BackgroundGenetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. MethodsEleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome.ResultsWe performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet.ConclusionThe Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%–80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.

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Background: Patients at increased risk of breast (BC) and/or ovarian (OC) cancer can opt for risk-reducing surgeries (RRS). However, there are disparities in access to genomic cancer risk assessment (GCRA) and cancer prevention interventions related to geography, socioeconomic status, and limited public health support. We studied factors that affect the uptake of risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) in Hispanic patients of Latin America (LatAm) and the United States (US). Methods: Hispanic women enrolled in the Clinical Cancer Genomics Community Research Network registry between 1997-2019 who underwent genetic testing, had a personal or family history (FHX) of BC or OC, and had ≥6 months of follow-up data were considered eligible. Demographic and clinical factors associated with risk-appropriate uptake of RRS were considered. Data were analyzed using Fisher’s exact tests and logistic regression models. Results: 1818 patients with a median follow-up of 43 months were studied. Most were from the US (65%), followed by Mexico (21%), Peru (10%), Colombia (2%), and Puerto Rico (2%). Median age at enrollment was 44 years; 81% had a personal history of BC and 5% of OC. Cancer-associated pathogenic variants (PVs) were identified in 459 patients (25%); 409 were in BRCA, 36 had other BC-susceptibility PVs (ATM, CHEK2, PALB2, PTEN, or TP53), and 14 had other OC-susceptibility PVs (BRIP1, MSH2, MSH6, MLH1, or RAD51C). Overall, 449/1715 (26.2%) patients underwent RRM, with a higher rate among patients in the US than those in LatAm (31% vs. 17%, p<0.01); 377/1517 (25%) patients underwent RRSO, with no regional differences observed (24% vs. 27%, p=0.22). The factors associated with undergoing RRM were US residence (OR 2.2; 95% CI 1.7-2.8), age ≤50 (OR 2.2; 95% CI 1.7-2.8), carrying a BC-predisposing PV (OR 3.5; 95% CI 2.8-4.4), positive FHX for BC (OR 1.5; 95% CI 1.2-1.9), and personal history of cancer (OR 3.6; 95% CI 2.4-5.6). In a multivariate model, US residence, age, and previous BC diagnosis remained independent predictors for RRM in BC-susceptibility gene PV carriers, while age was not a significant factor in non-carriers. The factors associated with undergoing RRSO included being a carrier of an OC-predisposing PV (OR 6.3; 95% CI 4.8-8.1), positive FHX for OC (OR 2.1; 95% CI 1.5-2.8), and previous cancer diagnosis (OR 1.7; 95% CI 1.2-2.5). In carriers of OC-susceptibility gene PVs, residing in US and previous cancer diagnosis were independently associated with RRSO, while positive FHX for OC and previous cancer diagnosis were identified as independent factors in non-carriers. Conclusion: There are disparities in the uptake of RRS outside the US. Beyond limitations in resources, understanding the factors associated with undergoing RRS could be key to developing targeted interventions to improve the uptake of risk-appropriate measures in hereditary cancer syndrome patients. Citation Format: Jeffrey N. Weitzel, Yanin Chavarri-Guerra, Ana Ferrigno, Pamela Mora-Alférez, Annette Campbell-Fontaine, Cynthia Villarreal-Garza, Alejandro Mohar-Betancourt, Gubidxa Gutierrez-Seymour, Gary W. Unzeitig, Sandra Brown, Bita Nehoray, Azucena del Toro-Valero, Pamela Ganschow, Ian Komenaka, Yenni Rodriguez, Francisco Gutierrez-Delgado, Kathleen R. Blazer. Disparity in the uptake of risk-reducing surgery after GCRA in Hispanic patients in Latin America and in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2214.

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