MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma

Abstract

Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL.Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics.Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P ¼ 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine.Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients

“…Furthermore, these genes explain w2% of all PCC/PGL cases in our series, independently of the age of onset, so only by increasing the number of pediatric cases analyzed, we should be able to confirm the absence of association of these four genes with young-age PCC/PGL development. On the other hand, the occurrence of one MAX case among pediatric probands is in agreement with its recently reported role as a PCC/PGL susceptibility gene (Burnichon et al 2012). This finding becomes more relevant when considering that the prevalence of MAX mutations (1.1% in our whole series) is quite similar to that reported for the latest identified PCC/PGL susceptibility genes (Welander et al 2011).…”

“…Before the discovery of these genes, 30-40% of PCC/PGL cases were thought to be hereditary with autosomal inheritance caused by germline mutations affecting one of six major susceptibility genes: RET, VHL, SDHB, SDHC, SDHD, and NF1 (Cascon et al 2009b, Mannelli et al 2009). Recent international collaborations, focused on establishing the involvement of the novel identified genes, suggested that overall they could explain an additional 6% of the negative-tested patients (Bayley et al 2010, Burnichon et al 2012. In addition to this high and heterogeneous genetic predisposition, there is a unknown percentage of familial cases (i.e.…”

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

“…У 37% прослеживался семейный анамнез, и только 10% имели мета стазы. Средний возраст манифестации заболевания -32 года, но в 21% случаев -до 18 лет, что обязало включить мутации МАХ наряду с VHL и SDHB в панели генетического тестирования в педиатрической практике [48]. Для опухолей характерны преобладание секреции норметанефрина и нормальный (или незначительно повышенный) уровень метанефрина.…”

Molecular and Therapeutic Advances in the Diagnosis and Management of Malignant Pheochromocytomas and Paragangliomas

“…MAX protein is a cofactor of the proto-oncogene MYC and is a key component of the MYC-MAX-MXD1 network that regulates cell proliferation and differentiation, exhibiting crosstalk with the mammalian target of rapamycin (mTOR) pathway. Burchinon et al [64] reported a multicentre series of 1,694 patients with PCCs/PGLs in whom MAX was sequenced. They ascertained that MAX germline mutations are present in 1.12% of cases of PCC/PGL in patients with no other known mutation.…”

“…In contrast, patients with VHL demonstrated solitary increases in normetanephrine, whereas 70% of patients with an SDH mutation demonstrated additional or solitary increases in methoxytyramine (dopamine production). More recently, it was reported that PCCs/PGLs associated with MAX mutations are characterized by substantial increases in normetanephrine and may be associated with normal or minor increases in metanephrine [64].…”