A rare case of atypical teratoid rhabdoid tumor (AT/RT) with homozygous SMARCB1 loss and one concurrent somatic heterozygous SMARCA4 variant

TL;DR

A rare case of a brain tumor in a young child shows genetic changes in both SMARCB1 and SMARCA4 genes, monitored using a non-invasive liquid biopsy technique.

Contribution

First reported case of AT/RT with concurrent SMARCB1 homozygous loss and SMARCA4 somatic variant, using liquid biopsy for monitoring.

Findings

A three-year-old patient had AT/RT with biallelic SMARCB1 alterations and a heterozygous SMARCA4 variant.

Liquid biopsy was successfully used to track disease progression and relapse in this patient.

The combination of mutations in both SMARCB1 and SMARCA4 may influence tumor biology and clinical outcomes.

Abstract

Atypical teratoid rhabdoid tumors (AT/RT) are characterized by a poor prognosis and a manifestation within the first 2 years of life. Genetic hallmark of these tumors is the homozygous inactivation of SMARCB1 or, in some rare cases, of SMARCA4. While heterozygous pathogenic variants of SMARCA4 have been described, inter alia, in the context of other CNS malignancies such as medulloblastoma or glioblastoma, the co-occurrence of pathogenic variants in both, SMARCB1 and SMARCA4, in the same AT/RT has to our knowledge not been reported previously. Liquid biopsy, a rapidly developing and promising technique measuring cell-free DNA (cfDNA) in body fluids such as the cerebrospinal fluid (CSF), offers a minimally invasive method to assess disease status. It has yet to be established as a standard procedure in the diagnostic workup of CNS tumors. We present the case of a three-year-old male diagnosed with an AT/RT that exhibits both biallelic alterations of SMARCB1 due to a frameshift mutation and loss of heterozygosity as well as a heterozygous missense variant in SMARCA4 presenting with early disease progression. We employed liquid biopsy successfully to monitor disease progression throughout treatment and the subsequent relapse. We highlight the ramifications that simultaneous alterations in two chromatin-modifying genes may have for tumor biology and clinical course.

Figures