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Contribution of allelic imbalance to colorectal cancer

Author

Listed:
  • Kimmo Palin

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Esa Pitkänen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Mikko Turunen

    (University of Helsinki, Biomedicum Helsinki)

  • Biswajyoti Sahu

    (University of Helsinki, Biomedicum Helsinki)

  • Päivi Pihlajamaa

    (University of Helsinki, Biomedicum Helsinki)

  • Teemu Kivioja

    (University of Helsinki, Biomedicum Helsinki)

  • Eevi Kaasinen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki
    Karolinska Institutet)

  • Niko Välimäki

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Ulrika A. Hänninen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Tatiana Cajuso

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Mervi Aavikko

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Sari Tuupanen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Outi Kilpivaara

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Linda van den Berg

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Johanna Kondelin

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Tomas Tanskanen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Riku Katainen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Marta Grau

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Heli Rauanheimo

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Roosa-Maria Plaketti

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Aurora Taira

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Päivi Sulo

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Tuomo Hartonen

    (University of Helsinki, Biomedicum Helsinki)

  • Kashyap Dave

    (Karolinska Institutet)

  • Bernhard Schmierer

    (Karolinska Institutet)

  • Sandeep Botla

    (Karolinska Institutet)

  • Maria Sokolova

    (University of Helsinki, Biomedicum Helsinki)

  • Anna Vähärautio

    (University of Helsinki, Biomedicum Helsinki)

  • Kornelia Gladysz

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki)

  • Halit Ongen

    (University of Geneva Medical School-CMU)

  • Emmanouil Dermitzakis

    (University of Geneva Medical School-CMU)

  • Jesper Bertram Bramsen

    (Aarhus University Hospital)

  • Torben Falck Ørntoft

    (Aarhus University Hospital)

  • Claus Lindbjerg Andersen

    (Aarhus University Hospital)

  • Ari Ristimäki

    (University of Helsinki, Biomedicum Helsinki
    HUSLAB and Haartman Institute, Helsinki University Central Hospital)

  • Anna Lepistö

    (Helsinki University Hospital, University of Helsinki)

  • Laura Renkonen-Sinisalo

    (Helsinki University Hospital, University of Helsinki)

  • Jukka-Pekka Mecklin

    (Jyväskylä Central Hospital
    University of Jyväskylä)

  • Jussi Taipale

    (University of Helsinki, Biomedicum Helsinki
    Karolinska Institutet
    University of Cambridge)

  • Lauri A. Aaltonen

    (University of Helsinki, Biomedicum Helsinki
    University of Helsinki, Biomedicum Helsinki
    Karolinska Institutet)

Abstract

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.

Suggested Citation

  • Kimmo Palin & Esa Pitkänen & Mikko Turunen & Biswajyoti Sahu & Päivi Pihlajamaa & Teemu Kivioja & Eevi Kaasinen & Niko Välimäki & Ulrika A. Hänninen & Tatiana Cajuso & Mervi Aavikko & Sari Tuupanen & , 2018. "Contribution of allelic imbalance to colorectal cancer," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06132-1
    DOI: 10.1038/s41467-018-06132-1
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