Discussion
RTPS1 is characterized by early-onset and even congenital ATRT, and less commonly extracranial rhabdoid tumors. Synchronous or metachronous tumor sequences occur. Thus, RTPS1 is a negative prognosticator in ATRT. Mutations in RTPS1 are usually truncating mutations in distinction to those in Schwannomatosis or Coffin-Siris syndrome1. However, overlap between Schwannomatosis and ATRT has been observed3. We here report a family in which a gain of SMARCB1 exon 6 segregates with malignant diseases including ATRT. Though we formally cannot rule out an integration of the gained segment elsewhere in the genome, the combination of germline and somatic analyses strongly suggest this change to be pathogenic to one allele ofSMARCB1, which is retained in the tumors lacking INI1 staining. Interestingly, SMARCB1 exon 6 duplications have previously been reported in a pedigree with ATRT and schwannoma4. Another pedigree with a CRINET and incomplete penetrance of germlineSMARCB1 exon 6 duplication is on record5.
Our index patient III.1 , his sister III.2 , and his father II.2 did not present any schwannoma on clinical or MRI examination. One cousin IV.1 died from a malignant brain tumor in infancy. Her mother III.4 is an asymptomatic carrier of theSMARCB1 gain, it is possible that she was also afflicted with an ATRT. Regarding the many siblings and half siblings of the father we could not accrue more information. Thus, the exact incidence of further neoplasm was not ascertained and the founding mutation could not be traced back.
A differential diagnosis of a CRINET was entertained for III.1 , as CRINETs may be similar to ATRT-TYR on methylation profiling, immunochemistry, and by clinical outcome. However, the absence of any cribriform features and rosettes combined with an abundance of typical rhabdoid cells did not support CRINET as a differential diagnosis. No rhabdoid features were seen in the myxopapillary ependymoma ofII.2 . DNA methylation profiling did neither assign a significant score for the ATRT nor for the myxopapillary ependymoma on the Heidelberg classifier. While this is a frequent phenomenon for tumors with germline alterations (unpublished observations), thet -SNE suggested the ATRT to belong to the prognostically favorable TYR subgroup, in line with the long-term remission observed in our patient. The spinal tumor showed, both histologically and regarding DNA methylation high similarity to the subgroup of myxopapillary ependymoma, a subgroup that is usually occurring in a sporadic setting.
Apart from the myxopapillary ependymoma, the father suffered from a HCL-v. Classical hairy cell leukemia (HCL-c) is typically associated with oncogenic BRAF V600E mutations. Epigenetic driver mutations affecting members of the SWI/SNF complex (e.g. ARID1A ) have been detected in some of those HCL-c, but at increased frequency in hairy cell leukemia variants (HCL-v) that occur without the BRAF V600E mutation.6,7 However, both ependymoma and HCL-v have so far not been observed in the context of SMARCB1 mutations.
Together, our report highlights the incomplete penetrance of RTPS1 caused by SMARCB1 gains and the expanding spectrum of malignancies associated with these mutations.