Constantine Stratakis

Integrity of the pheochromocytoma susceptibility TMEM127 gene in patients with pediatric malignancies.

Germline mutations of the tumor suppressor gene TMEM127 occur in the neural-crest-derived tumors, pheochromocytomas and paragangliomas (Qin et al. 2010, Yao et al. 2010, Neumann et al. 2011), and have also been detected in renal cell carcinomas (Qin et al. 2014). Genes involved in susceptibility to pheochromocytomas and renal cancers are also mutated in other malignancies. To determine whether TMEM127 mutations also predispose to cancers affecting the pediatric population, herein, we investigated the integrity of TMEM127 in 155 samples of various cancer types from patients younger than 18 years of age.One group comprised 16 gastrointestinal stromal tumor samples, four germline and 12 tumors, from 13 patients. A second group encompassed germline DNA from 139 pediatric patients and included 53 hematological malignancies (39 acute lymphoid leukemias, three acute myeloid leukemias, five Hodgkin’s and six non-Hodgkin’s lymphomas), 22 osteosarcomas, 16 CNS tumors (five medulloblastomas, one astrocytoma, two gliomas, one craniopharyngioma, one atypical teratoid rhabdoid tumor, and five with unspecified histology), 12 germ cell tumors, eight Ewing’s sarcomas, six neuroblastic tumors, five Wilms’ tumors, four retinoblastomas, three rhabdomyosarcomas, three liver tumors (two hepatoblastomas and one hepatocarcinoma), one synovial sarcoma, one fibrosarcoma, one mesothelioma, one adrenocortical carcinoma, one desmoid tumor, one non-Langerhans histiocytosis, and one primitive myxoid mesenchymal tumor of nasal arch. Three patients had more than one tumor. Informed consent was obtained from all patients (approved by UTHSCSA and NIH IRB committees) and sequencing of the TMEM127 coding region was performed as described previously (Yao et al. 2010). Two germline TMEM127 missense variants were detected: c. 67COA, p.Leu23Met, a novel variant, in one patient with Ewing’s sarcoma and c.268GOA, p.Val90Met in one case of craniopharyngioma (Fig. 1). The Val90Met variant has been previously reported in pheochromocytomas (Qin et al. 2010, Abermil et al. 2012), and has also been