Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma

Abstract

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…All participants have adopted, and reported on, NGS-based technologies in their research and/or clinical practice [14][15][16][17][18][19][20][21][22][23][24][25][26] . Discussions took place via conference calls, e-mail communications and file exchanges and one plenary session (at the 14th ENS@T Scientific Meeting on November 20th, 2015, Munich, Germany).…”

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

“…In addition, germline mutations in KIF1Bβ have been found in patients with PCCs, neuroblastomas and other neural and non-neural tumors [12,13]. More recently, EPAS1/HIF2A germline mutations were found in patients with PCCs/PGLs and polycythemia (polycythemia-paraganglioma syndrome) [14] Susceptibility genes for which no syndromic form has been described yet include EGLN1 [15], TMEM127 [16] and MAX [17].…”

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

“…[47]. В последующем несколько исследований, в одном из кото-рых принимали участие 1694 пациента, под-твердили связь мутации MAX с развитием ФХ у 1,3% пациентов, у 21% из них встре-чались грудные и брюшные параганглиомы в сочетании с ФХ, не выявлено ни одного пациента с ПГ без ФХ.…”