Journal Article

Investigation of the Birt–Hogg–Dubé tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer

Nahorski, Michael S, Rehal, Pauline K, Gille, Johan J P, Ploeger, H Martijn, Menko, Fred H, Lim, Derek H K, van Steensel, Maurice, Latif, Farida, McKay, Kirsten, Tomlinson, Ian P, Martin, Lynn, Maher, Eamonn R

2010

Overview

BackgroundBirt–Hogg–Dubé (BHD) syndrome is an autosomal dominant multisystem disorder with skin (fibrofolliculomas or trichodiscomas), lung (cysts and pneumothorax) and kidney (renal cell carcinoma) tumours. Although colorectal neoplasia was reported initially to be part of the BHD phenotype, some recent studies have not confirmed this association.MethodsA series of clinical and laboratory studies was undertaken to investigate possible relationships between colorectal neoplasia and the BHD gene (FLCN). The studies investigated whether individuals with familial colorectal cancer of unknown cause might have unsuspected germline FLCN mutations, looked for somatic FLCN C8 tract mutations in microsatellite unstable sporadic colorectal cancers, and assessed the risk of colorectal neoplasia and possible genotype–phenotype correlations in BHD patients.ResultsAlthough it was found previously that germline FLCN mutations can be detected in ∼5% of patients with familial renal cell carcinoma, germline FLCN mutations were not detected in 50 patients with familial non-syndromic colorectal cancer. Analysis of genotype-phenotype correlations for two recurrent FLCN mutations identified in a subset of 51 families with BHD demonstrated a significantly higher risk of colorectal neoplasia in c.1285dupC mutation (within the exon 11 C8 mononucleotide tract) carriers than in c.610delGCinsTA mutation carriers (χ2=5.78, p=0.016). Somatic frameshift mutations in the FLCN exon 11 C8 mononucleotide tract were detected in 23% of sporadic colorectal cancers with microsatellite instability, suggesting that FLCN inactivation might contribute to colorectal tumourigenesis.ConclusionsThese findings suggest that the previously reported clinical heterogeneity for colorectal neoplasia may reflect allelic heterogeneity and the risk of colorectal neoplasia in BHD syndrome requires further investigation.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group,BMJ Publishing Group LTD
• Subject: Abnormalities, Multiple - genetics / Abnormalities, Multiple - pathology / Adult / Aged / Base Sequence / Biological and medical sciences / cancer: colon / Carcinoma, Renal Cell - complications / clinical genetics / Colorectal cancer / Colorectal Neoplasms - complications / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Cysts - complications / DNA Mutational Analysis / Family Health / Female / Fundamental and applied biological sciences. Psychology / Gastroenterology / General aspects. Genetic counseling / Genes / Genetic testing / Genetics of eukaryotes. Biological and molecular evolution / Genotype / Germ-Line Mutation / Humans / Investigations / Kidney Neoplasms - complications / Lung Diseases - complications / Male / Medical genetics / Medical sciences / Microsatellite Instability / Microsatellite Repeats - genetics / Middle Aged / Molecular and cellular biology / Mutation / Pathogenesis / Phenotype / Pneumothorax - complications / Polyps / Proto-Oncogene Proteins - genetics / Skin Diseases - complications / Syndrome / Tumor Suppressor Proteins - genetics / Tumors / Yeast