Rivero-García Pamela, Chavarri-Guerra Yanin, Rodríguez Olivares José Luis, Weitzel Jeffrey N, Herzog Josef, Candanedo-González Fernando, Ríos-Valencia Javier, Mutchinick Osvaldo M, Arteaga-Vázquez Jazmín
Department of Genetics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez, Sección XVI, Delegación Tlalpan, 14080, Mexico City, Mexico.
Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Belisario Domínguez, Sección XVI, Delegación Tlalpan, 14080, Mexico City, Mexico.
Heliyon. 2024 May 24;10(11):e31855. doi: 10.1016/j.heliyon.2024.e31855. eCollection 2024 Jun 15.
Lynch syndrome (LS) is the most frequent cancer predisposition syndrome affecting the colon and rectum. A pathogenic variant (PV) disrupting one of the mismatch repair (MMR) genes is responsible for the disease. The spectrum of tumors in LS is heterogeneous and includes cancer of the colon and rectum (CRC), endometrium, ovaries, stomach, small bowel, urinary tract, bladder, pancreas, and skin. Knowledge of the phenotypic variation of patients with LS, the type and frequency of PVs, and cascade testing studies in the Latin American population is limited. The present study aims to recognize the PVs in MMR genes, describe the phenotype in Mexican-Mestizo patients and their relatives, and identify the acceptance rate of cascade testing of relatives at risk. We included 40 carriers of a MMR gene PV and 142 relatives that developed a LS-related neoplasm. Patients' clinical data, number, and type of malignancies were obtained from their medical records. Amsterdam I-II, Bethesda criteria, and PREMM5® predictive model score were estimated. Available immunohistochemistry (IHC) reports were analyzed. Relatives at risk were determined from index cases pedigrees. The distribution of MMR gene mutations among 40 probands was: (67.5 %) (22.5 %) (7.5 %), and (2.5 %). Out of the 182 LS cases, 58 % exhibited the LS phenotype before age 50. The most common tumor was CRC, followed by endometrial cancer in women and gastric cancer in males. We found a 90.0 % concordance between the IHC and germline PV. The most frequent PV in our sample was c.676C > T, occurring in 1/6 index cases. All probands disclosed their molecular test result to their family. Out of the 451 asymptomatic relatives at risk, 28.2 % underwent germline testing. Our results highlight the importance of conducting germline genetic studies in LS since it allows the establishment of appropriate cancer screening, risk-reducing measures, and genetic cascade testing among relatives at risk. Interestingly, we observed a significantly higher prevalence of the c.676C > T variant in probably a singular characteristic of the Mexican-Mestizo population. New strategies to facilitate accurate communication between index cases and relatives should be implemented to improve the cascade testing acceptance rate.
林奇综合征（LS）是最常见的影响结肠和直肠的癌症易感综合征。一个破坏错配修复（MMR）基因之一的致病变异（PV）是该疾病的病因。LS中的肿瘤谱是异质性的，包括结肠癌和直肠癌（CRC）、子宫内膜癌、卵巢癌、胃癌、小肠癌、泌尿系统癌、膀胱癌、胰腺癌和皮肤癌。关于拉丁裔人群中LS患者的表型变异、PV的类型和频率以及级联检测研究的知识有限。本研究旨在识别MMR基因中的PV，描述墨西哥梅斯蒂索患者及其亲属的表型，并确定有风险亲属的级联检测接受率。我们纳入了40名MMR基因PV携带者和142名发生与LS相关肿瘤的亲属。从患者的病历中获取患者的临床数据、恶性肿瘤的数量和类型。评估阿姆斯特丹I-II标准、贝塞斯达标准和PREMM5®预测模型评分。分析可用的免疫组织化学（IHC）报告。从索引病例的家系中确定有风险的亲属。40名先证者中MMR基因突变的分布为：（67.5%）（22.5%）（7.5%）和（2.5%）。在182例LS病例中，58%在50岁之前表现出LS表型。最常见的肿瘤是CRC，其次是女性的子宫内膜癌和男性的胃癌。我们发现IHC与种系PV之间的一致性为90.0%。我们样本中最常见的PV是c.676C>T，在1/6的索引病例中出现。所有先证者都向其家人披露了他们的分子检测结果。在451名有风险的无症状亲属中，28.2%接受了种系检测。我们的结果强调了在LS中进行种系基因研究的重要性，因为它有助于建立适当的癌症筛查、降低风险措施以及对有风险亲属进行基因级联检测。有趣的是，我们观察到c.676C>T变异在中的患病率显著更高，这可能是墨西哥梅斯蒂索人群的一个独特特征。应该实施新的策略来促进索引病例和亲属之间的准确沟通，以提高级联检测接受率。
