Mathó Cecilia, Chávez Santiago, Fort Rafael Sebastián, Della Valle Adriana, Neffa Florencia, Sotelo-Silveira José Roberto, Artagaveytia Nora, Duhagon María Ana
Unidad Académica de Genética, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Plataforma de Secuenciación Masiva, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay.
Front Oncol. 2025 Aug 1;15:1589765. doi: 10.3389/fonc.2025.1589765. eCollection 2025.
Lynch Syndrome accounts for 1-7% of all colorectal cancers and is caused by germline mutations in DNA mismatch repair (MMR) genes. Timely molecular diagnosis is crucial for effective genetic counseling and management. Among understudied Latin American populations, Uruguay's genetic admixture provides an opportunity to identify novel Lynch Syndrome related variants.
This study analyzed 70 unrelated Uruguayan colorectal cancer patients meeting Lynch Syndrome clinical criteria to identify carriers of pathogenic variants. A customized Next-Generation Sequencing (NGS) panel was developed and sequenced on the Ion Torrent platform to analyze nine genes: , and . Copy number variations and large EPCAM deletions are not detected by the assay. Gene variants were prioritized based on allelic frequency, predictions, pathogenicity records, and ACMG guidelines. The performance of this custom NGS panel was evaluated for in-house applications, and its limitations were thoroughly assessed.
The custom NGS panel demonstrated effectiveness for scalable in-house testing despite minor disclosed sequence coverage limitations. Pathogenic and likely pathogenic variants were identified in 25 patients, including four novel Lynch Syndrome-associated variants. In four patients, a rare ambiguously classified gene variant co-occurs with a known pathogenic variant in another gene. The mutation profile correlated with clinical parameters such as age of diagnosis, diagnosis criteria, tumor location, and microsatellite instability (MSI).
This is the most comprehensive genetic study to date on a Uruguayan Lynch syndrome cohort. The mutational landscape aligns with findings in other populations while highlighting novel variants of clinical relevance. These findings highlight the value of customized panels for improving genetic screening in small-scale healthcare facilities.
林奇综合征占所有结直肠癌的1%-7%，由DNA错配修复（MMR）基因的种系突变引起。及时进行分子诊断对于有效的遗传咨询和管理至关重要。在研究较少的拉丁美洲人群中，乌拉圭的基因混合情况为鉴定与林奇综合征相关的新变异提供了机会。
本研究分析了70名符合林奇综合征临床标准的乌拉圭结直肠癌患者，以确定致病变异的携带者。开发了一个定制的下一代测序（NGS）面板，并在Ion Torrent平台上进行测序，以分析9个基因： 、 和 。该检测方法未检测到拷贝数变异和EPCAM大缺失。根据等位基因频率、预测结果、致病性记录和美国医学遗传学与基因组学学会（ACMG）指南对基因变异进行优先级排序。评估了该定制NGS面板在内部应用中的性能，并对其局限性进行了全面评估。
尽管存在一些公开的序列覆盖范围限制，但定制的NGS面板在可扩展的内部检测中显示出有效性。在25名患者中鉴定出致病性和可能致病性变异，包括4个与林奇综合征相关的新变异。在4名患者中，一种罕见的分类不明确的基因变异与另一个基因中的已知致病变异同时出现。突变谱与临床参数相关，如诊断年龄、诊断标准、肿瘤位置和微卫星不稳定性（MSI）。
这是迄今为止对乌拉圭林奇综合征队列进行的最全面的基因研究。突变情况与其他人群的研究结果一致，同时突出了具有临床相关性的新变异。这些发现凸显了定制面板在改善小规模医疗机构基因筛查方面的价值。
