Association of Germline Mutations in the Fumarate Hydratase Gene and Uterine Fibroids in Women With Hereditary Leiomyomatosis and Renal Cell Cancer

Stewart, Laura C.; Glenn, Gladys; Stratton, Pamela; Goldstein, Alisa M.; Merino, María J.; Tucker, Margaret A.; Linehan, W. Marston; Toro, Jorge R.

doi:10.1001/archdermatol.2008.517

Cited by 91 publications

(80 citation statements)

References 38 publications

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“…The penetrance of CLM is higher in men harboring an FH mutation because by the age of 35 all men but only 55% of women are affected [5]. With age the prevalence in women increases up to 76-80% [5,6]. The Fig.…”

Section: Cutaneous Tumorsmentioning

confidence: 95%

“…For these reasons over 80% of the HLRCC patients with ULM report the tumors to cause moderate or severe negative effect on their lives [5]. The severity of the symptoms is reflected by the necessity of early-age surgical treatment for a large proportion (64-91%) of the ULM patients [5,6,11,14,15]. Of the surgical operations the majority is hysterectomies (occasionally performed despite prior myomectomy), in many cases already before the age of 30 [5,11,14].…”

Section: Uterine Tumorsmentioning

confidence: 99%

“…Of the surgical operations the majority is hysterectomies (occasionally performed despite prior myomectomy), in many cases already before the age of 30 [5,11,14]. Although leiomyomas in general and in HLRCC are reported to cause reduced fertility, a study on HLRCC patients with less prominent effects on fertility has also been presented [5,6]. A recent meta analysis on ULM and infertility concluded submucosal and intramural tumors to reduce fertility in contrast to subserosal ones [19].…”

Section: Uterine Tumorsmentioning

confidence: 99%

“…The penetrance of different tumors varies in the syndrome but as a whole, 90-100% of FH mutation carriers are clinically affected by the age of 45 [5,6]. The risk of developing RCC is clearly lower than that of developing leiomyomas and seems to be pronounced in certain populations and families.…”

mentioning

confidence: 99%

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Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

2011

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Hereditary leiomyomatosis and renal cell cancer (HLRCC, also known as multiple cutaneous and uterine leiomyomatosis, MCUL) is a highly penetrant autosomal dominant tumor predisposition syndrome characterized by benign leiomyomas of the skin and the uterus. Renal cell carcinomas, occurring in a subset of the HLRCC families, are exceptionally aggressive. Therefore careful, frequent surveillance strategies are recommended. Association of malignant smooth-muscle tumors, leiomyosarcomas, with HLRCC has been observed but the risk appears to be smaller than initially estimated. To date inactivating heterozygous mutations in the fumarate hydratase (FH, fumarase) gene, predisposing to HLRCC, have been found in approximately 180 families worldwide. The most extensively studied hypothesis on molecular mechanisms of HLRCC tumorigenesis is activation of the hypoxia pathway due to aberrant stabilization of the HIF1 transcription factor. HIF1 regulates transcription of genes relevant for vascularization, glucose transport and glycolysis, processes that facilitate tumor growth. However, additional mechanisms underlying tumor formation are likely to exist.

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Section: Cutaneous Tumorsmentioning

confidence: 95%

Section: Uterine Tumorsmentioning

confidence: 99%

Section: Uterine Tumorsmentioning

confidence: 99%

mentioning

confidence: 99%

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Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

2011

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“…It is well documented that FH underlies a tumor susceptibility syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). This syndrome is characterized by benign cutaneous and uterine leiomyomas, renal cell carcinomas, and uterine leiomyosarcomas (Stewart et al, 2008). Recently, down-regulation of FH was found in stabilization of transcription factor hypoxia-inducible factor (HIF).…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of mitochondrial antioxidation signals in ovarian cancer cells with aggressive biologic behavior

Wang

Dong

Cui

et al. 2011

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Recently, a high frequency of mutations in mitochondrial DNA (mtDNA) has been detected in ovarian cancer. To explore the alterations of proteins in mitochondria in ovarian cancer, a pair of human ovarian carcinoma cell lines (SKOV3/SKOV3.ip1) with different metastatic potentials was examined. Methods: Cancer cells SKOV3.ip1 were derived from the ascitic tumor cells of nude mice bearing a tumor of ovarian cancer cells SKOV3. SKOV3.ip1 exhibited a higher degree of migration potential than its paired cell line SKOV3. The proteins in the mitochondria of these two cells were isolated and separated by 2-D gel electrophoresis. The differently expressed proteins were extracted and identified using matrix assisted laser desorption ionisation/time-of-flight/time-of-flight (MALDI-TOF/TOF), and finally a selected protein candidate was further investigated by immunohistochemistry (IHC) method in nude mice bearing tumor tissues of these two cells. Results: A total of 35 spots with different expressions were identified between the two cells using 2D-polyacrylamide gel electrophoresis (PAGE) approach. Among them, 17 spots were detected only in either SKOV3 or SKOV3.ip1 cells. Eighteen spots expressed different levels, with as much as a three-fold difference between the two cells. Twenty spots were analyzed using MALDI-TOF/TOF, and 11 of them were identified successfully; four were known to be located in mitochondria, including superoxide dismutase 2 (SOD2), fumarate hydratase (FH), mitochondrial ribosomal protein L38 (MRPL38), and mRNA turnover 4 homolog (MRTO4). An increased staining of SOD2 was observed in SKOV3.ip1 over that of SKOV3 in IHC analysis. Conclusions: Our results indicate that the enhanced antioxidation and metabolic potentials of ovarian cancer cells might contribute to their aggressive and metastatic behaviors. The underlying mechanism warrants further study.

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Hereditary Cancer Syndromes

Schneider

2011

Counseling About Cancer

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Association of Germline Mutations in the Fumarate Hydratase Gene and Uterine Fibroids in Women With Hereditary Leiomyomatosis and Renal Cell Cancer

Cited by 91 publications

References 38 publications

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics

Up-regulation of mitochondrial antioxidation signals in ovarian cancer cells with aggressive biologic behavior

Hereditary Cancer Syndromes

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