Germline Mutations in TMEM127 Confer Susceptibility to Pheochromocytoma



Accession Number: GSE19987

GPL96: [HG-U133A] Affymetrix Human Genome U133A Array
GPL571: [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array

Organism: Homo sapiens

Published on 2010-02-14

Pheochromocytomas, catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis.

Overall Design:
We performed comparative analysis of expression profiling of 125 Pheochromocytomas and paragangliomas with a variety of mutations representatives of distinct pheochromocytoma susceptibility syndromes, sporadic tumors and familial tumors without an identifiable mutation. This dataset combines data from 75 initial tumors and 50 new tumor samples, three samples were processed in duplicate.

Name: Patricia L. Dahia
Organization: UTHSCSA
Deparment: Medicine/Cel&Struct Biology
Address: 7703 Floyd Curl Dr MC7880 San Antonio TX 78229 USA
Phone: 210 5674866

Organization: Affymetrix, Inc.
Address: Santa Clara CA 95051 USA
Phone: 888-362-2447
Datos disponiblesene 21 2010
EditorGene Expression Omnibus

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