Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas

Abstract

Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an 'SDH-like' molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P = 0.007) and multiple tumors (P = 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.

PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

“…Additional tumors have been reported among individuals with FH pathogenic variants, although more data are needed to understand the true extent of association with HLRCC (34). Interestingly, a recent report found five individuals with germline FH pathogenic variants among a cohort of 598 patients with paragangliomas/pheochromocytomas (35).…”

Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations

“…1,2,[4][5][6][7][8][9] In addition, mutations in fumarate hydratase (FH), another member of the TCA cycle and which catalyzes the hydration of fumarate to malate, predispose to tumor formation, including RCCs, cutaneous and uterine leiomyomas, and PCCs/PGLs. 10,11 Finally, isocitrate dehydrogenase (IDH), which catalyzes the oxidative decarboxylation of isocitrate, is frequently mutated in specific types of cartilaginous tumors, hematological malignancies, and gliomas. [12][13][14] The currently known mechanisms underlying tumorigenesis linked to defects in the TCA cycle are well reviewed.…”

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

“…Открыты в 2013 г. при обследовании 600 пациентов с ФХ/ПГ, имеющих отрица-тельные генетические тесты на ранее извест-ные мутации [44]. Выяснилось, что инактива-ция фумаразы, отвечающей за гидратацию/ дегидратацию фумарата до малата в цикле трикарбоновых кислот, является предикто-ром образования не только ФХ, но и лейо-миомы, папиллярного рака почек.…”