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

Abstract

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.

Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers

“…The most extensively studied hypothesis is activation of the hypoxia pathway (50). Biallelic loss of FH results is accumulation of intracellular fumarate, which in turn may inhibit the degradation of hypoxia-inducible factor 1-alpha (HIF1α), leading to pseudohypoxia through aberrant accumulation of this key protein.…”

PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

“…Diagnostic molecular testing should be considered for individuals who do not meet full clinical criteria, as syndromic features may not have manifested, or family history may not be fully known (33). Additional tumors have been reported among individuals with FH pathogenic variants, although more data are needed to understand the true extent of association with HLRCC (34). Interestingly, a recent report found five individuals with germline FH pathogenic variants among a cohort of 598 patients with paragangliomas/pheochromocytomas (35).…”

“…These lesions are often painful, and pain may be elicited by cold, heat, or touch (36). The majority of individuals with HLRCC present with cutaneous leiomyomas, with an increase in prevalence with age (32,34). These can occur in childhood, but they usually develop during the second decade of life (36).…”

“…Younger women from the midteens to early 20s may already note gradually worsening symptoms that may include menorrhagia, abdominal pain, and abnormal bleeding (34,36). The significant morbidity caused by the presence of these aggressive uterine leiomyomata has led to about 80% of individuals reporting a moderate to severe impact on quality of life (36).…”

“…Type II papillary RCC has been most commonly described in the setting of HLRCC, although other renal cancers, including collecting duct carcinoma as well as clear cell carcinoma, have also been described (33,34,38). In contrast with renal tumors seen in other cancer predisposition syndromes such as Von Hippel Lindau and Birt-Hogg-Dub e, in which the acquisition of metastatic potential is thought to occur only in the setting of larger primary tumors, the RCCs in HLRCC are generally of an exceptionally aggressive type, with a distinct histologic phenotype (38,39).…”