Mechanisms of Disease: Hereditary Leiomyomatosis Renal Cell Cancer -- A Distinct Form of Hereditary Kidney Cancer

Sunil Sudarshan; Peter A. Pinto; Len Neckers; W. Marston Linehan


Nat Clin Pract Urol. 2007;4(2):104-110. 

In This Article

Summary and Introduction


Renal cell carcinoma (RCC) represents a group of diseases linked by their primary site of origin, the kidney. Studies of families with a genetic predisposition to the development of kidney cancer have revealed that multiple genes are involved in the molecular pathogenesis of RCC. Germline mutations in a gene that encodes a Krebs cycle enzyme have been found to result in a distinct clinical entity referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is inherited in an autosomal-dominant fashion. Affected individuals in HLRCC families are at risk for the development of leiomyomas of the skin and uterus as well as renal cancers. HLRCC-associated kidney tumors are often biologically aggressive. Linkage analysis has identified germline alterations in the fumarate hydratase (FH) gene associated with HLRCC. While the mechanisms of molecular carcinogenesis are not entirely understood, several lines of evidence derived from clinical and basic research suggest that pseudohypoxia might drive cellular transformation. The role of FH mutations in sporadic tumors seems to be limited. Nevertheless, continued investigation of HLRCC should provide further insight into the mechanisms of kidney cancer development, and could potentially identify targets for new therapeutic approaches to RCC.


It is now well established that kidney cancer does not represent a single disease, but rather a collection of different types of cancers. Significant insight into the molecular pathogenesis of these cancers has been gained through the study of families with multiple members affected with kidney malignancies. Evaluation of these families has led to the identification of genes involved in the development of a number of different types of kidney cancer. Previously identified familial forms of kidney cancer include von Hippel–Lindau disease (VHL), hereditary papillary renal carcinoma, and Birt–Hogg–Dubé syndrome. All three disorders are associated with a genetic predisposition to the formation of kidney cancers that results from an inherited, germline mutation. Linkage studies of affected families have led to the identification of the causative gene in each of these clinical entities.

A hereditary form of kidney cancer referred to as hereditary leiomyomatosis and renal cell cancer (HLRCC) has been identified, in which affected family members have cutaneous leiomyomas, uterine fibroids, and/or kidney cancers.[1] The renal malignancies that develop in HLRCC families are often metastatic at presentation and are a significant cause of mortality in these families. Analysis of families with this disorder has identified the responsible gene locus as FH.[2] This gene encodes fumarate hydratase (FH), an enzyme that is part of the mitochondrial Krebs or tricarboxylic acid (TCA) cycle. The mechanism by which alterations in FH lead to HLRCC remains to be determined, but it apparently involves increased cellular dependence on glycolysis. This article summarizes the currently known clinical, genetic, and molecular aspects of HLRCC, to assist the clinician in the detection and management of this potentially life-threatening disorder.


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