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No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome

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Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. Cutaneous and uterine leiomyomas are the most common clinical manifestations of HLRCC, whereas only approximately 20% of the families display renal cell cancer (RCC). The number of RCC cases in these families varies from one to five. Interestingly, families with multiple RCC cases are mainly found in Finland and the USA. Such aggregation of RCC in only some families and populations has led to the hypothesis that besides FH mutations also other inherited genetic and/or environmental factors may contribute to the malignant kidney tumor formation. To search for such a genetic modifier we have performed a genome-wide linkage analysis in two and an identical by descent analysis in four Finnish HLRCC families with several RCC patients. Additional Finnish and French families were used in fine-mapping and haplotype analyses. The only region compatible with linkage was the locus surrounding the FH gene itself in chromosome 1q43. The genes in the putative candidate region were screened, but no potentially pathogenic alterations were observed. Although these data do not rule out the existence of a genetic modifier, they emphasize the contribution of the FH genotype in HLRCC related RCC. Therefore, as all FH mutation carriers may have an increased risk for developing renal cancer, counseling and genetic testing should be offered for all HLRCC family members and clinical follow-up should be organized for the mutation carriers.

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Abbreviations

CHRM3 :

Muscarinic acetylcholine receptor M3

cM:

Centimorgan

FH :

Fumarate hydratase (gene)

FH:

Fumarase (enzyme)

FMN2 :

Formin 2

GREM2 :

Gremlin-2 precursor

HIF:

Hypoxia-inducible factor

HLRCC:

Hereditary leiomyomatosis and renal cell cancer

IBD:

Identical by descent

LOD:

Logarithm of odds

Mb:

Mega base pairs

MRI:

Magnetic resonance imaging

RCC:

Renal cell cancer

SDH:

Succinate dehydrogenase complex

SNP:

Single nucleotide polymorphism

TCAC:

Tricarboxylic acid cycle

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Acknowledgments

Sini Marttinen, Iina Vuoristo, Inga-Lill Svedberg, Mikko Aho, and Anniina Raitila are warmly thanked for excellent technical assistance. The study has been supported by grants from European Commission (LSHC-CT-2005-518200), Academy of Finland (Center of excellence in Translational Genome-Scale Biology and grants 212901, 214323, 213183, 214268), Finnish Cancer Society, the French National Cancer Institute (Kidney PNES, INCa) and the French League against Cancer (Comités du Cher et de l’Indre).

Author information

Authors and Affiliations

  1. Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland

    Pia Vahteristo, Taru A. Koski, Laura Näätsaari, Maija Kiuru, Auli Karhu, Kristiina Aittomäki, Lauri A. Aaltonen, Virpi Launonen & Rainer Lehtonen

  2. Oulu University Hospital, Oulu, Finland

    Riitta Herva

  3. Department of Pediatrics, Genetics Outpatient Clinic, Tampere University Hospital, Tampere, Finland

    Satu-Leena Sallinen

  4. Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland

    Outi Vierimaa

  5. Clinical Genetics Unit, Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden

    Erik Björck

  6. Génetique Oncologique EPHE-CNRS FRE 2939, Institut de Cancérologie Gustave Roussy, Villejuif, France

    Stéphane Richard & Betty Gardie

  7. Faculté de Médecine Paris-Sud, Paris, France

    Stéphane Richard & Betty Gardie

  8. Centre de Référence Tumeurs Rares INCa, Assistance Publique-Hopitaux de Paris, Service d’Urologie, CHU de Bicêtre, Le Kremlin Bicêtre, France

    Stéphane Richard & Betty Gardie

  9. Service de Dermatologie, Hôpital Saint-Eloi, CHU de Montpellier, Université Montpellier 1, Montpellier, France

    Didier Bessis

  10. Service d’Urologie, Centre Hospitalier André Grégoire, Montreuil sous Bois, France

    Emmanuel Van Glabeke

  11. Genetic Counseling Unit, Prevention and Cancer Control Department, and Translational Research Laboratory, IDIBELL-Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain

    Ignacio Blanco

  12. Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK

    Richard Houlston

  13. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Leigha Senter

  14. Department of Medical Biochemistry and Genetics, University of Turku and Turku University Hospital, Turku, Finland

    Marja Hietala

  15. Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland

    Kristiina Aittomäki

  16. Department of Biological and Environmental Sciences, University of Helsinki, PO BOX 65 (Viikinkaari 1), 00014, Helsinki, Finland

    Rainer Lehtonen

Authors
  1. Pia Vahteristo
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  2. Taru A. Koski
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  3. Laura Näätsaari
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  4. Maija Kiuru
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  7. Satu-Leena Sallinen
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  8. Outi Vierimaa
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  9. Erik Björck
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  11. Betty Gardie
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  12. Didier Bessis
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  13. Emmanuel Van Glabeke
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  14. Ignacio Blanco
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  15. Richard Houlston
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  16. Leigha Senter
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  17. Marja Hietala
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  18. Kristiina Aittomäki
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  19. Lauri A. Aaltonen
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  20. Virpi Launonen
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  21. Rainer Lehtonen
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Corresponding author

Correspondence to Rainer Lehtonen.

Additional information

The authors Pia Vahteristo and Taru A. Koski have contributed equally to this work.

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Vahteristo, P., Koski, T.A., Näätsaari, L. et al. No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome. Familial Cancer 9, 245–251 (2010). https://doi.org/10.1007/s10689-009-9312-2

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  • DOI: https://doi.org/10.1007/s10689-009-9312-2

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