Localization of a Gene (MCUL1) for Multiple Cutaneous Leiomyomata and Uterine Fibroids to Chromosome 1q42.3-q43

Alam, Neyaz; Bevan, Steve; Churchman, Mike; Barclay, Ella; Barker, Karen; Jaeger, Emma; Nelson, Hal; Healy, Eugene; Pembroke, A.C.; Friedmann, Ps.; Dalziel, K.; Calonje, Eduardo; Anderson, Jennifer; August, P.J.; Davies, Meirion; Felix, R H; Munro, Colin S.; Me, Murdoch; Rendall, J.R.; Kennedy, Stephen; Leigh, I. M.; Kelsell, David P.; Tomlinson, Ian; Houlston, Richard S.

doi:10.1086/320124

Cited by 139 publications

(80 citation statements)

References 18 publications

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“…16 A recent work mapped a predisposition locus for multiple cutaneous leiomyomatosis to the HLRCC locus in 1q42-q44. 23 However, susceptibility to renal cell cancer in the families was not reported. It is conceivable that if leiomyomatosis phenotype is the first selection criteria, families with less prominent renal cell cancer patterns are identified.…”

Section: Discussionmentioning

confidence: 98%

Familial Cutaneous Leiomyomatosis Is a Two-Hit Condition Associated with Renal Cell Cancer of Characteristic Histopathology

Kiuru

Launonen

Hietala

et al. 2001

The American Journal of Pathology

175

109

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Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wildtype allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. Cutaneous leiomyomas are rare benign tumors of the skin, which are thought to originate from the arrectores pilorum muscle. Clinically, cutaneous leiomyomas are manifested as erythematous firm nodules, varying in number from a few to thousands. They usually appear on the face, back, and extensor surfaces of the extremities, and are painful to touch.

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Section: Discussionmentioning

confidence: 98%

Familial Cutaneous Leiomyomatosis Is a Two-Hit Condition Associated with Renal Cell Cancer of Characteristic Histopathology

Kiuru

Launonen

Hietala

et al. 2001

The American Journal of Pathology

175

109

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“…The family histories in these cases suggest an autosomal dominant inheritance with incomplete penetrance. Recent reports of several families in England and Finland with multiple uterine and cutaneous leiomyomata, and a subset of these with papillary renal cell carcinoma, have independently linked this disorder to a predisposition gene in the region of chromosome 1q42.3-q43 (Alam et al 2001;Kiuru et al 2001;Launonen et al 2001). In follow-up studies of this chromosomal region, mutations were detected only in the fumarate hydratase gene (Tomlinson et al 2002)-a surprising finding, as this enzyme is a component of the essential energy-producing tricarboxylic acid cycle (Rustin et al 1997).…”

Section: The Genetic Findingsmentioning

confidence: 99%

“…In follow-up studies of this chromosomal region, mutations were detected only in the fumarate hydratase gene (Tomlinson et al 2002)-a surprising finding, as this enzyme is a component of the essential energy-producing tricarboxylic acid cycle (Rustin et al 1997). Furthermore, the gene appears to act as a classic tumor suppressor in that loss of the wildtype allele was observed frequently in the leiomyomata and renal cell cancers (Alam et al 2001;Kiuru et al 2001;Launonen et al 2001). Although this hereditary syndrome is itself rare, the association with inactivation of the fumarate hydratase gene is of interest, as it is possible that other mechanisms of transcriptional silencing of this gene such as promoter hypermethylation could be involved in the development of sporadic leiomyomas .…”

Section: The Genetic Findingsmentioning

confidence: 99%

Etiology and pathogenesis of uterine leiomyomas: a review.

Flake

Andersen

Dixon

2003

Environ Health Perspect

492

392

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Uterine leiomyomas, or fibroids, represent a major public health problem. It is believed that these tumors develop in the majority of American women and become symptomatic in one-third of these women. They are the most frequent indication for hysterectomy in the United States. Although the initiator or initiators of fibroids are unknown, several predisposing factors have been identified, including age (late reproductive years), African-American ethnicity, nulliparity, and obesity. Nonrandom cytogenetic abnormalities have been found in about 40% of tumors examined. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has only recently been explored. Growth factors with mitogenic activity, such as transforming growth factor-β 3, basic fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I, are elevated in fibroids and may be the effectors of estrogen and progesterone promotion. These data offer clues to the etiology and pathogenesis of this common condition, which we have analyzed and summarized in this review.

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“…Genetic linkage analysis led to the identification of the locus associated with the development of HLRCC (38,42,43). The responsible locus is on the long arm of chromosome 1 (1q) and was mapped to the gene encoding the enzyme FH (44).…”

Section: Fh Gene and Its Role As A Tumor Suppressormentioning

confidence: 99%

Pseudohypoxic Pathways in Renal Cell Carcinoma

Bratslavsky

Sudarshan

Neckers

et al. 2007

Clinical Cancer Research

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Mutations of the von Hippel-Lindau (VHL) or fumarate hydratase (FH) genes lead to morphologically different renal cell carcinomas with distinct clinical courses and outcomes. The VHL protein is a part of an ubiquitin ligase complex that targets proteins for proteosomal degradation. FH is one of the mitochondrial enzymes of the Kreb's cycle. Despite two different functionalities and cellular locations, loss of either VHL or FH products has been shown to alter expression levels of hypoxia-inducible factors (HIF-1a and HIF-2a) and their downstream targets. HIF proteins are key regulators of oxygen homeostasis. Tight regulation of HIF allows for cell survival and growth at the time of hypoxic stress. HIF acts via transcriptional regulation of vascular endothelial growth factor, platelet derived growth factor, endothelial growth factor receptor, glucose transporter protein 1, erythropoietin, and transforming growth factor-a. Loss of VHL or FH is thought to result in a pseudohypoxic state so that cellular response pathways mediated by HIF are activated despite normal oxygen conditions. Understanding of these pseudohypoxic pathways has provided a better appreciation of the molecular mechanisms of carcinogenesis in addition to providing a rationale for targeted therapeutic approaches.

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Localization of a Gene (MCUL1) for Multiple Cutaneous Leiomyomata and Uterine Fibroids to Chromosome 1q42.3-q43

Cited by 139 publications

References 18 publications

Familial Cutaneous Leiomyomatosis Is a Two-Hit Condition Associated with Renal Cell Cancer of Characteristic Histopathology

Familial Cutaneous Leiomyomatosis Is a Two-Hit Condition Associated with Renal Cell Cancer of Characteristic Histopathology

Etiology and pathogenesis of uterine leiomyomas: a review.

Pseudohypoxic Pathways in Renal Cell Carcinoma

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