title: No evidence for a genetic modifier for renal cell cancer risk in HLRCC syndrome.
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.
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Taru A
authors.initials: TA
authors.lastname: Koski
authors.forename: Laura
authors.initials: L
authors.lastname: Näätsaari
authors.forename: Maija
authors.initials: M
authors.lastname: Kiuru
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Riitta
authors.initials: R
authors.lastname: Herva
authors.forename: Satu-Leena
authors.initials: SL
authors.lastname: Sallinen
authors.forename: Outi
authors.initials: O
authors.lastname: Vierimaa
authors.forename: Erik
authors.initials: E
authors.lastname: Björck
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
authors.forename: Betty
authors.initials: B
authors.lastname: Gardie
authors.forename: Didier
authors.initials: D
authors.lastname: Bessis
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Van Glabeke
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.forename: Leigha
authors.initials: L
authors.lastname: Senter
authors.forename: Marja
authors.initials: M
authors.lastname: Hietala
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehtonen
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis / Q000009:adverse effects; D019317:Evidence-Based Medicine; D005260:Female; D005387:Finland / Q000453:epidemiology; D005649:Fumarate Hydratase / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000235:genetics*; D007889:Leiomyoma / Q000209:etiology; D018231:Leiomyomatosis / Q000209:etiology* / Q000235:genetics; D008297:Male; D014481:United States / Q000453:epidemiology; D014594:Uterine Neoplasms / Q000235:genetics / Q000503:physiopathology*
chemical_list: D005649:Fumarate Hydratase