N93: Hereditary Gastrointestinal Cancer Mutational Registry in Uruguay

P. Esperon1,2, F. Neffa1, N. Artagaveytia1, M. Sapone1, C. Vergara1, F. Carusso1, A. Della Valle1

Introduction: Since 1996, the Uruguayan Collaborative Group (UCG), a nonprofit organization is devoted to the registry, diagnosis, management and investigation of hereditary cancer. UGC is integrated by a multidisciplinary team of experts and represents in the country, a reference center for genetic counselling and risk assessment.

Objective: To present an updated Uruguayan mutation catalog for gastrointestinal (GI) hereditary cancer susceptibility.

Methodology: The UCG registry is integrated by 1536 non-related families. 548 families (35%) are defined as GI-high risk population following the National Comprehensive Cancer Network 2018 guidelines. These families were classified as: Amsterdam I-II, Bethesda, Li Fraumeni, Peutz Jeghers, Familial Adenomatous Polyposis, MUTYH-Associated Polyposis, or Serrated polyposis syndrome. Selected probands for genetic testing signed informed consent prior to obtain saliva or blood samples. Several DNA-analysis techniques were used over these 22 years, from Sanger sequencing alone (until 2010), Next Generation Sequencing of a group of genes and large rearrangements detection methods, to nowadays, panels of 30 genes.

Results: At present a total of 234 (43%) GI-high risk, non-related probands were tested and 63 families were diagnosed. We found 49 different mutations, classified according to ACMG as “Pathogenic” and distributed among the following genes: MLH1 (9), MSH2(11), PMS2(3), MSH6 (3), EPCAM(1), APC (11), STK11(2), NF1(1), FAN1(1), RAD51(1), SDHB(1), BMPR1A(1), MUTYH biallelic (3). A family carried a mutation class 4 (likely Pathogenic) in MLH1. In nine probands with a characteristic hereditary colon cancer phenotype, only MUTYH monoallelic mutations were found. An increasing number of variant of uncertain significance were found.

Conclusion: A research period of 22 years has unveiled the mutational spectrum of GI-high risk cancer of the Uruguayan population, allowing a broader vision regarding hereditary cancer profile in an understudied population. In spite of the large gene selection, only a few were involved in cancer predisposition. Lynch Syndrome, as expected, was the most frequent diagnosis, but with a relatively low pathogenic variant presentation.

Acknowledgement: Fundación Génesis Uruguay.