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

Michael Nahorski (1) , Derek Lim (1) , Lynn Martin (1) , Johan Gille (2) , Kirstin Mckay (3) , Pauline Rehal (3) , H. Martijn Ploeger (2) , Maurice van Steensel (4) , Ian Tomlinson (5) , Farida Latif (1) , Fred Menko (2) , Eamonn Maher (1)

1 University of Birmingham [Birmingham]
2 VU University Medical Center [Amsterdam]
3 Birmingham Womens Hospital
4 MUMC - Maastricht University Medical Centre
5 University of Oxford

Birt–Hogg–Dube´ (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. We undertook a series of clinical and laboratory studies to investigate possible relationships between colorectal neoplasia and the BHD gene (FLCN). Thus we 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. Although we found previously that germline FLCN mutations can be detected in ~5% of patients with familial renal cell carcinoma, we did not detect germline FLCN mutations in 51 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 (2=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. Our 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.

Mots clés: Gastroenterology; Clinical genetics; Cancer: colon

Michael Nahorski, Derek Lim, Lynn Martin, Johan Gille, Kirstin Mckay, et al.. Investigation of the Birt-Hogg-Dubé tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer. Journal of Medical Genetics, 2010, 47 (6), pp.385. ⟨10.1136/jmg.2009.073304⟩. ⟨hal-00557374⟩