TRPS1 gene alterations in human subependymoma.

Subependymoma is a rare primary brain tumor, constituting 0.07-0.51% of brain tumors. Genetic alterations in subependymoma are largely unknown, but familial occurrences have been reported. Trichorhinophalangeal syndrome type 1 (TRPS1) is a rare hereditary malformation complex caused by mutations in a gene identified in the year 2000 on 8q24.12. We report two patients with TRPS I and surgically treated subependymomas, one of whom has a first degree relative, now deceased, who was affected and also had a subependymoma. We therefore sought a role for the TRPS1 gene in the molecular oncogenesis of subependymoma. Formalin fixed tumor specimens and saliva samples were obtained from the two index patients as well as tumor samples from six sporadic subependymoma surgical specimens. A heterozygous TRPS1 germ line mutation predicted to cause a frame shift leading to a premature stop codon was found in the first index patient and also present in the associated tumor. No germline mutation was found in the second index patient, but his tumor displayed copy number neutral loss of heterozygosity in TRPS1. TRPS1 mutation analysis of the sporadic subependymomas revealed genetic, mostly loss of function alterations in one-third (two of six) of samples. Genetic alterations in TRPS1 likely play a role in at least a subgroup of subependymomas. Confirmation and further (epi)genetic investigations, ideally in newly acquired, fresh-frozen tumor samples, are warranted.