Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas

Abstract

Germline mutations in the fumarate hydratase gene at 1q43 predispose to dominantly inherited skin and uterine leiomyomata and leiomyosarcomas. The enzyme, which is a component of the tricarboxylic acid cycle, acts as a tumour suppressor. To evaluate fumarate hydratase in respective sporadic tumours, we analysed a series of 26 leiomyosarcomas and 129 uterine leiomyomas (from 21 patients) for somatic mutations in fumarate hydratase and allelic imbalance around 1q43. None of the 26 leiomyosarcomas harboured somatic mutations in fumarate hydratase. Fifty per cent of leiomysarcomas tested showed evidence of allelic imbalance at 1q, but this was not confined to the vicinity of fumarate hydratase. Only 5% (seven out of 129) of the leiomyomas showed allele imbalance at 1q42-q43 and no somatic mutations in fumarate hydratase were observed. Our findings indicate that mutations in fumarate hydratase do not play a major role in the development of sporadic leiomyosarcomas or uterine leiomyomas.

Fumarate Hydratase and S-(2-Succinyl)-Cysteine Immunohistochemistry Shows Evidence of Fumarate Hydratase Deficiency in 2% of Uterine Leiomyosarcomas: A Cohort Study of 348 Tumors

“…Three of these credible cases occurred in Finnish HLRCC patients 31,32(p12), and 2 were identified by homozygous FH deletion in a molecular study without immunohistochemical or clinicopathologic correlation 33. We identified 305 reported cases of uLMS studied by FH IHC, none of which were found to be FHd 2–4,6,21,34–36. And of 197 uLMS examined for FH deficiency by molecular testing 33–37, only 2 had molecular alterations consistent with FH inactivation, both of which stemmed from a single study of just 8 uLMS 33.…”

“…We identified 305 reported cases of uLMS studied by FH IHC, none of which were found to be FHd 2–4,6,21,34–36. And of 197 uLMS examined for FH deficiency by molecular testing 33–37, only 2 had molecular alterations consistent with FH inactivation, both of which stemmed from a single study of just 8 uLMS 33. Available data, though limited, likewise suggests that prospective morphologic screening for FHd uLMS is likely low-yield, if not entirely unfeasible 4,37.…”

Hereditary leiomyomatosis and renal cell cancer syndrome – case report and review of the literature

“…Multiple studies have also reported an association between FH gene mutations and the development of sporadic tumors, therefore it has been hypothesized that it functions as a tumor suppressor gene [5,17]. However, this is still a controversial issue as subsequent research did not confirm the role of FH gene defects in sporadic tumorigenesis [18,19].…”