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Publication . Article . 2019

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

M Staninova-Stojovska; N Matevska-Geskovska; Milco Panovski; Bistra Angelovska; Nenad Mitrevski; M Ristevski; Rubens Jovanovic; +1 Authors
Open Access   English  
Published: 01 Dec 2019 Journal: Balkan Journal of Medical Genetics, volume 22, issue 2, pages 5-16 (issn: 1311-0160, Copyright policy )
Publisher: Sciendo
Abstract 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.
Subjects by Vocabulary

Medical Subject Headings: digestive system diseases neoplasms

Microsoft Academic Graph classification: Proband DNA mismatch repair Microsatellite instability medicine.disease medicine Genetic heterogeneity Cancer research Germline mutation DNA repair Familial adenomatous polyposis Biology Population education.field_of_study education


hereditary colorectal cancer (crc), macedonian population, mutations, Genetics, QH426-470, Genetics (clinical), Original Article

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