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Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours

Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes.2–5 The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6,7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair.8,9

Birt-Hogg-Dube syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons.10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients,11 including diverse types of kidney tumours12–17 and spontaneous pneumothorax.12–16,18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia,13,19–22 although a large study of 223 patients from 33 BHD families could not establish such a relation.23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis.13 The BHD gene has been mapped to chromosome subband 17p11.212,14 and recently identified to encode a novel protein named follicullin.15 Based on the presence of inactivating BHD mutations in BHD …