Cascade Fumarate Hydratase mutation screening allows early detection of kidney tumour: a case report

Chan, Melanie; Barnicoat, Angela; Mumtaz, Faiz; Aitchison, Michael; Side, Lucy; Brittain, Helen; Bates, Alan; Gale, Daniel P.

doi:10.1186/s12881-017-0436-1

Cited by 15 publications

(17 citation statements)

References 22 publications

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“…Most strikingly, early diagnosis and adherence to recommended conservative metabolic management using combinations of dietary treatment, cofactors, carnitine supplementation, nonabsorbable antibiotics, and intensified emergency management during catabolic episodes cannot reliably prevent disease progression, which does not even spare those who have not had a single acute metabolic decompensation for years (if ever) 20‐25 . Furthermore, a growing number of individuals with OADs are found to develop cerebral neoplasms such as in l ‐2‐hydroxyglutaric aciduria (OMIM #236792) and GA1, 26,27 and hepatic neoplasms like in MMA 28,29 . Lastly, although plasma ammonium, acid‐base balance, and anion gap are useful to estimate the risk of a metabolic decompensation in a “classic” OAD patient and to guide therapeutic decision‐making, 30,31 these basic biomarkers as well as disease‐specific carbonic acids and acylcarnitines have a low predictive value for the long‐term outcome 20 .…”

Section: Old Roads Major Gapsmentioning

confidence: 99%

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Dimitrov

Molema

Williams

et al. 2020

J of Inher Metab Disea

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Organic acidurias (OADs) comprise a biochemically defined group of inherited metabolic diseases. Increasing awareness, reliable diagnostic work‐up, newborn screening programs for some OADs, optimized neonatal and intensive care, and the development of evidence‐based recommendations have improved neonatal survival and short‐term outcome of affected individuals. However, chronic progression of organ dysfunction in an aging patient population cannot be reliably prevented with traditional therapeutic measures. Evidence is increasing that disease progression might be best explained by mitochondrial dysfunction. Previous studies have demonstrated that some toxic metabolites target mitochondrial proteins inducing synergistic bioenergetic impairment. Although these potentially reversible mechanisms help to understand the development of acute metabolic decompensations during catabolic state, they currently cannot completely explain disease progression with age. Recent studies identified unbalanced autophagy as a novel mechanism in the renal pathology of methylmalonic aciduria, resulting in impaired quality control of organelles, mitochondrial aging and, subsequently, progressive organ dysfunction. In addition, the discovery of post‐translational short‐chain lysine acylation of histones and mitochondrial enzymes helps to understand how intracellular key metabolites modulate gene expression and enzyme function. While acylation is considered an important mechanism for metabolic adaptation, the chronic accumulation of potential substrates of short‐chain lysine acylation in inherited metabolic diseases might exert the opposite effect, in the long run. Recently, changed glutarylation patterns of mitochondrial proteins have been demonstrated in glutaric aciduria type 1. These new insights might bridge the gap between natural history and pathophysiology in OADs, and their exploitation for the development of targeted therapies seems promising.

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Section: Old Roads Major Gapsmentioning

confidence: 99%

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Dimitrov

Molema

Williams

et al. 2020

J of Inher Metab Disea

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“…HLRCC frequently involves a R190H mutation on the FH gene, which generates a dominant negative protein (Lorenzato et al , ). To improve early diagnosis and predict disease prognosis, clinical studies have highlighted the necessity to include FH mutational screening in pathologies including PGL/PCC, hereditary leiomyomatosis, HLRCC, and fumaric aciduria (Ezgu, Krejci, & Wilcox, ; Castro‐Vega et al , ; Chan et al , ; Udager et al , ). Notably, FH is regulated at the mRNA level by miRNA‐378*, a miRNA derived from the same hairpin producing miRNA‐378 but expressed at a lower level which however increases during breast cancer progression (Eichner et al , ), and at post‐translational level by 5′ adenosine monophosphate‐activated protein kinase (AMPK), which increases FH activity both in vitro and in vivo (Klaus et al , ).…”

Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2-hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti-cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.

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“…However, with aggressive screening of affected individuals, renal tumors may be found with localized and curable disease. 13 We sought to estimate FH alterations in publicly available databases containing whole exome and genome data. We hypothesized that HLRCC is a fairly common disease with low RCC penetrance.…”

Section: Introductionmentioning

confidence: 99%

“…Even for individuals affected by RCC, an opportunity for diagnosis may be missed because of the challenging pathologic recognition of HLRCC. However, with aggressive screening of affected individuals, renal tumors may be found with localized and curable disease 13 …”

Section: Introductionmentioning

confidence: 99%

Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer

Shuch

Risch

et al. 2020

Cancer

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BACKGROUND: Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance. METHODS: Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss-offunction alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence. RESULTS: The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10-3 (1 in 393) and 1.20 × 10-3 (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%. CONCLUSIONS: FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.

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Cascade Fumarate Hydratase mutation screening allows early detection of kidney tumour: a case report

Cited by 15 publications

References 22 publications

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise

Oncometabolites in cancer aggressiveness and tumour repopulation

Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer

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