Thoracic chordoma following intracranial meningioma in a patient with a novel germline SMARCE1 variant

Abstract

Paediatric cancer predisposing factors (CPFs), such as DICER1 syndrome, Li-Fraumeni syndrome, and SMARC-related syndromes, are increasingly being identified through genome-wide sequencing of surgical specimens. Among these, mutations in the SWItch/Sucrose Non-Fermentable chromatin-remodelling complex, particularly involving the SMARCE1 gene, have been implicated in various paediatric tumours, including clear cell meningioma (CCM). However, the role of SMARCE1 mutations in other rare tumours like chordoma remains undetermined. TBXT is a gain-of-function driver mutation of chordoma alongside upregulated transforming growth factor beta 1 (TGFβ1) and epidermal growth factor receptor (EGFR). Herein, we report a rare case of thoracic chordoma with sudden abdominal pain after treatment for intracranial CCM. Germline analyses of surgical specimens from CCM and chordoma showed heterozygous mutations in both the SMARCE1 (chromosome 17q21.2) and TBXT (brachyury, chromosome 6q27) genes. Somatic mutation analyses showed loss of heterozygosity at the SMARCE1 gene region in both CCM and chordoma surgical specimens, as well as at the TBXT gene region in CCM, but not in chordoma. We speculated that both TBXT and SMARCE1 might indirectly promote EGFR signalling to drive chordoma cell proliferation and survival, although the direct interaction between TBXT and SMARCE1 is unknown. To our knowledge, this is the first report of a patient with a spinal chordoma after CCM treatment, suggesting that SMARCE1 is a candidate pathological factor in chordoma.