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首页> 外文期刊>Balkan journal of medical genetics: BJMG >MOLECULAR BASIS OF INHERITED COLORECTAL CARCINOMAS IN THE MACEDONIAN POPULATION: AN UPDATE
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MOLECULAR BASIS OF INHERITED COLORECTAL CARCINOMAS IN THE MACEDONIAN POPULATION: AN UPDATE

机译：Macedonian人群中遗传结肠直肠癌的分子基础：更新

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摘要

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 (? = 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 oligopolypo-sis. 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.
机译：遗传因素被认为在-35.0-45.0%的结直肠癌（CRC）中起作用，约5.0-10.0%与遗传性息肉病（HP）或遗传性非息肉病综合征（HNPCC）相关基因的高渗透性致病突变有关。尽管错配修复（MMR）和APC基因的遗传性种系突变对大肠癌有显著影响，但仍有50.0%以上的家族病例无法获得遗传诊断。我们提供了通过下一代测序（NGS）获得的临床诊断为HP（？=41）或HNPCC（n=66）的马其顿人群中107名先证者的最新数据，其中有三个不同的基因面板，涵盖114个癌症易感基因的编码区、侧翼区和启动子区。使用这种方法，我们能够在65/107（60.7%）患者中检测到有害突变，其中50.4%在已知的CRC易感基因中，10.2%在DNA修复基因（DRG）中。正如预期的那样，在家族性腺瘤性息肉病（FAP）和伴有微卫星不稳定性（MSI）肿瘤的HNPCC患者中检测到的有害变异频率最高（分别为93.8%和87.1%）。107例患者中有24例（22.4%）检测到未知显著性变异（VUS），主要是在HNPCC患者中检测到微卫星稳定型（MSS）肿瘤或寡聚息肉病患者。大多数VU也在DRG基因中发现，表明双链制动DNA修复途径缺陷在结直肠癌发生中的潜在作用。我们未能在18/107（16.8%）患者中检测到任何变异，这支持了遗传性大肠癌的遗传异质性，尤其是在患有MSS肿瘤的HNPCC家族和寡聚息肉病家族中。

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