Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors

Abstract

Background: Germline mutations and deletions of SMARCB1/INI1 in chromosome band 22q11.2 predispose patients to rhabdoid tumor and schwannomatosis. Previous estimates suggested that 15-20% of rhabdoid tumors were caused by an underlying germline abnormality of SMARCB1. However, these studies were limited by case selection and an inability to detect intragenic deletions and duplications.

Procedure: One hundred matched tumor and blood samples from patients with rhabdoid tumors of the brain, kidney, or soft tissues were analyzed for mutations and deletions of SMARCB1 by FISH, multiplex ligation-dependent probe amplification (MLPA), sequence analysis and high resolution Illumina 610K SNP-based oligonucleotide array studies.

Results: Thirty-five of 100 patients were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions including regions both proximal and distal to SMARCB1. There were nine cases that demonstrated parent to child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma, and two of the eight families presented with multiple affected children in a manner consistent with gonadal mosaicism.

Conclusions: Approximately one-third of newly diagnosed patients with rhabdoid tumor have an underlying genetic predisposition to tumors due to a germline SMARCB1 alteration. Families may demonstrate incomplete penetrance and gonadal mosaicism, which must be considered when counseling families of patients with rhabdoid tumor.

Fig 1

Germline alterations were found in 35 cases and included mutations, duplications and deletions (shown in black). The “second hit,” found only in tumor cells, is shown in white. The last seven patients (01-135, 07-315, 00-214, 09-289, 06-147, 06-175, and 06-216) have homozygous deletions in their tumors that are the same size as germline heterozygous deletions, so they appear only as black bars.

Fig. 2

Illumina Beadstudio depiction of chromosome 22 showing a heterozygous deletion in the blood of patient 08-237. A decrease in the Log R ratio corresponding to the absence of heterozygous SNPs indicates a deletion, the location of which is demonstrated by the black arrow. This deletion includes GNAZ, but not SMARCB1. The tumor shows a whole chromosome 22 deletion.

Fig. 3

Pedigree of family 09-013. Two affected sisters had the same SMARCB1 exon 1 mutation (c.20_43delinsT). Neither parent had the mutation, consistent with gonadal mosaicism (A). Pedigree of family 07-367. The proband (III.1) was found to have a germline mutation in SMARCB1 exon 4 (c.472C>T), inherited from her paternal grandmother (B). Pedigree of family 08-143. The SMARCB1 exon 4 mutation (c.367C>T) was identified in two affected siblings as well as their mother. She had a de novo mutation and was subsequently diagnosed with a benign CNS lesion (C).