Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: hereditary leiomyomatosis and renal cell cancer—a distinct form of hereditary kidney cancer

Nature Clinical Practice Urology volume 4, pages 104–110 (2007)Cite this article

Abstract

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.

Key Points

  • Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a genetic disease that predisposes individuals to the development of leiomyomas of the skin and uterus as well as kidney cancer

  • Kidney cancers in patients with HLRCC are often biologically aggressive

  • HLRCC is caused by germline mutations of the FH gene, which encodes the Krebs cycle enzyme fumarate hydratase

  • Fumarate-induced pseudohypoxia could drive tumor formation

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clinical and pathologic manifestations of HLRCC.
Figure 2: The tricarboxylic acid (TCA) cycle and hereditary cancer syndromes.
Figure 3: Under normoxic conditions HIF is hydroxylated by HPH.

Similar content being viewed by others

References

  1. Launonen V et al. (2001) Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 98: 3387–3392

    Article  CAS  Google Scholar 

  2. Tomlinson IP et al. (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30: 406–410

    Article  CAS  Google Scholar 

  3. Wei MH et al. (2006) Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 43: 18–27

    Article  CAS  Google Scholar 

  4. Toro JR et al. (2003) Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. Am J Hum Genet 73: 95–106

    Article  CAS  Google Scholar 

  5. Kiuru M et al. (2002) Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res 62: 4554–4557

    CAS  PubMed  Google Scholar 

  6. Reed WB et al. (1973) Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 53: 409–416

    CAS  PubMed  Google Scholar 

  7. Alam NA et al. (2003) Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 12: 1241–1252

    Article  CAS  Google Scholar 

  8. Merino MJ et al. (2003) Hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC); clinical, histopathological and molecular features of the first American families described [abstract]. Mod Pathol 16: 739

    Google Scholar 

  9. Knudson AG Jr (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823

    Article  Google Scholar 

  10. Gellera C et al. (1990) Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 40: 495–499

    Article  CAS  Google Scholar 

  11. Friedrich CA (2001) Genotype–phenotype correlation in von Hippel–Lindau syndrome. Hum Mol Genet 10: 763–767

    Article  CAS  Google Scholar 

  12. Gnarra JR et al. (1994) Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 7: 85–90

    Article  CAS  Google Scholar 

  13. Shuin T et al. (1994) Frequent somatic mutations and loss of heterozygosity of the von Hippel–Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 54: 2852–2855

    CAS  PubMed  Google Scholar 

  14. Morris MR et al. (2004) Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma. J Clin Pathol 57: 706–711

    Article  CAS  Google Scholar 

  15. Astuti D et al. (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69: 49–54

    Article  CAS  Google Scholar 

  16. Niemann S and Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26: 268–270

    Article  CAS  Google Scholar 

  17. Baysal BE et al. (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287: 848–851

    Article  CAS  Google Scholar 

  18. Vanharanta S et al. (2004) Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet 74: 153–159

    Article  CAS  Google Scholar 

  19. Gottlieb E and Tomlinson IP (2005) Mitochondrial tumour suppressors: a genetic and biochemical update. Nat Rev Cancer 5: 857–866

    Article  CAS  Google Scholar 

  20. Pause A et al. (1997) The von Hippel–Lindau tumor-suppressor gene product forms a stable complex with human Cul-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci USA 94: 2156–2161

    Article  CAS  Google Scholar 

  21. Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2: 673–682

    Article  CAS  Google Scholar 

  22. Kaelin WG Jr (2003) The von Hippel–Lindau gene, kidney cancer, and oxygen sensing. J Am Soc Nephrol 14: 2703–2711

    Article  Google Scholar 

  23. Pugh CW and Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9: 677–684

    Article  CAS  Google Scholar 

  24. Linehan WM et al. (2003) The genetic basis of cancer of the kidney. J Urol 170: 2163–2172

    Article  CAS  Google Scholar 

  25. Bruick RK and McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294: 1337–1340

    Article  CAS  Google Scholar 

  26. Epstein AC et al. (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43–54

    Article  CAS  Google Scholar 

  27. Ivan M et al. (2001) HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292: 464–468

    Article  CAS  Google Scholar 

  28. Jaakkola P et al. (2001) Targeting of HIF-α to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468–472

    Article  CAS  Google Scholar 

  29. Yu F et al. (2001) HIF-1α binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98: 9630–9635

    Article  CAS  Google Scholar 

  30. Isaacs JS et al. (2005) HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8: 143–153

    Article  CAS  Google Scholar 

  31. Iliopoulos O et al. (1996) Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein. Proc Natl Acad Sci USA 93: 10595–10599

    Article  CAS  Google Scholar 

  32. Wiesener MS et al. (2001) Constitutive activation of hypoxia-inducible genes related to overexpression of hypoxia-inducible factor-1α in clear cell renal carcinomas. Cancer Res 61: 5215–5222

    CAS  PubMed  Google Scholar 

  33. Pollard PJ et al. (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14: 2231–2239

    Article  CAS  Google Scholar 

  34. Pollard P et al. (2005) Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome. J Pathol 205: 41–49

    Article  Google Scholar 

  35. Selak MA et al. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7: 77–85

    Article  CAS  Google Scholar 

  36. Edwards YH and Hopkinson DA (1979) The genetic determination of fumarase isozymes in human tissues. Ann Hum Genet 42: 303–313

    Article  CAS  Google Scholar 

  37. Linehan WM et al. (2004) Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res 10 (Pt 2): 6282S–6289S

    Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

Author information

Authors and Affiliations

  1. S Sudarshan is a Urologic Oncology Fellow, PA Pinto is a Senior Attending, L Neckers is a Senior Investigator and WM Linehan is Chief of the Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.,

    Sunil Sudarshan, Peter A Pinto, Len Neckers & W Marston Linehan

Authors
  1. Sunil Sudarshan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter A Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Len Neckers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W Marston Linehan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to W Marston Linehan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sudarshan, S., Pinto, P., Neckers, L. et al. Mechanisms of Disease: hereditary leiomyomatosis and renal cell cancer—a distinct form of hereditary kidney cancer. Nat Rev Urol 4, 104–110 (2007). https://doi.org/10.1038/ncpuro0711

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpuro0711

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing