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Published September 10, 2018 | Version v1
Dataset Open

Contribution of allelic imbalance to colorectal cancer

Description

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, and unbiased CRISPR-Cas9 knockout and activation screens identified altogether 79 genes within AI peaks regulating cell growth. Genetic and functional data implicates 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.

Notes

This work was supported by grants from the Jane and Aatos Erkko Foundation, Academy of Finland (Finnish Center of Excellence Program 2012–2017, 250345), the Finnish Cancer Society, the Finnish Cancer Foundation, the Paulo Foundation, K. Albin Johanssons stiftelse, Päivikki and Sakari Sohlberg Foundation, Cancer Society of Finland, the State Research Funding, Integrated Life Science Doctoral Program (ILS), University of Helsinki, the Sigrid Juselius Foundation and SYSCOL (an EU FP7 Collaborative Project, 258236), the Novo Nordic Foundation (NNF14OC0012747), the Danish Cancer Society (R107-A7035 and R133-A8520), the Danish Council for Independent Research | Medical Science (DFF - 4183-00619), the Nordic Information for Action eScience Center (NIASC); a Nordic Center of Excellence financed by NordForsk (Project number 62721) and Nordic biobank-based study of causes and biomarkers of cancer: Pilot study financed by NordForsk 07 BM 11/424. We acknowledge the computational resources provided by the ELIXIR node hosted at CSC - IT Center for Science funded by the Academy of Finland (grants 271642, 263164) and the Ministry of Education and Culture, Finland. The Danish Cancer Biobank is acknowledged for biological material. We also acknowledge the support from Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, the National Genomics Infrastructure funded by the Swedish Research Council, and Uppsala Multidisciplinary Center for Advanced Computational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure.

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Additional details

Related works

Is supplement to
10.1038/s41467-018-06132-1 (DOI)

Funding

SYSCOL – Systems Biology of Colorectal Cancer 258236
European Commission

References

  • Palin et.al. Contribution of allelic imbalance to colorectal cancer (2018) Nature Communications