Cancer Spectrum in Mexican Patients with the CHEK2 p.(Leu236Pro) Variant: A Retrospective Study

This study aimed to characterize the cancer spectrum associated with the most frequent pathogenic CHEK2 p.(Leu236Pro) variant for the first time in Mexican individuals. Despite its frequent detection in multi-gene panel testing, limited data on its associated cancer risks complicate genetic counseling and surveillance strategies. We retrospectively analyzed 5,759 patients with a multi-gene panel tested due to suspected hereditary cancer syndromes (August 2015 - August 2024), identifying 58 carriers of p.(Leu236Pro) with confirmed cancer diagnoses. Geographical clustering was observed: 47/58 patients (81%) originated from central Mexico (Mexico City, México, Hidalgo, Puebla, Morelos, Tlaxcala), suggesting regional founder effects. Eight distinct clinical indications for genetic testing were identified, with Hereditary Breast and Ovarian Cancer (HBOC) syndrome as the primary indication (74.1%, n = 43/58). The mean age at first diagnosis was 43.8 ± 12 years, with 69.4% reporting a family history of cancer in first-degree relatives. A second or third primary cancer occurred in 20.3% of cases. 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. Tumors were identified in twelve distinct anatomical sites, supporting the role of p.(Leu236Pro) as a potential multi-organ carcinogenesis risk factor. These findings underscore the need for organ-specific surveillance in carriers and emphasize the clinical significance of the variant in Mexican populations. Larger studies are needed to validate these associations and refine risk estimates. Incorporating p.(Leu236Pro) into clinical decision-making tools could enhance risk assessment, support personalized surveillance, and improve clinical outcomes.