Contribution of allelic imbalance to colorectal cancer

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  • Kimmo Palin, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Esa Pitkänen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Mikko Turunen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Biswajyoti Sahu, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Päivi Pihlajamaa, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Teemu Kivioja, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Eevi Kaasinen, Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17165, Stockholm, Sweden.
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  • Niko Välimäki, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Ulrika A Hänninen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Tatiana Cajuso, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Mervi Aavikko, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Sari Tuupanen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Outi Kilpivaara, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Linda van den Berg, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Johanna Kondelin, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Tomas Tanskanen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Riku Katainen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Marta Grau, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Heli Rauanheimo, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Roosa-Maria Plaketti, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Aurora Taira, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Päivi Sulo, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Tuomo Hartonen, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Kashyap Dave, Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17165, Stockholm, Sweden.
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  • Bernhard Schmierer, Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17165, Stockholm, Sweden.
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  • Sandeep Botla, Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17165, Stockholm, Sweden.
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  • Maria Sokolova, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Anna Vähärautio, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Kornelia Gladysz, Research Programs Unit, Genome-Scale Biology Research Program, University of Helsinki, Biomedicum, PO Box 63 (Haartmaninkatu 8), Helsinki FIN-00014, Finland.
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  • Halit Ongen, Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, 1211, Geneva, Switzerland.
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  • Emmanouil Dermitzakis, Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, 1211, Geneva, Switzerland.
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  • Jesper Bertram Bramsen
  • Torben Falck Ørntoft
  • Claus Lindbjerg Andersen
  • Ari Ristimäki, Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital, Haartmaninkatu 3, FI-00290, Helsinki, Finland.
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  • Anna Lepistö, Department of Gastrointestinal Surgery, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 4, FI-00290, Helsinki, Finland.
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  • Laura Renkonen-Sinisalo, Department of Gastrointestinal Surgery, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 4, FI-00290, Helsinki, Finland.
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  • Jukka-Pekka Mecklin, Department of Health Sciences, Faculty of Sport and Health Sciences, University of Jyväskylä, PO Box 35, FI-40014, Jyväskylä, Finland.
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  • Jussi Taipale, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1GA, UK. ajt208@cam.ac.uk.
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  • Lauri A Aaltonen, Department of Biosciences and Nutrition, Karolinska Institutet, SE-17177, Stockholm, Sweden. lauri.aaltonen@helsinki.fi.

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.

OriginalsprogEngelsk
Artikelnummer3664
TidsskriftNature Communications
Vol/bind9
ISSN2041-1723
DOI
StatusUdgivet - 10 sep. 2018

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