Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

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Porkka , N , Valo , S , Nieminen , T T , Olkinuora , A , Mäki-Nevala , S , Eldfors , S & Peltomäki , P 2017 , ' Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations ' , Oncotarget , vol. 8 , no. 64 , pp. 108020-108030 . https://doi.org/10.18632/oncotarget.22445

Title: Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations
Author: Porkka, Noora; Valo, Satu; Nieminen, Taina T.; Olkinuora, Alisa; Mäki-Nevala, Satu; Eldfors, Samuli; Peltomäki, Päivi
Contributor: University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Medicum
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Medicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Medicum
Date: 2017-11-14
Language: eng
Number of pages: 11
Belongs to series: Oncotarget
ISSN: 1949-2553
URI: http://hdl.handle.net/10138/231431
Abstract: Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively. Genes harboring mutations with allele frequency 25 % or higher in at least 31 % of tumors were regarded to be possible drivers. Among 72 and 10 such genes identified in colorectal and ovarian tumors, respectively, the most frequently mutated genes BRD4 and MLL2 (62 % of colorectal tumors) and ARID1A (50 % of ovarian carcinomas) are involved in epigenetic regulation. The total number of somatic mutations or mutant genes per tumor were significantly associated with CIMP. Our results suggest that even in an inherited disease, tumor type-specific epigenetic changes are significant and may result from regulatory changes (CIMP) or structural events (mutations of epigenetic regulatory genes). The findings are clinically relevant since many of the affected pathways can be therapeutically targeted.
Subject: 1184 Genetics, developmental biology, physiology
1182 Biochemistry, cell and molecular biology
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