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Familial Cancer

, Volume 10, Issue 2, pp 397–411 | Cite as

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

  • Heli J. Lehtonen
Article

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.

Keywords

Fumarate hydratase (FH) HIF1 HLRCC Kidney Leiomyoma Leiomyosarcoma MCUL Renal cell cancer Tricarboxylic acid cycle 

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

Notes

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.

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© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  1. 1.Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, Haartman InstituteUniversity of HelsinkiHelsinkiFinland

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