Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Familial Cancer Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

α-KG:

α-ketoglutarate

CDC:

Collecting duct carcinoma

CLM:

Cutaneous leiomyoma

FH:

Fumarate hydratase

FHD:

Fumarate hydratase deficiency

FIH:

Factor inhibiting HIF

HIF1:

Hypoxia inducible factor 1

HLRCC:

Hereditary leiomyomatosis and renal cell cancer

HPRC:

Hereditary papillary renal carcinoma

GLUT1:

Glucose transporter 1

LDHA:

Lactate dehydrogenase A

LOH:

Loss of heterozygosity

MCUL:

Multiple cutaneous and uterine leiomyomatosis

MLPA:

Multiplex ligation-dependent probe amplification

MRI:

Magnetic resonance imaging

PET-CT:

Positron emission tomography-computed tomography

PHD:

Prolyl hydroxylase domain protein

RCC:

Renal cell cancer

SDHA/B/C/D:

Succinate dehydrogenase subunit A, B, C or D

TCA cycle:

Tricaboxylic acid cycle

ULM:

Uterine leiomyoma

ULMS:

Uterine leiomyosarcoma

VEGFA:

Vascular endothelial growth factor A

VEFGR:

Vascular endothelial growth factor receptor

VHL:

Von Hippel Lindau syndrome

References

  1. Reed WB, Walker R, Horowitz R (1973) Cutaneous leiomyomata with uterine leiomyomata. Acta Derm Venereol 53:409–416

    PubMed  CAS  Google Scholar 

  2. Launonen V, Vierimaa O, Kiuru M et al (2001) Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci USA 98:3387–3392

    Article  PubMed  CAS  Google Scholar 

  3. Alam NA, Bevan S, Churchman M et al (2001) Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43. Am J Hum Genet 68:1264–1269

    Article  PubMed  CAS  Google Scholar 

  4. Tomlinson IP, Alam NA, Rowan AJ 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  PubMed  CAS  Google Scholar 

  5. Alam NA, Barclay E, Rowan AJ et al (2005) Clinical features of multiple cutaneous and uterine leiomyomatosis: an underdiagnosed tumor syndrome. Arch Dermatol 141:199–206

    Article  PubMed  Google Scholar 

  6. Stewart L, Glenn GM, Stratton P et al (2008) Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer. Arch Dermatol 144:1584–1592

    Article  PubMed  Google Scholar 

  7. Zinn AB, Kerr DS, Hoppel CL (1986) Fumarase deficiency: a new cause of mitochondrial encephalomyopathy. N Engl J Med 315:469–475

    Article  PubMed  CAS  Google Scholar 

  8. Deschauer M, Gizatullina Z, Schulze A et al (2006) Molecular and biochemical investigations in fumarase deficiency. Mol Genet Metab 88:146–152

    Article  PubMed  CAS  Google Scholar 

  9. Petrova-Benedict R, Robinson BH, Stacey TE et al (1987) Deficient fumarase activity in an infant with fumaricacidemia and its distribution between the different forms of the enzyme seen on isoelectric focusing. Am J Hum Genet 40:257–266

    PubMed  CAS  Google Scholar 

  10. Bayley JP, Launonen V, Tomlinson IP (2008) The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 9:20

    Article  PubMed  CAS  Google Scholar 

  11. Smit DL, Mensenkamp AR, Badeloe S et al. (2010) Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clin Genet

  12. Ahvenainen T, Lehtonen HJ, Lehtonen R et al (2008) Mutation screening of fumarate hydratase by multiplex ligation-dependent probe amplification: detection of exonic deletion in a patient with leiomyomatosis and renal cell cancer. Cancer Genet Cytogenet 183:83–88

    Article  PubMed  CAS  Google Scholar 

  13. Ritzmann S, Hanneken S, Neumann NJ et al (2006) Type 2 segmental manifestation of cutaneous leiomyomatosis in four unrelated women with additional uterine leiomyomas (Reed’s syndrome). Dermatology 212:84–87

    Article  PubMed  Google Scholar 

  14. Toro JR, Nickerson ML, Wei MH 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  PubMed  CAS  Google Scholar 

  15. Wei MH, Toure O, Glenn GM 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  PubMed  CAS  Google Scholar 

  16. Badeloe S, van Geest AJ, van Marion AM et al (2008) Absence of fumarate hydratase mutation in a family with cutaneous leiomyosarcoma and renal cancer. Int J Dermatol 47(Suppl 1):18–20

    Article  PubMed  Google Scholar 

  17. Cramer SF, Patel A (1990) The frequency of uterine leiomyomas. Am J Clin Pathol 94:435–438

    PubMed  CAS  Google Scholar 

  18. Flake GP, Andersen J, Dixon D (2003) Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect 111:1037–1054

    Article  PubMed  CAS  Google Scholar 

  19. Pritts EA, Parker WH, Olive DL (2009) Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 91:1215–1223

    Article  PubMed  Google Scholar 

  20. D’Angelo E, Prat J (2010) Uterine sarcomas: a review. Gynecol Oncol 116:131–139

    Article  PubMed  CAS  Google Scholar 

  21. Tavassoli FA, Devilee P (eds) (2003) World Health Organization classification of tumours: pathology & genetics of tumours of the breast and female genital organs. IARC Press, Lyon

    Google Scholar 

  22. Kiuru M, Launonen V, Hietala M et al (2001) Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology. Am J Pathol 159:825–829

    Article  PubMed  CAS  Google Scholar 

  23. Lehtonen HJ, Kiuru M, Ylisaukko-Oja SK et al (2006) Increased risk of cancer in patients with fumarate hydratase germline mutation. J Med Genet 43:523–526

    Article  PubMed  CAS  Google Scholar 

  24. Lehtonen HJ (2008) Molecular and clinical characteristics of tricarboxylic acid cycle-associated tumors. Dissertation, University of Helsinki

  25. Ylisaukko-oja SK, Kiuru M, Lehtonen HJ et al (2006) Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int J Cancer 119:283–287

    Article  PubMed  CAS  Google Scholar 

  26. Lehtonen HJ, Blanco I, Piulats JM et al (2007) Conventional renal cancer in a patient with fumarate hydratase mutation. Hum Pathol 38:793–796

    Article  PubMed  CAS  Google Scholar 

  27. Wortham NC, Alam NA, Barclay E et al (2006) Aberrant expression of apoptosis proteins and ultrastructural aberrations in uterine leiomyomas from patients with hereditary leiomyomatosis and renal cell carcinoma. Fertil Steril 86:961–971

    Article  PubMed  CAS  Google Scholar 

  28. Cohen HT, McGovern FJ (2005) Renal-cell carcinoma. N Engl J Med 353:2477–2490

    Article  PubMed  CAS  Google Scholar 

  29. Eble JN, Sauter G, Epstein JI, Sesterhenn IA (eds) (2004) World Health Organization classification of tumours: pathology & genetics of tumours of the urinary system and male genital organs. IARC Press, Lyon

    Google Scholar 

  30. Koski TA (2010) Molecular genetic background of tumours in hereditary leiomyomatosis and renal cell cancer syndrome. Dissertation, University of Helsinki

  31. Alrashdi I, Levine S, Paterson J et al (2010) Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam Cancer 9:239–243

    Article  PubMed  Google Scholar 

  32. Kiuru M, Launonen V (2004) Hereditary leiomyomatosis and renal cell cancer (HLRCC). Curr Mol Med 4:869–875

    Article  PubMed  CAS  Google Scholar 

  33. Alam NA, Rowan AJ, Wortham NC 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  PubMed  CAS  Google Scholar 

  34. Chan I, Wong T, Martinez-Mir A et al (2005) Familial multiple cutaneous and uterine leiomyomas associated with papillary renal cell cancer. Clin Exp Dermatol 30:75–78

    Article  PubMed  CAS  Google Scholar 

  35. Chuang GS, Martinez-Mir A, Engler DE et al (2006) Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene. Clin Exp Dermatol 31:118–121

    Article  PubMed  CAS  Google Scholar 

  36. Chuang GS, Martinez-Mir A, Geyer A et al (2005) Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata. J Am Acad Dermatol 52:410–416

    Article  PubMed  Google Scholar 

  37. Refae MA, Wong N, Patenaude F et al (2007) Hereditary leiomyomatosis and renal cell cancer: an unusual and aggressive form of hereditary renal carcinoma. Nat Clin Pract Oncol 4:256–261

    Article  PubMed  CAS  Google Scholar 

  38. Badeloe S, van Geel M, van Steensel MA et al (2006) Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature. Exp Dermatol 15:735–741

    Article  PubMed  CAS  Google Scholar 

  39. Frey MK, Worley MJ Jr, Heyman KP et al (2010) A case report of hereditary leiomyomatosis and renal cell cancer. Am J Obstet Gynecol 202:e8–e9

    Article  PubMed  Google Scholar 

  40. Grubb RL 3rd, Franks ME, Toro J et al (2007) Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol 177:2074–2079 discussion 2079–80

    Article  PubMed  CAS  Google Scholar 

  41. Merino MJ, Torres-Cabala C, Pinto P et al (2007) The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Am J Surg Pathol 31:1578–1585

    Article  PubMed  Google Scholar 

  42. Delahunt B, Eble JN (1997) Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10:537–544

    PubMed  CAS  Google Scholar 

  43. Badeloe S, van Spaendonck-Zwarts KY, van Steensel MA et al (2009) Wilms tumour as a possible early manifestation of hereditary leiomyomatosis and renal cell cancer? Br J Dermatol 160:707–709

    Article  PubMed  CAS  Google Scholar 

  44. Koski TA, Lehtonen HJ, Jee KJ et al (2009) Array comparative genomic hybridization identifies a distinct DNA copy number profile in renal cell cancer associated with hereditary leiomyomatosis and renal cell cancer. Genes Chromosomes Cancer 48:544–551

    Article  PubMed  CAS  Google Scholar 

  45. Terada N, Ichioka K, Matsuta Y et al (2002) The natural history of simple renal cysts. J Urol 167:21–23

    Article  PubMed  Google Scholar 

  46. Carrim ZI, Murchison JT (2003) The prevalence of simple renal and hepatic cysts detected by spiral computed tomography. Clin Radiol 58:626–629

    Article  PubMed  CAS  Google Scholar 

  47. Pollard PJ, Spencer-Dene B, Shukla D et al (2007) Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. Cancer Cell 11:311–319

    Article  PubMed  CAS  Google Scholar 

  48. Mandriota SJ, Turner KJ, Davies DR et al (2002) HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1:459–468

    Article  PubMed  CAS  Google Scholar 

  49. Ylisaukko-oja SK, Cybulski C, Lehtonen R et al (2006) Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma. Eur J Hum Genet 14:880–883

    Article  PubMed  CAS  Google Scholar 

  50. Lamba M, Verma S, Prokopetz R et al (2005) Multiple cutaneous and uterine leiomyomas associated with gastric GIST. J Cutan Med Surg 9:332–335

    Article  PubMed  Google Scholar 

  51. Campione E, Terrinoni A, Orlandi A et al (2007) Cerebral cavernomas in a family with multiple cutaneous and uterine leiomyomas associated with a new mutation in the fumarate hydratase gene. J Invest Dermatol 127:2271–2273

    Article  PubMed  CAS  Google Scholar 

  52. Varol A, Stapleton K, Roscioli T (2006) The syndrome of hereditary leiomyomatosis and renal cell cancer (HLRCC): the clinical features of an individual with a fumarate hydratase gene mutation. Australas J Dermatol 47:274–276

    Article  PubMed  Google Scholar 

  53. Matyakhina L, Freedman RJ, Bourdeau I et al (2005) Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical Cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab 90:3773–3779

    Article  PubMed  CAS  Google Scholar 

  54. Carvajal-Carmona LG, Alam NA, Pollard PJ et al (2006) Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations. J Clin Endocrinol Metab 91:3071–3075

    Article  PubMed  CAS  Google Scholar 

  55. McKelvey KD Jr, Siraj S, Kelsay J et al (2010) Male infertility associated with hereditary leiomyomatosis and renal cell carcinoma. Fertil Steril 93:2075.e1–2075.e2

    Article  Google Scholar 

  56. Kiuru M, Lehtonen R, Arola J 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

    PubMed  CAS  Google Scholar 

  57. Kiuru M, Lehtonen R, Eerola H et al (2005) No germline FH mutations in familial breast cancer patients. Eur J Hum Genet 13:506–509

    Article  PubMed  CAS  Google Scholar 

  58. Bevan S, Edwards SM, Ardern Jones A et al (2003) Germline mutations in fumarate hydratase (FH) do not predispose to prostate cancer. Prostate Cancer Prostatic Dis 6:12–14

    Article  PubMed  CAS  Google Scholar 

  59. Lehtonen R, Kiuru M, Vanharanta S et al (2004) Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol 164:17–22

    Article  PubMed  CAS  Google Scholar 

  60. Lehtonen R, Kiuru M, Rokman A et al (2003) No fumarate hydratase (FH) mutations in hereditary prostate cancer. J Med Genet 40:e19

    Article  PubMed  CAS  Google Scholar 

  61. Barker KT, Bevan S, Wang R et al (2002) Low frequency of somatic mutations in the FH/multiple cutaneous leiomyomatosis gene in sporadic leiomyosarcomas and uterine leiomyomas. Br J Cancer 87:446–448

    Article  PubMed  CAS  Google Scholar 

  62. Gross KL, Panhuysen CI, Kleinman MS et al (2004) Involvement of fumarate hydratase in nonsyndromic uterine leiomyomas: genetic linkage analysis and FISH studies. Genes Chromosomes Cancer 41:183–190

    Article  PubMed  CAS  Google Scholar 

  63. Maradin M, Fumic K, Hansikova H et al (2006) Fumaric aciduria: mild phenotype in a 8-year-old girl with novel mutations. J Inherit Metab Dis 29:683

    Article  PubMed  CAS  Google Scholar 

  64. Shih VE, Mandell R (2009) Fumarate hydratase deficiency. Available via http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=fum

  65. Kinsella BT, Doonan S (1986) Nucleotide sequence of a cDNA coding for mitochondrial fumarase from human liver. Biosci Rep 6:921–929

    Article  PubMed  CAS  Google Scholar 

  66. Tolley E, Craig I (1975) Presence of two forms of fumarase (Fumarate Hydratase E.C. 4.2.1.2) in mammalian cells: immunological characterization and genetic analysis in somatic cell hybrids. Confirmation of the assignment of a gene necessary for the enzyme expression to human chromosome 1. Biochem Genet 13:867–883

    Article  PubMed  CAS  Google Scholar 

  67. Sass E, Karniely S, Pines O (2003) Folding of fumarase during mitochondrial import determines its dual targeting in yeast. J Biol Chem 278:45109–45116

    Article  PubMed  CAS  Google Scholar 

  68. Lorenzato A, Olivero M, Perro M et al (2008) A cancer-predisposing “hot spot” mutation of the fumarase gene creates a dominant negative protein. Int J Cancer 122:947–951

    Article  PubMed  CAS  Google Scholar 

  69. Rongioletti F, Fausti V, Ferrando B et al (2010) A novel missense mutation in fumarate hydratase in an italian patient with a diffuse variant of cutaneous leiomyomatosis (Reed’s syndrome). Dermatology 221:378–380

    Article  PubMed  CAS  Google Scholar 

  70. Vahteristo P, Koski TA, Naatsaari L et al (2010) No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome. Fam Cancer 9:245–251

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  72. Hao HX, Khalimonchuk O, Schraders M et al (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325:1139–1142

    Article  PubMed  CAS  Google Scholar 

  73. Semenza GL (2010) Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med 2:336–361

    Article  PubMed  CAS  Google Scholar 

  74. O’Flaherty L, Adam J, Heather LC et al (2010) Dysregulation of hypoxia pathways in fumarate hydratase-deficient cells is independent of defective mitochondrial metabolism. Hum Mol Genet 19:3844–3851

    Article  PubMed  CAS  Google Scholar 

  75. Selak MA, Armour SM, MacKenzie ED et al (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7:77–85

    Article  PubMed  CAS  Google Scholar 

  76. Pollard PJ, Briere JJ, Alam NA et al (2005) Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet 14:2231–2239

    Article  PubMed  CAS  Google Scholar 

  77. Isaacs JS, Jung YJ, Mole DR 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  PubMed  CAS  Google Scholar 

  78. MacKenzie ED, Selak MA, Tennant DA et al (2007) Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol Cell Biol 27:3282–3289

    Article  PubMed  CAS  Google Scholar 

  79. Pan Y, Mansfield KD, Bertozzi CC et al (2007) Multiple factors affecting cellular redox status and energy metabolism modulate hypoxia-inducible factor prolyl hydroxylase activity in vivo and in vitro. Mol Cell Biol 27:912–925

    Article  PubMed  CAS  Google Scholar 

  80. Koivunen P, Hirsila M, Remes AM et al (2007) Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J Biol Chem 282:4524–4532

    Article  PubMed  CAS  Google Scholar 

  81. Catherino WH, Mayers CM, Mantzouris T et al (2007) Compensatory alterations in energy homeostasis characterized in uterine tumors from hereditary leiomyomatosis and renal cell cancer. Fertil Steril 88:1039–1048

    Article  PubMed  CAS  Google Scholar 

  82. Vanharanta S, Pollard PJ, Lehtonen HJ et al (2006) Distinct expression profile in fumarate-hydratase-deficient uterine fibroids. Hum Mol Genet 15:97–103

    Article  PubMed  CAS  Google Scholar 

  83. Pollard P, Wortham N, Barclay E 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  PubMed  Google Scholar 

  84. Ashrafian H, O’Flaherty L, Adam J et al (2010) Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res 70:9153–9165

    Article  PubMed  CAS  Google Scholar 

  85. Raimundo N, Ahtinen J, Fumic K et al (2008) Differential metabolic consequences of fumarate hydratase and respiratory chain defects. Biochim Biophys Acta 1782:287–294

    PubMed  CAS  Google Scholar 

  86. Greijer AE, van der Wall E (2004) The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J Clin Pathol 57:1009–1014

    Article  PubMed  CAS  Google Scholar 

  87. Costa B, Dettori D, Lorenzato A et al (2010) Fumarase tumor suppressor gene and MET oncogene cooperate in upholding transformation and tumorigenesis. FASEB J 24:2680–2688

    Article  PubMed  CAS  Google Scholar 

  88. Bayley JP, Devilee P (2010) Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree? Curr Opin Genet Dev 20:324–329

    Article  PubMed  CAS  Google Scholar 

  89. Sudarshan S, Sourbier C, Kong HS et al (2009) Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol 29:4080–4090

    Article  PubMed  CAS  Google Scholar 

  90. Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530

    Article  PubMed  CAS  Google Scholar 

  91. Gillies RJ, Gatenby RA (2007) Adaptive landscapes and emergent phenotypes: why do cancers have high glycolysis? J Bioenerg Biomembr 39:251–257

    Article  PubMed  CAS  Google Scholar 

  92. Bui T, Thompson CB (2006) Cancer’s sweet tooth. Cancer Cell 9:419–420

    Article  PubMed  CAS  Google Scholar 

  93. Yan H, Parsons DW, Jin G et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773

    Article  PubMed  CAS  Google Scholar 

  94. Yogev O, Yogev O, Singer E et al (2010) Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol 8:e1000328

    Article  PubMed  CAS  Google Scholar 

  95. Pithukpakorn M, Toro JR (2007) Hereditary leiomyomatosis and renal cell cancer. Available via http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hlrcc

  96. Parker WH (2007) Uterine myomas: management. Fertil Steril 88:255–271

    Article  PubMed  Google Scholar 

  97. Catherino WH, Malik M, Driggers P et al (2010) Novel, orally active selective progesterone receptor modulator CP8947 Inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium. J Steroid Biochem Mol Biol 122:279–286

    Article  PubMed  CAS  Google Scholar 

  98. Linehan WM, Pinto PA, Bratslavsky G et al (2009) Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer 115:2252–2261

    Article  PubMed  CAS  Google Scholar 

  99. Pavlovich CP, Schmidt LS (2004) Searching for the hereditary causes of renal-cell carcinoma. Nat Rev Cancer 4:381–393

    Article  PubMed  CAS  Google Scholar 

  100. Gupta GN, Peterson J, Thakore KN et al (2010) Oncological outcomes of partial nephrectomy for multifocal renal cell carcinoma greater than 4 Cm. J Urol 184:59–63

    Article  PubMed  Google Scholar 

  101. Singer EA, Bratslavsky G, Linehan WM et al (2010) Targeted therapies for non-clear renal cell carcinoma. Target Oncol 5:119–129

    Article  PubMed  Google Scholar 

  102. Vladimir AV, Youfeng Y, Beatriz AW et al (2010) 367 evaluation of the VEGF-VEGF receptor axis in hereditary leiomyomatosis renal cell carcinoma (HLRCC) kidney tumors. J Urol 183

  103. Airley RE, Mobasheri A (2007) Hypoxic regulation of glucose transport, anaerobic metabolism and angiogenesis in cancer: novel pathways and targets for anticancer therapeutics. Chemotherapy 53:233–256

    Article  PubMed  CAS  Google Scholar 

  104. Yang Y, Valera VA, Padilla-Nash HM et al (2010) UOK 262 cell line, fumarate hydratase deficient (FH-/FH-) hereditary leiomyomatosis renal cell carcinoma: in vitro and in vivo model of an aberrant energy metabolic pathway in human cancer. Cancer Genet Cytogenet 196:45–55

    Article  PubMed  CAS  Google Scholar 

  105. Xie H, Valera VA, Merino MJ et al (2009) LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Mol Cancer Ther 8:626–635

    Article  PubMed  CAS  Google Scholar 

  106. Tennant DA, Frezza C, MacKenzie ED et al (2009) Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death. Oncogene 28:4009–4021

    Article  PubMed  CAS  Google Scholar 

  107. Temes E, Martin-Puig S, Acosta-Iborra B et al (2005) Activation of HIF-prolyl hydroxylases by R59949, an inhibitor of the diacylglycerol kinase. J Biol Chem 280:24238–24244

    Article  PubMed  CAS  Google Scholar 

  108. Gao P, Zhang H, Dinavahi R et al (2007) HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12:230–238

    Article  PubMed  CAS  Google Scholar 

  109. Sourbier C, Valera-Romero V, Giubellino A et al (2010) Increasing reactive oxygen species as a therapeutic approach to treat hereditary leiomyomatosis and renal cell carcinoma. Cell Cycle 9:4183–4189

    Article  PubMed  CAS  Google Scholar 

  110. Pollard PJ, Ratcliffe PJ (2009) Cancer. Puzzling patterns of predisposition. Science 324:192–194

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Prof Lauri Aaltonen is acknowledged for the comments on the manuscript. Prof Kristiina Aittomäki and Dr Pia Alhopuro are thanked for consultation on surveillance guidelines and Prof Johanna Arola for help on histopathological items. Ms Johanna Kondelin is thanked for editing the text. Figure 1 is presented by the courtesy of Dr Erik Björck and Fig. 3 is formulated with kind help of Dr Iulia Diaconu.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, Haartman Institute, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, Helsinki, 00290, Finland

    Heli J. Lehtonen

Authors
  1. Heli J. Lehtonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heli J. Lehtonen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lehtonen, H.J. Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Familial Cancer 10, 397–411 (2011). https://doi.org/10.1007/s10689-011-9428-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-011-9428-z

Keywords

Search

Navigation