Ozdemir Ozkan, Bychkovsky Brittany L, Unal Busra, Onder Gizem, Amanvermez Ufuk, Aydin Eylul, Ergun Berk, Sahin Ilayda, Gokbayrak Merve, Ugurtas Cansu, Koroglu Merve Nur, Cakir Berfin, Kalay Irem, Cine Naci, Ozbek Ugur, Rana Huma Q, Hatirnaz Ng Ozden, Agaoglu Nihat Bugra
Department of Medical Biology, School of Medicine, Acibadem University, 34752 Istanbul, Türkiye.
Rare Diseases and Orphan Drugs Application and Research Center (ACURARE), Acibadem University, 34752 Istanbul, Türkiye.
Cancers (Basel). 2024 Nov 20;16(22):3876. doi: 10.3390/cancers16223876.
() is a tumor suppressor gene involved in DNA repair and cell cycle regulation. Pathogenic or likely pathogenic (P/LP) variants in are associated with increased cancer risk. Conversely, recent large cohort studies have identified certain variants that, despite being classified as P/LP by in silico analysis, are considered low risk. Thus, the genotype-phenotype correlations of require a better understanding. In this study, we aimed to characterize germline variants from a group of individuals who applied to cancer genetic clinics in the Marmara Region of Türkiye. We also aimed to assess the phenotypic impacts of these variants by using a new score of statistically significant in silico predictors (SSIPs). We analyzed 1707 individuals with high risk cancer predisposition, focusing on germline variants, using SSIP scores and population-specific data. variants appeared in approximately 8% of cases. The SSIP scores indicated that the missense mutation, p.Arg117Gly, significantly impairs DNA repair. Almost half of the variants had higher allele frequencies than the variants listed in the Genome Aggregation Database (gnomAD), and three variants had significantly higher frequencies compared to the variants listed on the Turkish Variome database (p.Thr476Met, p.Arg137Gln, c.592+3A>T), emphasizing the importance of population-specific data. This comprehensive analysis of variants in the Turkish population provides crucial insights for cancer geneticists and oncologists. Our findings will help to enhance the evaluation and management of cancer predisposition associated with in Türkiye and other regions that have significant Turkish populations.
（）是一种参与DNA修复和细胞周期调控的肿瘤抑制基因。该基因的致病性或可能致病性（P/LP）变异与癌症风险增加相关。相反，最近的大型队列研究发现，某些变异尽管在计算机分析中被归类为P/LP，但被认为风险较低。因此，需要更好地理解该基因的基因型-表型相关性。在本研究中，我们旨在对一组申请土耳其马尔马拉地区癌症遗传诊所的个体的种系变异进行特征描述。我们还旨在通过使用一种新的具有统计学意义的计算机预测因子（SSIPs）评分来评估这些变异的表型影响。我们使用SSIP评分和特定人群数据，分析了1707名具有高风险癌症易感性的个体，重点关注种系变异。约8%的病例出现了变异。SSIP评分表明，错义突变p.Arg117Gly显著损害DNA修复。几乎一半的变异等位基因频率高于基因组聚合数据库（gnomAD）中列出的变异，与土耳其变异组数据库中列出的变异相比，三个变异的频率显著更高（p.Thr476Met、p.Arg137Gln、c.592+3A>T），强调了特定人群数据的重要性。对土耳其人群中变异的这种全面分析为癌症遗传学家和肿瘤学家提供了关键见解。我们的研究结果将有助于加强对土耳其及其他有大量土耳其人口地区与该基因相关的癌症易感性的评估和管理。
