N91: Hereditary Cancer Program (ProCanHe): 21 years of experience at a referral registry In Argentina

T. A. Piñero1,2, I. Herrando2, P. Kalfayan2, M. Gonzalez2, A. Ferro2, J. Santino2, R. Cajal1, D. Falconi2, G. Guerrero2, A. Verzura2, M. Riggi2, J. Church3, P. Peltomäki4, A. Martins5, W. Pavicic2,4,6, M. Dominguez7, C. Vaccaro2

Aim: Registries in South America were initiated in the early 90’s with the help of Henry T. Lynch. The Programa de Cancer Hereditario (Pro.Can.He), is a multidisciplinary program established in 1996 at the Hospital Italiano, Argentina. The aim of the study is to update our 21-year experience to determine the applicability of genetic tests highlighting the most informative molecular findings in relation to Lynch syndrome mostly.

Materials and methods: Families undergoing genetic testing after genetic counselling between1996-2018 were included. Data were obtained from a prospective IRB approved database. Clinical-epidemiological and molecular variables were analyzed. Genetic tests were carried out after a genetic counselling session and obtaining the informed consent of the patient.Molecular testing: Until 2015, the search for variants was carried out by PCR and Sanger sequencing of exons and adjacent intronic regions of MLH1 and MSH2. Then, sequencing of MLH1/MSH2/MSH6/PMS2/EPCAM genes was performed by NGS and large rearrangements were detected by MLPA. The variants were classified according to international databases. Variants with uncertain or unreported clinical significance were analysed In-silico using the PolyPhen, SIFT and/ or Human Splicing finder 3.0 software.

Results: A total of 83 families (49 fulfilled Amsterdam Criteria [AC] and 34 Bethesda Criteria [BC]) were analyzed. Pathogenic variants were found in 26 out of 83 (31.3%) families, been 23 pathogenic and 3 likely pathogenic.Splice site and large rearrangements represented 19.2% (5/26) and 11.5% (3/26) of the variants.23% (6/26 )of them were originally described in this series and 1 was a founding mutation from Piedmont, Italy. Affected genes include MSH2, MLH1, MSH6 and PMS2 (12, 11, 2 and 1 cases respectively). Mutation detection rates in AC and BT families were 48.9% (N=24) and 5.9% (N=2), p<0.01. Among AC families, those with identified mutation had a lower median age of cancer on set and higher incidence of extra-CCR cancer than those without identified mutations. Additionally, we have also studied other genes in patients with different clinical conditions included in the registry.We identified mutations in APC, MUTYH, BMPR1A, SMAD4, CDH1, BRCA1-2, CHEK2.

Conclusion: The multidisciplinary approach and the international collaborations allowed the correct implementation of the genetic tests. To our knowledge, this study is the first Characterization of AC families according to genetic tests in South America. This allowed the identification of AC families with different ages of onset and prevalence of extra-CRC cancers, as well as several significant variant not previously reported in international databases.