Molecular basis of inherited colorectal carcinomas in the Macedonian population: An update

Autor:	Aleksandar Dimovski, Rubens Jovanovic, N Matevska-Geskovska, Bistra Angelovska, Milco Panovski, M Staninova-Stojovska, Nenad Mitrevski, M Ristevski
Rok vydání:	2019
Předmět:	Proband DNA repair Population QH426-470 Biology Familial adenomatous polyposis 03 medical and health sciences 0302 clinical medicine Germline mutation hereditary colorectal cancer (crc) Genetics medicine education neoplasms Genetics (clinical) 030304 developmental biology 0303 health sciences education.field_of_study Genetic heterogeneity Microsatellite instability macedonian population mutations medicine.disease digestive system diseases 030220 oncology & carcinogenesis Cancer research Original Article DNA mismatch repair
Zdroj:	Balkan Journal of Medical Genetics, Vol 22, Iss 2, Pp 5-16 (2019) Balkan Journal of Medical Genetics : BJMG
ISSN:	1311-0160
DOI:	10.2478/bjmg-2019-0027
Popis:	Hereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.
Databáze:	OpenAIRE
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