Characterization of Screening Strategies for Lynch Syndrome in Latin America

Characterization of Screening Strategies for Lynch Syndrome in Latin America Item Type info:eu-repo/semantics/article Authors Campos-Segura, Anthony Vladimir; Alvarez, Karin; Murillo Carrasco, Alexis German; Rossi, Benedito Mauro; Bohorquez, Mabel; Spirandelli, Florencia; Benavides, Claudio; Balto, Aina; Della Valle, Adriana; Bruno, Luisina Inés; Lopez-Kostner, Francisco; Cruz-Correa, Marcia; Del Monte, Julio Sanchez; Rugeles, Jorge; Ramirez, Jesica Magalí; Nascimento, Ivana; Forones, Nora Manoukian; Cock-Rada, Alicia Maria; ReyesSilva, Carlos; Avila, Silvia; Apolinario, Leandro; Rossi, Norma Teresa; Martin, Claudia; Sulcahuaman, Yasser; Vaccaro, Carlos Alberto; Castro-Mujica, Maria del Carmen; Muñeton Peña, Carlos Mario; Assis, Roseane Bicalho; Silveira-Lucas, Elizabeth; Badir, Chahuan; Velez-Bohorquez, Daniel; Boggio, Gaston; Spirandelli, Enrique; Neffa, Florencia; Esperon, Patricia; Carusso, Florencia; Vergara, Carolina; Amat, Mora; Pombo, María Teresa; Noro, Laura; De la Fuente, Marjorie; Canales, Tamara; Cassana, Alessandra; Carrasco-Avino, Gonzalo; Pérez-Mayoral, Julyann; Gonzalez Pons, Maria; Hernández Guerrero, Angélica; Vidal Millán, Silvia; Furfuro, Sandra Beatriz; Machado Lopes, Taisa Manuela Bonfim; Bomfim Palma, Thais Ferreira; Freitas, Juliana Cortes; Toralles, Maria Betânia Pereira; Melo, Thamara Claudia Ferreira; Pimenta, Celia Aparecida Marques; Palacios Fuenmayor, Luis José; Galvez-Salazar, Gabriela; JaramilloKoupermann, Gabriela; Torres, Mariella; Pavicic, Walter Hernán; Herrando, Ignacio Alberto; Santino, Juan Pablo; Ferro, Fabiana Alejandra; Ayala, Carlos Afanador; Louro, Luri Drumond; Conedera, Silvio; Kristensen, Vessela; Torrezan, Giovana Tardin; Dominguez-Barrera, Constantino; Ayala Madrigal, María de la Luz; Gutierrez, Melva; Wernhoff, Patrik; Hovig, Eivind; Plazzer, John Paul; Møller, Pål; Balavarca, Yesilda; Dominguez-Valentin, Mev DOI 10.1016/j.cgh.2024.12.026 Publisher W.B. Saunders Journal Clinical Gastroenterology and Hepatology Rights info:eu-repo/semantics/openAccess; Attribution 4.0 International Download date 04/11/2025 02:50:22 Item License http://creativecommons.org/licenses/by/4.0/ Link to Item http://hdl.handle.net/10757/686643 COLORECTAL Characterization of Screening Strategies for Lynch Syndrome in Latin America Anthony Vladimir Campos-Segura, 1 Karin Alvarez, 2 Alexis German Murillo Carrasco, 3,4 Benedito Mauro Rossi, 5,6 Mabel Bohorquez, 7 Florencia Spirandelli, 8 Claudio Benavides, 9 Aina Balto, 10 Adriana Della Valle, 11 Luisina Inés Bruno, 12 Francisco Lopez-Kostner, 2 Marcia Cruz-Correa, 13 Julio Sanchez Del Monte, 14 Jorge Rugeles, 15 Jesica Magalí Ramirez, 16 Ivana Nascimento, 17,18 Nora Manoukian Forones, 19 Alicia Maria Cock-Rada, 20 Carlos Reyes-Silva, 21 Silvia Avila, 22 Leandro Apolinario, 23 Norma Teresa Rossi, 24 Claudia Martin, 25 Yasser Sulcahuaman, 26 Carlos Alberto Vaccaro, 27 Maria del Carmen Castro-Mujica, 28 Carlos Mario Muñeton Peña, 29 Roseane Bicalho Assis, 30 Elizabeth Silveira-Lucas, 31 Chahuan Badir, 32 Daniel Velez-Bohorquez, 7 Gaston Boggio, 8 Enrique Spirandelli, 33 Florencia Neffa, 11 Patricia Esperon, 11,34 Florencia Carusso, 11 Carolina Vergara, 11 Mora Amat, 12 María Teresa Pombo, 12 Laura Noro, 12 Marjorie De la Fuente, 35 Tamara Canales, 36 Alessandra Cassana, 37 Gonzalo Carrasco-Avino, 38 Julyann Pérez-Mayoral, 39 Maria Gonzalez Pons, 39 Angélica Hernández Guerrero, 14 Silvia Vidal Millán, 14 Sandra Beatriz Furfuro, 40 Taisa Manuela Bonfim Machado Lopes, 17 Thais Ferreira Bomfim Palma, 17 Juliana Cortes Freitas, 17 Maria Betânia Pereira Toralles, 17 Thamara Claudia Ferreira Melo, 38 Celia Aparecida Marques Pimenta, 19 Luis José Palacios Fuenmayor, 20 Gabriela Galvez-Salazar, 21 Gabriela Jaramillo-Koupermann, 11 Mariella Torres, 26 Walter Hernán Pavicic, 27 Ignacio Alberto Herrando, 27 Juan Pablo Santino, 27 Fabiana Alejandra Ferro, 27 Carlos Afanador Ayala, 29 Luri Drumond Louro, 30 Silvio Conedera, 41 Vessela Kristensen, 41 Giovana Tardin Torrezan, 1 Constantino Dominguez-Barrera, 42 MaríadelaLuzAyalaMadrigal, 43 Melva Gutierrez, 43,44 Patrik Wernhoff, 41 Eivind Hovig, 45,46 John-Paul Plazzer, 47 Pål Møller, 45 Yesilda Balavarca, 48 and Mev Dominguez-Valentin, 45 in collaboration with LA-GETH 1 Clinical and Functional Genomics Group, International Center of Research CIPE, A.C. Camargo Cancer Center, Sao Paulo, Brazil; 2 Centro Oncológico, Clinica Universidad de Los Andes, Región Metropolitana, Chile; 3 Centro de Investigação Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil; 4 Comprehensive Center for Precision Oncology, Universidade de Sao Paulo, São Paulo, Brazil; 5 Hospital Beneficência Portuguesa, São Paulo, Brazil; 6 Hospital Sirio Libanes, Sao Paulo, Brazil; 7 Grupo de Investigación Citogenética, Filogenia y Evolución de Poblaciones, Facultades de Ciencias de Salud y de Ciencias, Universidad del Tolima, Ibagué, Colombia; 8 Asesoría Genética Oncológica Sanatorio Parque, Consultorio Privado de Coloproctología, Rosario, Argentina; 9 Hospital Regional de Concepción, Concepción, Chile; 10 Department of Pathology, University of Oslo, Oslo, Norway; 11 Hospital Fuerzas Armadas, Grupo Colaborativo Uruguayo, Investigación de Afecciones Onco-lógicas Hereditarias, Montevideo, Uruguay; 12 Instituto Alexander Fleming, Buenos Aires, Argentina; 13 University of Puerto Rico Medical Sciences Campus, Department of Medicine, University of Puerto Rico Comprehensive Cancer Center, Division of Cancer Biology, San Juan, Puerto Rico; 14 Departamento de Gastroenterología, Instituto Nacional de Cancerología de México, México City, México; 15 Clinica IMAT Oncomedica Auna, Monteria, Colombia; 16 Servicio de Abbreviations used in this paper: CRC, colorectal cancer; dMMR, deficient MMR; GC, cancer genetic counseling; IHC, immunohistochemistry; LS, Lynch syndrome; MMR, mismatch repair; MSI, microsatellite instability; TS, traditional screening; UTS, universal tumor screening. Most current article © 2025 The Author(s). Published by Elsevier Inc. on behalf of the AGA Institute. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). 1542-3565 https://doi.org/10.1016/j.cgh.2024.12.026 Clinical Gastroenterology and Hepatology 2025;23:1642–1654 Oncología, Hospital Central de Mendoza, Mendoza, Argentina; 17 Laboratório de Imunologia e Biologia Molecular do Instituto de Ciências da Saúde/Universidade Federal da Bahia, Salvador, Brazil; 18 NOB/Oncoclínicas, Salvador, Brazil; 19 Gastroenterology Division, Universidade Federal de São Paulo, São Paulo, Brazil; 20 Instituto de Cancerología Las AméricasAuna, Medellín, Colombia; 21 Hospital de Especialidades Eugenio Espejo, Laboratorio de Biología Molecular, Área de Genética Clínica, Quito, Ecuador; 22 Neuquen Hospital, Neuquen, Argentina; 23 Hospital Universitário Oswaldo Cruz, Universidade de Pernambuco, Recife, Brazil; 24 Sanatorio Allende y Fundación para el Progreso de la Medicina, Córdoba, Argentina; 25 Hospital Privado Universitario de Córdoba, Córdoba, Argentina; 26 Universidad Peruana de Ciencias Aplicadas, Instituto de Investigación Genómica, Lima, Peru; 27 Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; 28 Instituto de Investigaciones en Ciencias Biomédicas, Facultad de Medicina Humana, Universidad Ricardo Palma, Lima, Peru; 29 Grupo de Genética Médica, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia; 30 Instituto Avançado de Gastroenterologia e Endoscopia, Vitória, Brazil; 31 Consultorio Genetica Clinica, Porto Alegre, Brazil; 32 Fundacion Arturo Lopez Perez, Santiago, Chile; 33 Consultorio Particular de Coloproctologia, Rosario, Argentina; 34 Molecular Genetic Unit, School of Chemistry, Universidad de la República, Montevideo, Uruguay; 35 Dirección Académica, Clínica Las Condes, Santiago, Chile; 36 Centro del Cáncer, Clínica Las Condes, Santiago, Chile; 37 Unidad de Coloproctología, Clinica Las Condes, Santiago, Chile; 38 Departamento de Anatomía Patológica, Clínica Las Condes, Hospital Clínico Universidad de Chile, Santiago, Chile; 39 University of Puerto Rico Comprehensive Cancer Center, Division of Cancer Biology, San Juan, Puerto Rico; 40 Laboratorio de Análisis de ADN Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina; 41 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; 42 Independent Researcher, Lima, Peru; 43 Instituto de Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México; 44 Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Jalisco, Mexico; 45 Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; 46 Institute for Informatics, University of Oslo, Oslo, Norway; 47 Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia; and 48 Unit of Biostatistics and Data Science, Staburo GmbH, Munich, Germany BACKGROUND & AIMS: In Latin America, genetic testing for Lynch syndrome (LS) has been partially implemented. Traditionally, LS diagnosis relied on the Amsterdam criteria and Bethesda guidelines, collectively known as traditional screening (TS). However, TS may miss up to 68% of LS cases. To improve detection rates, universal tumor screening (UTS) has been introduced. UTS involves screening all newly diagnosed patients with colorectal cancer for molecular markers to more effectively identify LS cases. METHODS: Clinical and molecular data on 1684 patients with colorectal cancer, collected between 1999 and 2020, were provided by 24 Latin American genetic cancer registries and centers. Germline genetic testing was not consistently performed across all cases. RESULTS: LS screening strategies were available for 72% (1209/1684) of cases, with germline testing conducted in one-quarter (304/1209) of these. Most cases (78%; n [943) underwent UTS, primarily in Argentina, Chile, and Uruguay, whereas 22% (266/1209) were screened through TS. UTS identified deficient mismatch repair tumors in 29% (272/943) of cases. The rate of LS confirmed by sequencing was higher with UTS (53.3%; 65/122) compared with TS (47.8%; 87/ 182), although the difference was not statistically significant (P[.175). CONCLUSIONS: UTS is widely implemented in Latin America; however, the low detection rate of LS demonstrated in this study raises concerns about the routine use of germline genetic testing in our region. Our study provides real-world outcomes that highlight disparities in screening uptake and counseling referrals, illustrating the challenges that Latin American countries face in hereditary cancer syndrome screening. These results contribute to the rationale for designing effective screening strategies for LS, which may also be applicable to other hereditary cancer syndromes, ultimately. Keywords: Lynch Syndrome; Traditional Screening; Universal Tumor Screening; Latin America. Genetic testing for Lynch syndrome (LS) is routinely used in Western populations. However, it has been partially implemented in Latin America. 1,2 Traditionally, cases of LS have been identified from personal and family histories using the Amsterdam criteria and Bethesda guidelines (herein termed as traditional screening [TS]). However, up to 68% of patients with LS may be missed when identified based on family history alone, 3 thus limiting the ability to identify and reduce the risk of colorectal cancer (CRC) and other types of cancer associated to LS. 4 Therefore, the use of universal tumor screening (UTS) was implemented as a molecular marker and involves the screening of all newly diagnosed patients with CRC, regardless of age and family history, by immunohistochemistry (IHC) or microsatellite instability (MSI) analysis 5,6 ; and it has been shown to have >90% sensitivity of identifying cases with LS. 7 When complemented with tumor MLH1 promoter methylation or BRAF p.V600E to exclude sporadic cancers, UTS has proven to be a cost-effective approach. 8 Prospective and epidemiologic studies have shown that there are 4 different dominantly inherited MSI August 2025 Lynch Syndrome 1643 cancer syndromes, caused by germline (likely) pathogenic variants in 1 of the 4 mismatch repair (MMR) genes (path_MMR): MSH2,MLH1,MSH6, and PMS2 or by deletion of the 30end of EPCAM (TACSTD1), which results in hypermethylation of the MSH2 promoter. 9 Each syndrome has a differential penetrance and expressivity of CRC and non-CRC. 10 Therefore, the identification of LS is important for clinical management, such as for the decision for surgery, appropriate surveillance, and/or clinical trial eligibility. Additionally, it provides an opportunity for risk reduction and early cancer detection, with enhanced surveillance for at-risk family members. In Latin America, there is an unbalanced distribution of resources and health care facilities in different geographic regions, not only when comparing highincome with low/middle-income countries, but also within countries (eg, rural vs urban areas). 11 Cancer genetic counseling (GC) services are scarce in some countries of Latin America but are growing despite limitations in infrastructure and qualified human resources. In a recent international collaborative study, we reported that 75% of participating centers have implemented GC for LS. 1 Because there are no regional guidelines or systematic screening for LS or other hereditary cancer syndromes in Latin America, this study aimed to characterize the current LS screening strategies, to explore the prevalence of LS, and to characterize the clinical and molecular profile of individuals with LS. We collected clinical, molecular, and genetic data of 1684 individuals with CRC from 24 existing cancer genetic registries/ centers from 9 countries of Latin America. Material and Methods Study Population The Latin American Network on LS, established in 2011, was founded after the first characterization of germline path_ MLH1 and path_MSH2 variants in unrelated South American individuals suspected of having LS. This network is primarily composed of the membership directories of the Latin-America Study Group on Hereditary Tumors (LA-GETH), and research and clinical collaborators who are actively involved in the assessment and treatment of patients affected by LS. 1,2 The network’s creation aimed to enhance the understanding of LS within the Latin American population by studying genetic mutations and providing clinical care. It serves as a platform for the exchange of research findings, clinical expertise, and advancements in genetic testing, with a focus on improving patient outcomes in hereditary cancer syndromes. Twenty-four representative Latin American genetic cancer registries/centers were included in the study. Information on clinical history, personal/family history of cancer, and molecular and genetic testing data was collected between 1999 and 2020. The use of multigene panel testing began in the early 2010s at research and academic institutions in larger countries, such as Brazil, Argentina, Mexico, and Chile. Currently, multigene panel testing is accessible in many countries across Latin America, and most of these panels include genes associated with hereditary cancer predisposition, incorporating the analysis of large deletions and duplications as part of their genetic assessment protocols. Provider data were collected using an Excel format sheet and then curated and imported into PostgreSQL. In addition, a survey was performed to characterize the structure of the Latin American centers and their screening practice. The MMR variants were classified according to the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) database (http://insight-database.org/). Lynch Syndrome Screening Strategies UTS involved screening of all patients with CRC regardless of age at diagnosis or fulfillment of existing clinical criteria for LS, using MSI or IHC, with or without testing of BRAF p.V600E and/or MLH1 promoter hypermethylation. TS was applied if the patient met 1 or several of the following criteria: Amsterdam criteria (I or II) 12,13 ; Bethesda guidelines 14 ; and “Others”that included an isolated case of a patient tested for IHC, MSI, or BRAF p.V600E, and/or MLH1 promoter hypermethylation. What You Need to Know Background Lynch Syndrome (LS) diagnosis in Latin America traditionally relies on the Amsterdam criteria and Bethesda guidelines but may miss up to 68% of cases. Universal Tumor Screening (UTS) aims to improve detection by screening all newly diagnosed colorectal cancer (CRC) patients for molecular markers. Findings Data from 1,684 CRC patients revealed UTS is widely implemented, with 78% undergoing UTS. Although UTS identified more deficient mismatch repair tumors, the LS confirmation rate by sequencing was not significantly higher compared to Traditional Screening (TS). Implications for patient care UTS can enhance LS detection rates in Latin America, but the low overall detection rate highlights the need for improving and standardizing germline genetic testing across the region. Effective screening strategies for LS are crucial for better hereditary cancer syndrome management. 1644 Campos-Segura et al Clinical Gastroenterology and Hepatology Vol. 23, Iss. 9 Statistical Analysis Descriptive statistics (frequencies and percentages) were obtained to describe the type of LS screening strategy and corresponding diagnostic methods applied to detect LS cases. The rate of LS cases confirmed by MMR sequencing (ie, true positives) was compared between the UTS and TS strategies using the Z-test. Cases having an unknown screening strategy were not considered in this analysis. Descriptive statistics (mean, standard deviation, frequencies, and percentages) were applied to report clinical and molecular characteristics of the CRC cases by the screening strategy (UTS and TS), and genetic confirmation of LS (LS and non-LS cases). The differences of patients’characteristics between screening strategies or between LS outcomes were evaluated using the Fisher exact test. The respective differences of patients’age were evaluated using the T-test. These differences were evaluated only for characteristics with more than 20% of data available. All reported P<.05 were considered statistically significant. Statistical analyses and figures of the study were performed using R software version 4.4.0. Ethics Statement The study has been approved by the Institutional Human Ethics Committees, institutional review boards, or national central authorities of the participating centers. Patients were informed of their inclusion in the study. Written informed consent was obtained from all participants during GC sessions. All reporting centers exported deidentified data. Results Demographics and Characteristics of the Latin American Genetic Cancer Registries/Centers Out of the 24 representative Latin American genetic cancer registries/centers, 6 centers were located in 5 cities of Argentina: Buenos Aires (2), Rosario (1), Neuquén (1), Mendoza (1), and Córdoba (1). Five centers were located in 5 cities of Brazil: Salvador, Porto Alegre, Recife, São Paulo, and Vitoria. Four centers were located in 3 cities of Colombia: Medellin (2), Monteria (1), and Ibague (1). Three centers were located in 2 cities of Chile: Santiago (2) and Concepcion (1). Two centers were located in the city of Lima (Peru). In addition, 1 registry/ center was also included from each of the following cities: Quito (Ecuador), Mexico DF (Mexico), San Juan (Puerto Rico), and Montevideo (Uruguay). Available information about the infrastructure and screening strategy was obtained from 21/24 of the genetic cancer registries/centers. Almost half (42.9%; 9/ 21) of the cancer registries/centers were reported as private clinics, 23.8% (5/21) as academic or public entities, followed by public/university hospitals (9.5%; 2/ 21). A hereditary gastrointestinal service/program has been established by most of the participating centers (76.2%; 16/21). Interestingly, only 14.3% (3/21) of the centers (located in Argentina and Uruguay) have reported to have a national hereditary cancer program. The first CRC Family registry in Latin America started in 1992 (São Paulo, Brazil), 15,16 whereas the youngest one was recently implemented in the Northeastern of Brazil (Recife) in 2019. The average number of patients seen per month for initial gastrointestinal cancer risk assessment has been represented as follows: 0 (5%), 1–5 (47%), 6–10 (29%), 11–20 (14%), and 21–39 (5%) patients. Lynch Syndrome Screening Diagnostic Practice in Latin America In total, data were collected from 1684 patients with CRC: 1209 cases having and 475 not having information on the practice of the screening strategy (UTS or TS). Of the 1209 cases, 943 (78%) were found using the UTS strategy, mainly in Argentina, Chile, and Uruguay, whereas 266 met the clinical criteria (TS strategy) (Figure 1 and Table 1). When UTS was used (n ¼943), IHC was more frequently applied (85.5%; 808/943), either alone or in combination with another method. IHC plus MSI (44.2%; 418/943) was the most frequently combined method. Out of UTS-evaluated patients, 28.8% (272/943) showed abnormal results (deficient MMR [dMMR]) based on either 1 or more combined methods described in Table 2. Out of these UTS-evaluated patients, 12.9% (122/943) were submitted to germline sequencing, identifying 65 LS-confirmed cases (Table 2). However, 266 CRC cases were enrolled by TS: 51.5% were based on the Amsterdam criteria (137/266) and 45.9% on Bethesda guidelines (122/266). Seven cases (3%) did not fully meet the Amsterdam or Bethesda criteria but were assessed by an isolated IHC or MSI or BRAF p.V600E testing. Out of these TS-evaluated patients, 68.4% (182/266) were submitted to germline sequencing, identifying 87 LS-confirmed cases (Figure 1). When analyzing the screening strategy by country, UTS was mainly applied by Argentina (n ¼21; 32.31%), followed by Uruguay (n ¼15; 23.08%), Chile (n ¼12; 18.46%), and Puerto Rico (n ¼11; 16.92%) (Figure 2A). TS was mainly used in Colombia, (n ¼61; 70.11%), followed by Brazil (n ¼15; 17.24%) and Mexico (n ¼7; 8.05%) (Figure 2B). Rate of the path_MMR Variants by Screening Strategy Overall, LS screening strategy and germline testing was available for 72% (1209/1684) and one-quarter August 2025 Lynch Syndrome 1645 (304/1209) of the cases, respectively (Figure 1). Therefore, the rate of path_MMR variants and its comparison between UTS and TS strategies could be evaluated using only a reduced number of cases (ie, 304 cases with available germline testing). Despite no statistical difference (P¼.175), the overall rate of positive LS cases confirmed by sequencing was higher for the UTS (53.3%; 65/122) than for the TS strategy (47.8%; 87/182) (Figure 1). Profile and Frequency of the path_MMR Variants in Latin America Regarding the profile and frequency of path_MMR variants, UTS identified 65 path_MMR carriers: 28 (43.08%) in MLH1, followed by 24 (36.92%) in MSH2,6 (9.23%) in MSH6, 4 (6.15%) in PMS2, and 3 (4.62%) large deletions that involving EPCAM or EPCAM-MSH2.Of the 87 path_MMR carriers identified by TS, 47 (54.02%) had path_MMR variant in MLH1, 38 (43.68%) in MSH2,1 (1.15%) in MSH6, and 1 (1.15%) in PMS2 (Figure 3). Clinical and Molecular Characterization of Lynch Syndrome and Non–Lynch Syndrome from Latin America In total, 31.2% (525/1684) of CRC cases were sequenced; of these, 40.4% (212/525) were LS and 59.6% (313/525) were non-LS. The mean age at CRC diagnosis was 41 years (standard deviation, 11.5) and 47 years (standard deviation, 12.5), respectively (P<.001) (Table 3). An overall profile of LS compared with non-LS cases from Latin America included a significant association between the location of the tumor (P<.001), with a predominance of right-sided tumors in the LS group. The personal history of multiple tumors and family history of CRC showed significant differences in the LS group (P¼ .012 and P<.001, respectively). However, non-LS patients presented more advanced disease at the diagnosis in comparison with LS (stage III and IV; P¼.039). dMMR proteins were mostly reported for the LS group (P< .001). However, a similar MSI-high rate was observed for both groups. Regarding BRAF p.V600E, a mutation rate of 5.1% was observed in the non-LS group (Table 3). Discussion In Latin America, there are some challenges that lowresource setting cities are facing, including a lack of global implementation of cancer screening programs, accurate data and statistics that may aid the health authorities to guide future public health activities, and reorient strategies, interventions, and budgets to promote lifestyles that help prevent disease. Current cancer care does not fully reflect ethnic, cultural, environmental, and resource differences. 17 In an effort to characterize hereditary cancer syndromes in Latin America, we have previously reported the genetic and clinical profile of individuals with LS, but there is limited information about the screening Figure 1. Flow diagram of the screening strategies for LS cases in Latin America. WT, wild type. 1646 Campos-Segura et al Clinical Gastroenterology and Hepatology Vol. 23, Iss. 9 Table 1. Overview of the Clinical, Molecular, and Family History Characteristics of 1684 Patients with CRC from Latin America, and by Use of LS Screening Strategy Total cohort UTS TS Pvalue a n(%)n(%)n(%) Total CRC cases 1684 b 943 266 Participating countries — Argentina 513 (30.5) 210 (22.3) 26 (9.8) Brazil 80 (4.7) 17 (1.8) 46 (17.3) Chile 504 (30.0) 456 (48.4) 3 (1.1) Colombia 126 (7.5) 3 (0.3) 122 (45.9) Ecuador 18 (1.1) 0 (0.0) 18 (6.8) Mexico 51 (3.0) 7 (0.7) 44 (16.5) Peru 23 (1.3) 0 (0.0) 7 (2.6) Puerto Rico 122 (7.2) 122 (12.9) 0 (0.0) Uruguay 247 (14.7) 128 (13.6) 0 (0.0) Age of CRC diagnosis <.001 Mean STD 55 17.3 56 16.4 44 13.9 Median; 25th–75th percentile 55; 41–68 57; 44–68 44; 34–55 Gender .1452 Female 862 (51.2) 455 (48.3) 142 (53.4) Male 821 (48.7) 488 (51.7) 124 (46.6) Missing 1 (0.1) 0 (0.0) 0 (0.0) Tumor location .0019 c Right colon 673 (40.0) 382 (40.5) 106 (39.8) Transverse colon 23 (1.3) 6 (0.6) 5 (1.9) Left colon 804 (47.8) 463 (49.1) 115 (43.2) Rectum 84 (5.0) 76 (8.2) 6 (2.3) Cecum 1 (0.1) 1 (0.1) 0 (0.0) Left and right 10 (0.5) 6 (0.6) 2 (0.8) Left and transverse 1 (0.1) 1 (0.1) 0 (0.0) Right, left, and transverse 1 (0.1) 1 (0.1) 0 (0.0) Missing 87 (5.1) 7 (0.7) 32 (12.0) Stage <.001 I 218 (13.0) 132 (14.0) 20 (7.5) II 589 (35.0) 309 (32.8) 96 (36.1) III 513 (30.5) 324 (34.3) 59 (22.2) IV 235 (14.0) 136 (14.4) 54 (20.3) Missing 129 (7.5) 42 (4.5) 37 (13.9) Presence of multiple tumors .5270 Yes 323 (19.2) 165 (17.5) 51 (19.2) No 1358 (80.6) 777 (82.4) 215 (80.8) Missing 3 (0.2) 1 (0.1) 0 (0.0) MMR expression <.001 Normal 775 (46.0) 544 (57.7) 51 (19.2) Absent 387 (23.0) 259 (27.5) 76 (28.5) Missing 522 (31.0) 140 (14.8) 139 (52.3) MSI status .0167 MSI-H 258 (15.3) 202 (21.4) 48 (18.0) MSS/MSI-L 408 (24.2) 352 (37.3) 48 (18) Missing 1018 (60.5) 389 (41.3) 170 (64.0) BRAF V600E — Yes 81 (4.8) 65 (6.9) 1 (0.5) No 300 (18.0) 251 (26.6) 39 (14.5) Missing 1303 (77.2) 627 (66.5) 226 (85.0) MLH1 methylation — Yes 22 (1.3) 19 (2.0) 3 (1.1) No 150 (9.0) 146 (15.5) 4 (1.5) Missing 1512 (89.7) 778 (82.5) 259 (97.4) August 2025 Lynch Syndrome 1647 strategies across all countries. Limited access to genetic care and counselling tailor the need to design a systematic screening approach for cancer risk genetic assessment to reduce cancer burden in this region. This study reported the current LS screening strategies in a large cohort of 1684 individuals with CRC from 9 countries in Latin America (Argentina, Brazil, Colombia, Chile, Peru, Ecuador, Mexico, Puerto Rico, and Uruguay) collected between 1999 and 2020. We aim to contribute with some rationale for designing screening strategies for LS and highlight ongoing research and the need for inclusive data to better serve diverse populations in Latin America. UTS is widely used in Latin America, particularly in Argentina, Chile, and Uruguay. These countries have been at the forefront of implementing molecular analysis and genetic testing protocols for LS since 2010. With the advent of new targeted treatments and a focus on personalized medicine in CRC, tumor molecular testing has rapidly evolved in Colombia in recent years. Following the introduction of immunotherapy for CRC, patients with stage II disease can now be selected for adjuvant 5-FU treatment based on their MMR results. Consequently, most pathology laboratories now routinely screen newly diagnosed patients with CRC for dMMR using IHC. Patients identified with dMMR are increasingly referred for genetic consultations to evaluate the need for germline testing and to receive GC. The mutation detection rate of UTS (53.3%) was comparable with TS (47.8%), although by crude percentages the UTS seemed to be slightly more effective in identifying individuals with LS. This detection rate reflects the limitations of genetic testing for LS, because it was applicable only to a subset of suspected cases (eg, 55% of patients having abnormal results in 1 of the UTS methods, did not undergo germline sequencing). The challenges in obtaining comprehensive genetic testing underscore the need for improved strategies in identifying individuals at risk in the region. In line with our study, Adar et al 18 reported that the UTS detection rate was very low (1.7%), because not all patients received GC, and consequently did not undergo germline genetic sequencing. The superiority of UTS has been widely reported 3,19 and it is recommended by the National Comprehensive Cancer Network and other societies. 20,21 In this study, the UTS strategy is estimated to correctly detect approximately 5.5% more LS cases than the TS approach. To our knowledge, in Latin America there is no health system/insurance that provide germline testing to all patients with CRC regardless of age; therefore, UTS strategy could be a feasible option to be implemented. Regarding the genetic and molecular profile, we identified that 24% (75 out of 313) of non-LS cases exhibited MSI-H or loss of expression of MMR proteins, without a germline path_MMR variant. This condition is Table 1.Continued Total cohort UTS TS Pvalue a n(%)n(%)n(%) Family history of CRC .004 Yes 263 (15.6) 115 (12.2) 50 (18.8) No 1212 (72.0) 817 (86.6) 206 (77.4) Missing 209 (12.4) 11 (1.2) 10 (3.8) Affected MMR gene — MLH1 144 (8.6) 34 (3.6) 47 (17.7) MSH2/EPCAM 105 (6.2) 30 (3.2) 40 (15.0) MSH6 14 (0.8) 6 (0.6) 1 (0.4) PMS2 12 (0.7) 4 (0.5) 1 (0.4) Other 20 (1.2) 10 (1.0) 0 (0.0) Missing 1389 (82.5) 859 (91.1) 177 (66.5) Type of genetic variant in MMR genes (only class 4/5) — Nonsense 89 (5.3) 12 (1.3) 47 (17.7) Frameshift_Indel 55 (3.3) 14 (1.5) 12 (4.5) Missense 61 (3.6) 17 (1.8) 15 (5.6) Exon deletion 24 (1.4) 11 (1.2) 3 (1.1) Intronic 18 (1.0) 8 (0.8) 4 (1.5) Other 15 (0.9) 6 (0.6) 1 (0.4) Missing 1422 (84.5) 875 (92.8) 184 (69.2) NOTE. 25th–75th percentile refers to the interquartile range statistics. Em dash refers to test was not performed because of >80% missing data. CRC, colorectal cancer; LS, Lynch syndrome; MMR, mismatch repair; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stable; STD, standard deviation; TS, traditional screening; UTS, universal tumor screening. a Fisher exact test was used for the association of cases’categorical characteristics and detection of LS (missing category was not included in the evaluation). Ttest was used to compare age of diagnosis between LS screening strategies. b Total CRC cases, including cases with unknown LS screening strategy; 475 did not present a defined screening method. c Evaluated only for tumor locations: right colon, transverse colon, left colon, rectum. 1648 Campos-Segura et al Clinical Gastroenterology and Hepatology Vol. 23, Iss. 9