Germline mutations in the TGF-beta and Wnt signalling pathways are a rare cause of the "multiple" adenoma phenotype.

The “multiple” colorectal adenoma phenotype is characterised by approximately 5–100 adenomatous polyps of the large bowel, resulting in an increased risk of colorectal cancer. The condition can be inherited as a Mendelian trait, either autosomal dominant or recessive, but can also occur in the form of isolated cases. Some patients with the “multiple” adenoma phenotype are classified as having attenuated polyposis (AFAP or AAPC) owing to a germline APC mutation, usually in exons 1–4, exon 9, or the second half of exon 15.1,2 However, most “multiple” adenoma patients have no underlying APC mutation and do not have the extracolonic manifestations sometimes associated with AAPC. Recently, recessive mutations of the base excision repair gene, human Mut Y homologue ( MYH ) on chromosome 1p34, were identified in 30% of patients presenting with 15 or more adenomas.3 MYH is a highly conserved base excision repair (BER) gene involved in the repair of 8-oxo-7, 8-dihydro2′deoxyguanosine (8-oxo-G) lesions induced by oxidative damage. Two further BER genes, human homologue of MutM ( OGG1 ) and human homologue of MutT ( MTH ) have previously been excluded as causing multiple adenomas.4 It seems plausible that mutations in APC related genes could cause multiple adenomas by promoting Wnt signalling. APC regulates Wnt signalling by controlling the levels of β-catenin reaching the cell nucleus. Once in the nucleus, β-catenin complexes with DNA binding proteins of the T cell factor (TCF) family and serves as a coactivator of transcription.5 In the absence of Wnt signalling, levels of β-catenin are minimised by degradation in the proteasome, after phosphorylation by a complex comprising APC, axin, conductin, and glycogen synthase kinase 3-β (GSK3-β).6,7 Wnt signalling activates a cascade, which inhibits GSK3-β, allowing β-catenin to escape degradation.8 Downstream targets of Wnt signalling include c-myc, matrilysin, CD44, urokinase type plasminogen activator receptor, …