Contribution of allelic imbalance to colorectal cancer

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.

Contribution of allelic imbalance to colorectal cancer

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, Outi Kilpivaara, Linda van den Berg, Johanna Kondelin, Tomas Tanskanen, Riku Katainen, Marta Grau, Heli Rauanheimo, Roosa-Maria Plaketti, Aurora Taira, Päivi Sulo, Tuomo Hartonen, Kashyap Dave, Bernhard Schmierer, Sandeep Botla, Maria Sokolova, Anna Vähärautio, Kornelia Gladysz, Halit Ongen, Emmanouil Dermitzakis, Jesper Bertram Bramsen, Torben Falck Ørntoft, Claus Lindbjerg Andersen, Ari Ristimäki, Anna Lepistö, Laura Renkonen-Sinisalo, Jukka-Pekka Mecklin, Jussi Taipale () and Lauri A. Aaltonen ()
Additional contact information
Kimmo Palin: University of Helsinki, Biomedicum Helsinki
Esa Pitkänen: 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
Niko Välimäki: University of Helsinki, Biomedicum Helsinki
Ulrika A. Hänninen: University of Helsinki, Biomedicum Helsinki
Tatiana Cajuso: University of Helsinki, Biomedicum Helsinki
Mervi Aavikko: University of Helsinki, Biomedicum Helsinki
Sari Tuupanen: University of Helsinki, Biomedicum Helsinki
Outi Kilpivaara: University of Helsinki, Biomedicum Helsinki
Linda van den Berg: University of Helsinki, Biomedicum Helsinki
Johanna Kondelin: University of Helsinki, Biomedicum Helsinki
Tomas Tanskanen: University of Helsinki, Biomedicum Helsinki
Riku Katainen: University of Helsinki, Biomedicum Helsinki
Marta Grau: University of Helsinki, Biomedicum Helsinki
Heli Rauanheimo: University of Helsinki, Biomedicum Helsinki
Roosa-Maria Plaketti: University of Helsinki, Biomedicum Helsinki
Aurora Taira: University of Helsinki, Biomedicum Helsinki
Päivi Sulo: 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
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
Anna Lepistö: Helsinki University Hospital, University of Helsinki
Laura Renkonen-Sinisalo: Helsinki University Hospital, University of Helsinki
Jukka-Pekka Mecklin: Jyväskylä Central Hospital
Jussi Taipale: University of Helsinki, Biomedicum Helsinki
Lauri A. Aaltonen: University of Helsinki, Biomedicum Helsinki

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06132-1

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