Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors

Lehtonen, Rainer; Kiuru, Maija; Vanharanta, Sakari; Sjöberg, Jari; Aaltonen, Leena-Maija; Aittomäki, Kristiina; Arola, Johanna; Bützow, Ralf; Eng, Charis; Husgafvel‐Pursiainen, Kirsti; Isola, Jorma; Järvinen, Heikki; Koivisto, Pasi A.; Mecklin∥, Jukka–Pekka; Peltomäki, Païvi; Salovaara, Reijo; Wasenius, Veli-Matti; Karhu, Auli; Launonen, Virpi; Nupponen, Nina N.; Aaltonen, Lauri A.

doi:10.1016/s0002-9440(10)63091-x

Cited by 160 publications

(104 citation statements)

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“…Like the SDH genes, FH mutations lead to loss of function and are associated with loss of the wild-type allele and FH activity in the tumours (Tomlinson et al, 2002;Wei et al, 2006). Unlike SDH, somatic FH mutations are rare and are restricted to uterus leiomyomas (Lehtonen et al, 2004).…”

Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.

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Section: Mitochondrial Tumour Suppressor Genesmentioning

confidence: 99%

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

2006

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“…Mutation analysis revealed no disease-causing changes. Three previously detected polymorphisms 23 (unpublished data) were found: 798 G4A (Pro266Pro) (two individuals, of which one heterozygous and one homozygous), IVS2 þ 61T4A (one individual), and IVS3 þ 32A4G (one individual) ( Table 2). The changes were not predicted to have an effect on splicing tested in silico by NetGene2 program.…”

Section: Resultsmentioning

confidence: 78%

“…The role of somatic FH inactivation in unselected breast cancers with lobular or other histology breast cancer has previously been evaluated in two separate studies also with negative results. 7,23 In HLRCC families, RCC appears to be more common in the Finnish HLRCC families (71%) than in the mutationpositive families in the United States (14%) and in the UK (3%). Uterine leiomyosarcoma and breast cancer have only been reported in the Finnish HLRCC families.…”

Section: Resultsmentioning

confidence: 99%

“…The collection of the breast cancer study material and BRCA1 and BRCA2 mutation analyses have been described previously. 14,20 -22 Mutation screening of samples was performed by denaturing high-performance liquid chromatography (DHPLC) method and direct sequencing as described by Lehtonen et al 23 The PCR reactions, conditions, and oligonucleotide primers used were identical to the study of Kiuru et al 7 The potential effect of intronic and silent changes to splicing was predicted by computational methods using NetGene2 splice site prediction web server (http://genome.cbs.dtu.dk/services/NetGene2/).…”

Section: Methodsmentioning

confidence: 99%

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No germline FH mutations in familial breast cancer patients

et al. 2004

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Fumarate hydratase (FH) was recently identified as the predisposing gene for a tumor predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC) (MIM 605839). In HLRCC, individuals with a germline heterozygous mutation in the FH gene typically develop benign leiomyomas of the skin and the uterus (fibroids, myomas). In a subset of the families, predisposition to renal cell carcinoma and uterine leiomyosarcoma occurs. Other malignancies including breast cancer have also been detected in patients with a germline FH mutation. To examine whether FH could be involved in predisposition to breast cancer, we analyzed germline FH mutations from 85 Finnish breast cancer patients. Most of the cases were selected based on positive family or personal history for malignancies associated with HLRCC. No mutations were found. These results show that FH is not a major predisposing gene for familial breast cancer. Benign tumors, leiomyomas of the skin and the uterus are the most common lesions in HLRCC families. In the Finnish families, these tumors have been detected in six out of seven families (86%). RCC has been detected more frequently in the mutation-positive families in Finland (five out of seven families, 71%) than in North America (five out of 35 families, 14%) or in the UK (one out of 35 families, 3%). The five Finnish HLRCC families include altogether 12 RCC cases. Uterine leiomyosarcoma has been detected in five patients in three Finnish HLRCC families (43%). Altogether three Finnish HLRCC patients carrying FH mutation in two families have been diagnosed with breast cancer. The first breast cancer detected in HLRCC patient displayed lobular histology, a histology which comprises 15% of unselected breast carcinomas. In addition, one case of prostate carcinoma, one case of multiple myeloma, and one case of Hodgkin's lymphoma have been detected. 1,10 In HLRCC families from other countries, in addition to RCC, only leiomyosarcoma of the skin has been reported in one North American patient. Recently, germline FH mutations were examined in prostate cancer families in two different studies. 11,12 In addition to prostate cancer being detected in one of the FH mutation carriers, positive linkage in prostate cancer families has previously been reported to 1q42 -q43, where the FH gene is localized. 13 Negative results of these studies provided evidence that mutations in FH do not confer susceptibility to familial prostate cancer.The susceptibility genes for familial breast cancer are still largely unknown. The major known high-penetrance predisposition genes BRCA1 and BRCA2 account for a large majority of families with multiple cases of early-onset breast cancer and ovarian cancer, but only a small fraction of familial breast cancer without these characteristics. 14,15 Genetic linkage studies have suggested breast cancer loci on chromosomes 2q32, 6q25, 8p21, and 13q22. 16 -19 So far, the putative susceptibility genes in these regions have not been identified.In the current study, we analyzed 85 Finnish breast...

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“…[7][8][9][10][11] As an example, uterine leiomyomas and RCC have been linked to mutations in fumarate hydratase. 12 Gene associated with Retinoid-Interferon-induced Mortality (GRIM)-19 was originally defined as a cell death regulatory gene, as it is essential for the tumor cell death induced by interferon-b and retinoic acid. 13 Subsequently, GRIM-19 was demonstrated to be a new subunit of the mitochondrial NAPDH:ubiquinone oxidoredutase (respiratory chain complex I) and is essential for the complex I assembly, activity and maintenance of mitochondrial membrane potential.…”

Section: Introductionmentioning

confidence: 99%

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

Cao

2010

J Hum Genet

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Biallelic Inactivation of Fumarate Hydratase (FH) Occurs in Nonsyndromic Uterine Leiomyomas but Is Rare in Other Tumors

Cited by 160 publications

References 31 publications

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer

No germline FH mutations in familial breast cancer patients

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

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