Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

Abstract

BACKGROUND:

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase (FH) gene.

METHODS:

As part of the French National Cancer Institute (INCa) 'Inherited predispositions to kidney cancer' network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic).

RESULTS:

The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations.

CONCLUSIONS:

This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

• Authors: Betty Gardie, Audrey Remenieras, Darouna Kattygnarath, Johny Bombled, Sandrine Lefèvre, Victoria Perrier-Trudova, Pierre Rustin, Michel Barrois, Abdelhamid Slama, Marie-Françoise Avril, Didier Bessis, Olivier Caron, Frédéric Caux, Patrick Collignon, Isabelle Coupier, Carol Cremin, Hélène Dollfus, Catherine Dugast, Bernard Escudier, Laurence Faivre, Michel Field, Brigitte Gilbert-Dussardier, Nicolas Janin, Yves Leport, Dominique Leroux, Dan Lipsker, Félicia Malthieu, Barbara McGilliwray, Christine Maugard, Arnaud Méjean, Isabelle Mortemousque, Ghislaine Plessis, Bruce Poppe, Christelle Pruvost-Balland, Serena Rooker, Joelle Roume, Nadem Soufir, Michelle Steinraths, Min-Han Tan, Christine Théodore, Luc Thomas, Pierre Vabres, Emmanuel Van Glabeke, Jean-Baptiste Meric, Virginie Verkarre, Gilbert Lenoir, Virginie Joulin, Sophie Deveaux, Veronica Cusin, Jean Feunteun, Bin Tean Teh, Brigitte Bressac-de Paillerets, Stéphane Richard, French National Cancer Institute "Inherited predisposition to kidney cancer" network
• Journal: Journal of medical genetics (J Med Genet) Vol. 48 Issue 4 Pg. 226-34 (Apr 2011) ISSN: 1468-6244 [Electronic] England
• PMID: 21398687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon, Nonsense
• Fumarate Hydratase

Topics

• Adult
• Aged
• Carcinoma, Renal Cell (genetics)
• Cell Line, Tumor
• Codon, Nonsense
• Female
• Frameshift Mutation
• Fumarate Hydratase (genetics)
• Gene Deletion
• Gene Rearrangement
• Genotype
• Germ-Line Mutation
• Humans
• INDEL Mutation
• Kidney Neoplasms (genetics)
• Leiomyomatosis (congenital, genetics)
• Male
• Middle Aged
• Mutation
• Mutation, Missense
• Neoplastic Syndromes, Hereditary
• Pedigree
• Skin Neoplasms
• Uterine Neoplasms