Dataset Information

Contribution of allelic imbalance to colorectal cancer.

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.

SUBMITTER: Palin K

PROVIDER: S-EPMC6131244 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Contribution of allelic imbalance to colorectal cancer.

Palin Kimmo K Pitkänen Esa E Turunen Mikko M Sahu Biswajyoti B Pihlajamaa Päivi P Kivioja Teemu T Kaasinen Eevi E Välimäki Niko N Hänninen Ulrika A UA Cajuso Tatiana T Aavikko Mervi M Tuupanen Sari S Kilpivaara Outi O van den Berg Linda L Kondelin Johanna J Tanskanen Tomas T Katainen Riku R Grau Marta M Rauanheimo Heli H Plaketti Roosa-Maria RM Taira Aurora A Sulo Päivi P Hartonen Tuomo T Dave Kashyap K Schmierer Bernhard B Botla Sandeep S Sokolova Maria M Vähärautio Anna A Gladysz Kornelia K Ongen Halit H Dermitzakis Emmanouil E Bramsen Jesper Bertram JB Ørntoft Torben Falck TF Andersen Claus Lindbjerg CL Ristimäki Ari A Lepistö Anna A Renkonen-Sinisalo Laura L Mecklin Jukka-Pekka JP Taipale Jussi J Aaltonen Lauri A LA

Nature communications 20180910 1

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 regulat ...[more]

PMID: 30202008

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Project description:Breast cancer is a heterogeneous disease with various histological features and molecular markers. These are utilized for the prediction of clinical outcome and therapeutic decision making. In addition to well established markers such as HER2 overexpression and estrogen and progesterone receptor (ER and PR) status, chromosomal instability is evolving as an important hallmark of cancers. The HER2/TOP2A locus is of great importance in breast cancer. The copy number variability at this locus has been proposed to be a marker for the degree of chromosomal instability. We therefore developed a Single Nucleotide Polymorphism (SNP) assay to evaluate allelic imbalance at the HER2/TOP2A locus in three different entities of primary breast tumors.Eleven SNPs were carefully selected and detected by real time PCR using DNA extracted from paired (histologically normal and tumor) paraffin-embedded tissues. Primary breast tumors of 44 patients were included, 15 tumors with HER2 overexpression, 16 triple negative tumors, defined by the absence of HER2 overexpression and a negative ER and PR status and 13 ER and PR positive tumors without HER2 overexpression. As controls, histologically normal breast tissues from 10 patients with no breast tumor were included.Allelic imbalance was observed in 13/15 (87 %) HER2 positive tumors, the remaining 2 being inconclusive. Of the 16 triple negative tumors, 12 (75 %) displayed instability, 3 (19 %) displayed no instability, and 1 was inconclusive. Of the 13 hormone receptor positive tumors, 5 (38 %) displayed allelic imbalance, while 8 did not.We conclude that the SNP assay is suitable for rapid testing of allelic (im)balance at the HER2/TOP2A locus using paraffin-embedded tissues. Based on allelic imbalance at this locus, both triple negative and ER and PR positive breast tumors can be subcategorized. The clinical relevance of the allelic (im)balance status at the HER2/TOP2A locus in breast cancer is subject of future study.The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2086062232155220.

Dataset Information

Contribution of allelic imbalance to colorectal cancer.

Publications

Contribution of allelic imbalance to colorectal cancer.

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