Increased risk of cancer in patients with fumarate hydratase germline mutation

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15–29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.

[1]  A. Paetau,et al.  Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer , 2002, Nature Genetics.

[2]  L. Schmidt,et al.  Searching for the hereditary causes of renal-cell carcinoma , 2004, Nature Reviews Cancer.

[3]  R. Poulsom,et al.  Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome , 2005, The Journal of pathology.

[4]  B. Glaser,et al.  Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata. , 2005, Journal of the American Academy of Dermatology.

[5]  I. Leigh,et al.  Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer , 2005, The British journal of dermatology.

[6]  A novel mutation of the fumarase gene in a family with autosomal recessive fumarase deficiency , 2004, Journal of Molecular Medicine.

[7]  N P Burrows,et al.  Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. , 2003, Human molecular genetics.

[8]  H Rantala,et al.  Fumarase deficiency: two siblings with enlarged cerebral ventricles and polyhydramnios in utero. , 1992, Pediatrics.

[9]  N. Terada,et al.  The natural history of simple renal cysts. , 2002, The Journal of urology.

[10]  B. Glaser,et al.  Germline fumarate hydratase mutations in families with multiple cutaneous and uterine leiomyomata. , 2003, The Journal of investigative dermatology.

[11]  L. Aaltonen,et al.  Inherited susceptibility to uterine leiomyomas and renal cell cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Gibson,et al.  An ultrasound renal cyst prevalence survey: specificity data for inherited renal cystic diseases. , 1993, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[13]  Eyal Gottlieb,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[14]  J. Murchison,et al.  The prevalence of simple renal and hepatic cysts detected by spiral computed tomography. , 2003, Clinical radiology.

[15]  E. Ritz,et al.  The simple renal cyst. , 2000, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[16]  P. Choyke,et al.  Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer , 2005, Journal of Medical Genetics.

[17]  J. McGrath,et al.  Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer , 2005, Clinical and experimental dermatology.

[18]  L. Aaltonen,et al.  Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. , 2001, The American journal of pathology.

[19]  M. Mclachlan,et al.  Aging and simple cysts of the kidney. , 1981, The British journal of radiology.

[20]  V. Launonen,et al.  Hereditary leiomyomatosis and renal cell cancer (HLRCC). , 2004, Current molecular medicine.

[21]  B. Delahunt,et al.  Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. , 2002, Cancer research.

[22]  A. Rowan,et al.  Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. , 2005, Archives of dermatology.

[23]  G. Palù,et al.  Prevalence and natural history of adrenal incidentalomas. , 2003, European journal of endocrinology.

[24]  David G. Watson,et al.  Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. , 2005, Cancer cell.

[25]  P. Choyke,et al.  Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America. , 2003, American journal of human genetics.