Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations
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Noora Porkka1, Satu Valo1, Taina T. Nieminen1, Alisa Olkinuora1, Satu Mäki-Nevala1, Samuli Eldfors2 and Päivi Peltomäki1
1Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
2Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Noora Porkka, email: [email protected]
Keywords: Lynch syndrome; colorectal tumor; ovarian cancer; epigenetic regulation; somatic mutation
Received: September 07, 2017 Accepted: October 27, 2017 Published: November 14, 2017
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.
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