N65: Etiology And Characterization Of Lynch-Like Syndrome Patients

M. Giner-Calabuig1, M. Juarez1, M. Alustiza-Fernández1, O. Murcia2, R. Jover2, X. Llor3, R. M. Xicola3

1 – Fisabio-Isabial. 2 – Hospital General Universitario de Alicante Fisabio-Isabial. 3 – University of Yale.


Aim: Lynch-like Syndrome  patients are younger at diagnosis and had a higher prevalence of cancer in their families than individuals with sporadic cancers. These characteristics suggest the presence of an underlying hereditary condition.

The aim of this study is to characterize  the molecular bases of LLS.

Method: We performed whole exome sequencing in a cohort of 27 LLS patients. We performed an analysis to identify rare likely pathogenic variants that could be predisposing to cancer. Only high-quality called variants, present with a population frequency <2.10-5  were included.

Based on the fact that the mutations in the MMR genes could be passenger mutations that drive further instability, a targeted analysis including a comprehensive list of DNA repair genes was also included.

We also performed tumor exome analysis from the matching samples to search for somatic hits.

Results: We identified 4 LLS patients with rare germinal variants in the following genes: AXIN1, PIWIL3, CD109, RECQL5 and GEN1. No somatic second hit was found in any of these genes. 2/8 cases where we could evaluate somatic events had a somatic mutation in one MMR gene and 1 showed LOH of the other copy. One tumor had a single mutation in a MMR gene and in one case I did not identify any somatic alterations.

Conclusion: Based on these results we hypothesize that there is a group of patients with predisposition to CRC due to a germinal variant  in one allele that triggers genomic inestability. But there is also another group of patients where it could be due to a biallelic somatic mutation in MMR genes.