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; Lauri A Aaltonen

doi:10.1038/s41467-018-06132-1

Contribution of allelic imbalance to colorectal cancer

Nat Commun. 2018 Sep 10;9(1):3664. doi: 10.1038/s41467-018-06132-1.

Authors

Kimmo Palin^{1

2}, Esa Pitkänen^{1

2}, Mikko Turunen², Biswajyoti Sahu², Päivi Pihlajamaa², Teemu Kivioja², Eevi Kaasinen^{1

2

3}, Niko Välimäki^{1

2}, Ulrika A Hänninen^{1

2}, Tatiana Cajuso^{1

2}, Mervi Aavikko^{1

2}, Sari Tuupanen^{1

2}, Outi Kilpivaara^{1

2}, Linda van den Berg^{1

2}, Johanna Kondelin^{1

2}, Tomas Tanskanen^{1

2}, Riku Katainen^{1

2}, Marta Grau^{1

2}, Heli Rauanheimo^{1

2}, Roosa-Maria Plaketti^{1

2}, Aurora Taira^{1

2}, Päivi Sulo^{1

2}, Tuomo Hartonen², Kashyap Dave³, Bernhard Schmierer³, Sandeep Botla³, Maria Sokolova², Anna Vähärautio², Kornelia Gladysz^{1

2}, Halit Ongen⁴, Emmanouil Dermitzakis⁴, Jesper Bertram Bramsen⁵, Torben Falck Ørntoft⁵, Claus Lindbjerg Andersen⁵, Ari Ristimäki^{2

6}, Anna Lepistö⁷, Laura Renkonen-Sinisalo⁷, Jukka-Pekka Mecklin^{8

9}, Jussi Taipale^{10

11

12}, Lauri A Aaltonen^{13

14

15}

Affiliations

¹ Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland.
² Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland.
³ Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17165, Stockholm, Sweden.
⁴ Genetic Medicine and Development, University of Geneva Medical School-CMU, 1 Rue Michel-Servet, 1211, Geneva, Switzerland.
⁵ Department of Molecular Medicine, Aarhus University Hospital, DK8200, Aarhus N, Denmark.
⁶ Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital, Haartmaninkatu 3, FI-00290, Helsinki, Finland.
⁷ Department of Gastrointestinal Surgery, Helsinki University Hospital, University of Helsinki, Haartmaninkatu 4, FI-00290, Helsinki, Finland.
⁸ Department of Surgery, Jyväskylä Central Hospital, Keskussairaalantie 19, FI-40620, Jyväskylä, Finland.
⁹ Department of Health Sciences, Faculty of Sport and Health Sciences, University of Jyväskylä, PO Box 35, FI-40014, Jyväskylä, Finland.
¹⁰ Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland. [email protected].
¹¹ Division of Functional Genomics and Systems Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles väg 2, SE-17165, Stockholm, Sweden. [email protected].
¹² Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1GA, UK. [email protected].
¹³ Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland. [email protected].
¹⁴ Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014, Helsinki, Finland. [email protected].
¹⁵ Department of Biosciences and Nutrition, Karolinska Institutet, SE-17177, Stockholm, Sweden. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allelic Imbalance*
CRISPR-Cas Systems
Chromosome Aberrations
Chromosomes, Human, Pair 8
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
DNA Copy Number Variations
Denmark
Gene Expression Profiling
Genetic Predisposition to Disease*
Genomics
Genotype
Humans
Loss of Heterozygosity
Microsatellite Repeats
Phenotype
Point Mutation
Proto-Oncogene Proteins p21(ras) / genetics
RNA, Small Interfering / genetics
Transcription Factors / genetics
Tumor Suppressor Protein p53 / genetics
Whole Genome Sequencing

Substances

KRAS protein, human
RNA, Small Interfering
TP53 protein, human
Transcription Factors
Tumor Suppressor Protein p53
Proto-Oncogene Proteins p21(ras)