N48: Molecular Tumor Testing In Lynch-Like Patients Reveals De Novo Mosaic DNA Mismatch Repair Gene Pathogenic Variants Transmitted To Offspring

E. Guillerm1, H. Delhomelle2, M. Warcoin1, A. Palmyre1, M. Svrcek2, A. Bardier Dupas1, I. Sourrouille2, N. Janin3, M. Eyries1, V. Cusin1, F. Soubrier1, F. Coulet1, C. Colas4

1 – Hôpital Universitaire Pitié Salpêtrière (Assistance Publique-Hôpitaux de Paris), Sorbone University, Paris, France. 2 – Hôpital Universitaire Saint Antoine (Assistance Publique-Hôpitaux de Paris), Sorbone University, Paris, France. 3 – Cliniques Universitaires Saint-Luc, Brussels, Belgium. 4 – Curie Institute, Paris, France.


Aim: Lynch-like syndrome (LLS) patients have tumors with Microsatellite Instability but no germline variant in Mismatch Repair genes (MMR) or somatic methylation of the MLH1 promoter. Double somatic hits are the usual explanation for these cases. Our purpose was to find other explanations, such as mosaicism, that could explain LLS and have an impact on genetic counselling.

Method: We analysed the MMR genes in frozen tumor tissue samples by NGS for 28 LLS patients. When a tumoral variant was found, we performed a targeted re-examination of the germline NGS results with lower detection rates and targeted Sanger analysis in normal adjacent tissue DNA and lymphocytes DNA from offspring when available.

Results: Eight patients had double somatic hits in their tumors. Two patients had a germline de novo mosaic variant of MSH2 with low variant allele frequency (9% and less than 2%). Those variants were missed by NGS analysis in lymphocytes DNA. Their identification in tumors allowed a targeted NGS reanalysis. In both cases, these variants were found to be heterozygous in one of the offspring.

Conclusion: These mosaic cases confirm that identification of the mechanism that causes tumors in LLS is crucial for genetic counselling and guiding screening of patients and their relatives.