Novel fumarate hydratase mutation in a family with atypical uterine leiomyomas and hereditary leiomyomatosis and renal cell cancer

Wheeler, Karen; Warr, Dillon J.; Warsetsky, Sarah I.; Barmat, Larry I.

doi:10.1016/j.fertnstert.2015.09.034

Cited by 14 publications

(13 citation statements)

References 16 publications

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“…Additionally, FH mutations in LMS have occasionally been reported 21, 22 . In those leiomyomas with FH gene mutations, some have characteristic histologic features, defined as SMT-FH 10, 11 (Table 4). These tumors are typically cellular with eosinophilic macronucleoli, perinucleolar halos, and eosinophilic cytoplasmic globules.…”

Section: Discussionmentioning

confidence: 99%

“…Further histologic analysis has revealed that some ULM with FH mutations have different nuclear and histologic features and can be referred to as smooth tumors with features of fumarate hydratase alteration (SMT-FH) 9, 10 . Historically, many sporadic SMT-FH were diagnosed as LM-BN due to the significant nuclear atypia 11, 12 . LM-BN also present with a wide range of histologic features 1, 3, 4 and in our set of tumors originally diagnosed as LM-BN, nearly half showed nuclear features similar to SMT-FH 9, 10 and we therefore defined them as type I LM-BN 13 .…”

Section: Introductionmentioning

confidence: 99%

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Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Zhang

Poropatich²,

Ubago³

et al. 2018

International Journal of Gynecological Pathology

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Leiomyoma with bizarre nuclei (LM-BN), is a variant of uterine smooth muscle tumor with atypical histologic features. Although some LM-BN share several significant genetic alterations with leiomyosarcoma, including p16 and p53, the underlying tumorigenesis of LM-BN remains largely unknown. As we previously reported, LM-BN can be divided into 2 subtypes, type I and type II, based on different nuclear features. Type I LM-BN have similar histologic features as uterine smooth muscle tumors with fumarate hydratase (FH) alterations. In this study, we examined FH expression and FH mutations in 77 LM-BN (40 type I cases and 37 type II cases). FH expression was examined by immunohistochemistry using S-(2-succino)-cysteine antibodies (2SC, a protein modification associated with FH inactivation and subsequent fumarate accumulation) and FH antibodies (FH gene products). Seventy-two LM-BN tumors underwent Sanger sequencing to detect FH mutations. We found that 51% (39/77) of LM-BN showed FH alterations detected by immunohistochemistry with both 2SC and FH. Mutational analysis showed that 21% (15/72) of LM-BN harbored FH gene mutations. Further analysis revealed that 85% (34/40) of those with FH alterations were type I LM-BN while 19% (7/37) were type II LM-BN. Our findings suggest that over half of histologically diagnosed LM-BN may be related to FH alterations or FH mutations and the majority of these have the characteristic histologic features of type I LM-BN.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Zhang

Poropatich²,

Ubago³

et al. 2018

International Journal of Gynecological Pathology

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“…It has been reported that the mutation of FH gene in the NCCFH1 cell lines from a metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2) results in glucose-dependent growth and impaired oxidative phosphorylation, which is consistent with the Warburg effect [ 9 ]. A clinic study shows that the mutation of FH gene results in the Reed syndrome, which is an autosomal dominant disorder characterized by cutaneous leiomyomas, uterine leiomyomas [ 15 ], and renal cell carcinoma [ 7 , 16 , 17 ], possibly representing genetic heritage lesions [ 18 ]. In addition, FH deficiency also could lead to metabolic disorders with severe encephalopathy, seizures and poor neurological outcome [ 10 ], suggesting an important role of FH in neurology as well.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal FH function/expression impairs mitochondrial function directly and has indirect effects on both glucose metabolism and oxidative phosphorylation by inappropriate activation of HIF1α and NRF2 [ 24 , 25 ]. Recently, there are reports showing that the mutation of FH may initiate renal cell carcinogenesis [ 7 , 9 , 18 , 26 – 29 ], implying tumor suppressor function of this gene. In our current study, we have histologically and immunohistochemically examined the kidney tissues.…”

Section: Discussionmentioning

confidence: 99%

Generation of TALEN-mediated FH knockout rat model

et al. 2016

Oncotarget

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Transcription activator-like effector nucleases (TALENs) are valuable tools for precise genome engineering of laboratory animals. Here we utilized this technique for efficient site-specific gene modification to create a fumarate hydratase (FH) gene knockout rat model, in which there was an 11 base-pair deletion in the first exon of the FH gene in 111 rats. 18 live-born targeted mutation offsprings were produced from 80 injected zygotes with 22.5% efficiency, indicating high TALEN knockout success in rat zygots. Only heterozygous deletion was observed in the offsprings. Sixteen pairs of heterozygous FH knockout (FH+/−) rats were arranged for mating experiments for six months without any homozygous KO rat identified. Sequencing from the pregnant rats embryo samples showed no homozygous FH KO, indicating that homozygous FH KO is embryonically lethal. Comparatively, the litter size was decreased in both male and female FH+/− KO rats. There was no behaviour difference between the FH+/− KO and the control rats except that the FH+/− KO male rats showed significantly higher body weight in the 16-week observation period. Clinical haematology and biochemical examinations showed hematopoietic and kidney dysfunction in the FH+/− KO rats. Small foci of anaplastic lesions of tubular epithelial cells around glomeruli were identified in the FH+/− kidney, and these anaplastic cells were comparatively positive for Ki67, p53 and Sox9, and such findings are most probably related to the kidney dysfunction reflected by the biochemical examinations of the rats. In conclusion, we have successfully established an FH+/− KO rat model, which will be useful for further functional FH studies.

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“…Indeed, 77% of histopathologic hysterectomy specimens demonstrate the presence of uterine leiomyomas 1 , 2 . Cytogenetic studies have shown that 40% to 50% of leiomyoma specimens exhibit chromosomal rearrangements and up to 70% of specimens display somatic mutations 1 , 3 . Despite the aforementioned genetic abnormalities, which may play a role in leiomyoma tumorigenesis, the only known genetic syndrome that leads to uterine leiomyomas is hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome.…”

mentioning

confidence: 99%

Novel Fumarate Hydratase Mutation in Siblings With Early Onset Uterine Leiomyomas and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

Gunnala

Pereira

Irani

et al. 2018

International Journal of Gynecological Pathology

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Hereditary leiomyomatosis renal cell cancer syndrome is an autosomal dominant disorder characterized by uterine and cutaneous leiomyomas and increased predisposition to renal cell carcinoma, papillary type II. The syndrome is caused by heterozygous mutations to the fumarate hydratase (FH) gene located on chromosome 1. Affected females generally present with early onset, atypical uterine leiomyomas and cutaneous findings, however, delays in diagnosis are very common in patients with isolated uterine findings. We present a case series of 2 sisters in their 20s who presented with isolated uterine leiomyomas and were found to carry a novel mutation for the fumarate hydratase gene. One patient was referred for treatment of infertility and recurrent miscarriages and the other was referred for acute symptomatic anemia due to myomas. Prompt diagnosis of hereditary leiomyomatosis renal cell cancer was made due to a high index of clinical suspicion based on early onset disease and familial clustering as well as characteristic pathologic findings on uterine leiomyoma surgical specimen. Timely diagnosis not only allowed for genetic counseling and renal cancer surveillance, but also for fertility counseling given the increased morbidity associated with uterine leiomyoma due to hereditary leiomyomatosis and renal cell cancer syndrome.

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Novel fumarate hydratase mutation in a family with atypical uterine leiomyomas and hereditary leiomyomatosis and renal cell cancer

Abstract: Patients with HLRCC are at risk for developing renal cancer as well as losing their fertility via early hysterectomy. Physicians must be aware of this condition and refer at-risk individuals for genetic testing.

Cited by 14 publications

References 16 publications

Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Fumarate Hydratase Mutations and Alterations in Leiomyoma With Bizarre Nuclei

Generation of TALEN-mediated FH knockout rat model

Novel Fumarate Hydratase Mutation in Siblings With Early Onset Uterine Leiomyomas and Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome

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