期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06132-1
关键词
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资金
- Jane and Aatos Erkko Foundation
- Academy of Finland [250345, 312041, 274555, 287665, 288836, 271642, 263164]
- Finnish Cancer Society
- Finnish Cancer Foundation
- Paulo Foundation
- K. Albin Johanssons stiftelse
- Paivikki and Sakari Sohlberg Foundation
- Cancer Society of Finland
- State Research Funding, Integrated Life Science Doctoral Program (ILS), University of Helsinki
- Sigrid Juselius Foundation
- SYSCOL (an EU FP7 Collaborative Project) [258236]
- Novo Nordic Foundation [NNF14OC0012747]
- Danish Cancer Society [R107-A7035, R133-A8520]
- Danish Council for Independent Research vertical bar Medical Science [DFF-4183-00619]
- Nordic Information for Action eScience Center (NIASC)
- NordForsk [62721, 07 BM 11/424]
- Ministry of Education and Culture, Finland
- Science for Life Laboratory
- Knut and Alice Wallenberg Foundation
- National Genomics Infrastructure - Swedish Research Council
- Uppsala Multidisciplinary Center for Advanced Computational Science
- Academy of Finland (AKA) [271642, 274555, 263164, 287665, 288836, 312041, 263164, 287665, 288836, 312041, 271642, 274555] Funding Source: Academy of Finland (AKA)
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 (Al) landscape in 1699 colorectal cancers, 256 of which have been whole-genome sequenced (WGSed). The imbalances pinpoint 38 genes as plausible Al targets based on previous knowledge. Unbiased CRISPR-Cas9 knockout and activation screens identified in total 79 genes within Al peaks regulating cell growth. Genetic and functional data implicate loss of TP53 as a sufficient driver of Al. The WGS highlights an influence of copy number aberrations on the rate of detected somatic point mutations. Importantly, the data reveal several associations between Al target genes, suggesting a role for a network of lineage-determining transcription factors in colorectal tumorigenesis. Overall, the results unravel the contribution of Al in colorectal cancer and provide a plausible explanation why so few genes are commonly affected by point mutations in cancers.
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