Flores-Lagunes L Leonardo, Alvarez-Gómez Rosa María, Molina-Garay Carolina, Jimenez-Olivares Marco, Acosta-Mendez Pablo Arturo, García-Solorio Joaquin, Prida-Riba Sebastián, Carillo-Sanchez Karol, Mendoza-Caamal Elvia Cristina, De la Fuente-Hernández Marcela Angélica, Fragoso-Ontiveros Verónica Zoraya, Reyes Casarrubias Rodrigo Estefano, Alaez-Verson Carmen
Laboratorio de Diagnóstico Genómico, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.
Programa de Maestría y Doctorado en Ciencias Médicas Odontológicas y de la Salud, Universidad Nacional Autónoma de México (UNAM), 04100, Mexico City, Mexico.
Fam Cancer. 2025 Sep 17;24(4):73. doi: 10.1007/s10689-025-00490-8.
This study aimed to characterize, for the first time, the cancer spectrum associated with the most frequent pathogenic CHEK2 variant-NM_007194.4(CHEK2):c.707T > C p.(Leu236Pro)-in Mexican individuals. Although this variant is frequently detected through multi-gene panel testing, limited data on its associated cancer risks complicates genetic counseling and surveillance strategies. We retrospectively analyzed 5,759 patients who underwent multi-gene panel testing between August 2015 and August 2024 due to suspected hereditary cancer syndromes. Among them, 58 CHEK2 p.(Leu236Pro) carriers with confirmed cancer diagnoses were identified. Geographical clustering was observed, with 81% of patients originating from central Mexico, suggesting a possible founder effect. Ten distinct clinical indications for genetic testing were identified, with hereditary breast and ovarian cancer (HBOC) syndrome being the most common (74.1%). The mean age at first diagnosis among carriers was 43.8 ± 12 years, and 61.1% of them reported a family history of cancer in first- or second-degree relatives. A second or third primary cancer occurred in 20.7% of cases. Tumors were identified in 12 anatomical sites. Breast cancer predominated (67.6%, including one male case), followed by ovarian (8.1%), prostate (6.7%), gastric (4.1%), thyroid (2.7%), and endometrial (2.7%) cancers. Lymphoma, lung, sacrococcygeal bone, colorectal, and non-melanoma skin cancers each occurred in a single patient. Significant risk association was identified only for breast, ovarian, and gastric cancers. These results highlight the need for personalized surveillance, especially for breast cancer. Incorporating CHEK2 p.(Leu236Pro) into clinical decision-making tools may enhance risk assessment in the Mexican population, but larger studies are needed to refine risk estimates and to clarify the possible founder effect.
本研究旨在首次描述墨西哥人群中与最常见的致病性CHEK2变异体-NM_007194.4(CHEK2):c.707T＞C p.(Leu236Pro)相关的癌症谱。尽管通过多基因检测经常能检测到这种变异体，但关于其相关癌症风险的数据有限，这使得遗传咨询和监测策略变得复杂。我们回顾性分析了2015年8月至2024年8月期间因疑似遗传性癌症综合征而接受多基因检测的5759例患者。其中，鉴定出58例确诊患有癌症的CHEK2 p.(Leu236Pro)携带者。观察到地理聚集现象，81%的患者来自墨西哥中部，提示可能存在奠基者效应。确定了10种不同的基因检测临床指征，其中遗传性乳腺癌和卵巢癌（HBOC）综合征最为常见（74.1%）。携带者的首次诊断平均年龄为43.8±12岁，61.1%的携带者报告一级或二级亲属有癌症家族史。20.7%的病例发生了第二原发性或第三原发性癌症。在12个解剖部位发现了肿瘤。乳腺癌占主导（67.6%，包括1例男性病例），其次是卵巢癌（8.1%）、前列腺癌（6.7%）、胃癌（4.1%）、甲状腺癌（2.7%）和子宫内膜癌（2.7%）。淋巴瘤、肺癌、骶尾骨癌、结直肠癌和非黑色素瘤皮肤癌各有1例患者。仅在乳腺癌、卵巢癌和胃癌中发现了显著的风险关联。这些结果凸显了个性化监测的必要性，尤其是对于乳腺癌。将CHEK2 p.(Leu236Pro)纳入临床决策工具可能会加强墨西哥人群的风险评估，但需要更大规模的研究来完善风险估计并阐明可能的奠基者效应。
