ATRT-21. Contribution of germline mosaic alterations of SMARCB1 in rhabdoid tumor predisposition syndrome

Abstract

Rhabdoid tumors are rare and aggressive tumors that usually arise in very young children. They are characterized by a bi-allelic inactivation of the SMARCB1 gene. Although the majority of alterations of SMARCB1 are acquired in tumors, a heterozygous germline alteration is seen in one third of patients and defines the rhabdoid tumors predisposition syndrome. Penetrance is almost complete and the vast majority of germline alterations of SMARCB1 are acquired de novo but rare familial cases with a healthy carrier have also been described. Since the advent of more sensitive molecular analysis technologies such as next-generation sequencing (NGS), the number of mosaicisms of genes involved in genetic diseases discovered from blood samples has increased considerably. The aim of our study was to explore the mosaicisms of SMARCB1 in the blood 1/ of children with rhabdoid tumors with at least one alteration of SMARCB1 previously identified in the tumor but not found in the blood with old-fashioned low-sensitivity technologies and 2/ in parents of children with heterozygous germline alteration of SMARCB1. We analyzed a custom NGS panel which covers the SMARCB1 gene with an average depth of 1.500X on blood samples of 111 children with rhabdoid tumors and 32 parents collected at the Institut Curie since 1999. The mosaicism rate found in index cases was 11.7% (13/111) and 3.1% (1/32) in parents. The variant allele frequency vary from 0.8% to 12.9%. Our results also indicate to be cautious about the possible confounding effect of circulating tumor DNA. This hitherto underestimated SMARCB1 mosaicism rate should motivate an optimization of the genetic counseling as well as the oncological monitoring of these children and thus have a significant medical impact given the catastrophic prognosis of rhabdoid tumors.