJukka-pekka MecklinEsa PitkänenEevi KaasinenEevi KaasinenHeli RauanheimoMarta GrauLauri A. AaltonenLauri A. AaltonenMikko P. TurunenAri RistimäkiAri RistimäkiLinda Van Den BergRiku KatainenTuomo HartonenJesper B. BramsenClaus L. AndersenTeemu KiviojaTomas TanskanenKimmo PalinBiswajyoti SahuLaura Renkonen-sinisalosubject
0301 basic medicineDenmarkLoss of HeterozygosityGeneral Physics and AstronomyAllelic ImbalanceLoss of heterozygosityGenotypeddc:576.5RNA Small Interferinglcsh:ScienceRNA Small Interfering/geneticsGeneticsMultidisciplinaryQGenomicsPhenotype3. Good healthGENOMEPhenotypesyöpägeenitAllelic ImbalanceTumor Suppressor Protein p53/geneticsColorectal NeoplasmsChromosomes Human Pair 8GENESDNA Copy Number VariationsGenotypeScienceTranscription Factors/geneticsGenomicscolorectal cancerBiologyArticleGeneral Biochemistry Genetics and Molecular BiologyProto-Oncogene Proteins p21(ras)Proto-Oncogene Proteins p21(ras)/genetics03 medical and health sciencesmedicineHumansPoint MutationGenetic Predisposition to DiseaseGenepaksusuolisyöpäChromosome AberrationsWhole Genome SequencingHUMAN-COLONGene Expression ProfilingPoint mutationCancerGeneral Chemistrymedicine.diseaseColorectal Neoplasms/geneticsENHANCERS030104 developmental biologyCELLSlcsh:Q3111 BiomedicineTumor Suppressor Protein p53CRISPR-Cas SystemsmutaatiotTranscription FactorsMicrosatellite Repeatsdescription
Point mutations in cancer have been extensively studied but chromosomal gains and losses have been more challenging to interpret due to their unspecific nature. Here we examine high-resolution allelic imbalance (AI) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible AI targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within AI peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of AI. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between AI target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of AI in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-09-10 |