Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas

Abstract

HEOCHROMOCYTOMAS AND paragangliomas are chromaffin cell tumors of neural crest origin that arise from the adrenal medulla or extra-adrenal sympathetic paraganglia, respectively, and are frequently catecholamine secreting. 1 These tumors are usually benign and can occur as a single entity or as part of various hereditary tumor syndromes. Genetically, pheochromocytomas and paragangliomas are heterogeneous , with at least one-third of cases resulting from germline but not somatic mutations in 1 of several independent genes: RET, VHL, NF1, and succinate dehydrogenase (SDH) subunit B, C, and D genes. 2-5 More recently, other candidate susceptibil-Author Affiliations are listed at the end of this article.

The clinical genetics of phaeochromocytoma and paraganglioma

“…Apart from which, extra-adrenal tumours were also found in rare EGLN1 mutation (47). Although, rare extra adrenal tumours can also be found in VHL, TMEM 127, NF1, and RET mutations as well (11,12,14,21,26,42,53).…”

“…Since the original report, more than 30 mutations have been identified in TMEM127. Although all variants were detected in germline DNA, less than 20% of patients carrying a TMEM127 mutation report a family history of phaeochromocytomas, suggesting low penetrance of the mutant alleles (42). TMEM127 encodes for a transmembrane protein which localizes to the plasma membrane and multiple components of the endosome machinery, including early, late and recycling endosome, Golgi complex and lysosome.…”

“…TMEM127 encodes for a transmembrane protein which localizes to the plasma membrane and multiple components of the endosome machinery, including early, late and recycling endosome, Golgi complex and lysosome. Once mutated, it is mostly located in the cytoplasm, suggesting the localization of TMEM127 to endomembrane pools is important for its tumour suppressor function (42).…”

“…In addition, bilateral phaeochromocytomas are mostly found with these same mutations (11,12,14,21,26,42,45,53). On the other hand, SDH mutations cause intra-adrenal tumours less commonly; 25% of SDHB-related tumours are phaeochromocytomas while the frequency of intraadrenal tumours in SDHD, SDHA and SDHC are even lower (4,7,36,37,41,53).…”

Personalized diagnostics of chromaffin tumors (pheochromocytoma, paraganglioma) in oncoendocrinology

“…Мутации описаны при обследовании 990 пациентов с ФХ и ПГ, имеющих отрица-тельные генетические тесты на RET-, VHL-и SDHB/C/D-мутации [45]. Средний возраст манифестации заболевания -43 года, харак-терна неполная пенетрантность, менее чем у 20% носителей прослеживается семейный анамнез, герминальная мутация TMEM127 обнаружена в единичных случаях светлокле-точной карциномы без ФХ/ПГ.…”