N57: Comprehensive Constitutional (Epi)Genetic Characterization Of Lynch-Like Patients

E. Dámaso1, M. González-Acosta1, 2, G. Vargas-Parra1, 2, M. Navarro1, 2, J. Balmaña3, T. Ramon y Cajal4, N. Tuset5, F. Marín1, A. Fernández1, C. Gómez1, À. Velasco1, A. Solanes1, S. Iglesias1, G. Urgell5, C. López4, J. del Valle1, O. Campos1, C. Gómez1, M. Santacana6, X. Matias-Guiu6, C. Lázaro1, 2, L. Valle1, 2, J. Brunet1, 2, M. Pineda1, 2, G. Capellá1, 2

1 – Hereditary Cancer Program, Catalan Institute of Oncology, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), ONCOBELL Program, L’Hospitalet de Llobregat, Barcelona, Spain.2 – Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. 3 -High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. 4 – Medical Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 5 – Genetic Counselling Unit, Hospital Arnau de Vilanova, Lleida, Spain. 6 – Department of Pathology, Hospital Arnau de Vilanova, Lleida, Spain.


Aim: In ~50% of Lynch syndrome (LS)-suspected patients (also called Lynch-like syndrome, LLS), the causal mechanism for cancer predisposition remains unknown. Our aim was to elucidate the constitutional basis of MMR-deficiency in LLS patients throughout a comprehensive (epi)genetic analysis.

Method: One hundred and fifteen LLS patients harboring MMR deficient tumors and no pathogenic germline mutations identified in MMR genes were included in this study. Pathogenicity of MMR VUS was assessed by mRNA analysis and multifactorial likelihood calculations. Mutational analysis of 26 CRC-associated genes was performed by a customized NGS panel. Methylome analysis was perfomed by Infinium 450K array.

Results: NGS analysis revealed the presence of two MMR truncating mutations not previously found. Five out of 15 MMR VUS were reclassified as pathogenic. Methylome analysis identified one case harboring a constitutional MLH1 epimutation. In addition, 12 predicted deleterious variants in other CRC-predisposing genes were found. Differentially methylated regions were not identified in samples from LLS patients compared to LS or healthy individuals.

Conclusion: In conclusion, the use of subexome gene panels combined with pathogenicity assessment of VUS allows the identification of MMR mutations as well as new LLS-candidate genes. Constitutional epimutations outside MMR genes are not responsible for the MMR-deficient phenotype observed in LLS patients.