Contribution of allelic imbalance to colorectal cancer
| Autor: | Palin, Kimmo, Pitkänen, Esa, Turunen, Mikko, Sahu, Biswajyoti, Pihlajamaa, Päivi, Kivioja, Teemu, Kaasinen, Eevi, Välimäki, Niko, Hänninen, Ulrika A, Cajuso, Tatiana, Aavikko, Mervi, Tuupanen, Sari, Kilpivaara, Outi, Van Den Berg, Linda, Kondelin, Johanna, Tanskanen, Tomas, Katainen, Riku, Grau, Marta, Rauanheimo, Heli, Plaketti, Roosa-Maria, Taira, Aurora, Sulo, Päivi, Hartonen, Tuomo, Dave, Kashyap, Schmierer, Bernhard, Botla, Sandeep, Sokolova, Maria, Vähärautio, Anna, Gladysz, Kornelia, Ongen, Halit, Dermitzakis, Emmanouil, Bramsen, Jesper Bertram, Ørntoft, Torben Falck, Andersen, Claus Lindbjerg, Ristimäki, Ari, Lepistö, Anna, Renkonen-Sinisalo, Laura, Mecklin, Jukka-Pekka, Taipale, Jussi, Aaltonen, Lauri A |
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| Předmět: |
Chromosome Aberrations
DNA Copy Number Variations Genotype Whole Genome Sequencing Denmark Gene Expression Profiling Loss of Heterozygosity Genomics Allelic Imbalance 3. Good health Proto-Oncogene Proteins p21(ras) Phenotype Humans Point Mutation Genetic Predisposition to Disease CRISPR-Cas Systems RNA Small Interfering Tumor Suppressor Protein p53 Colorectal Neoplasms Chromosomes Human Pair 8 Microsatellite Repeats Transcription Factors |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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