Screening SMAD1, SMAD2, SMAD3, and SMAD5 for germline mutations in juvenile polyposis syndrome

Background and aims-Juvenile polyps occur in several Mendelian disorders, w hether in association with gastrointestinal cancer alone (juvenile polyposi s syndrome, JPS) or as part of known syndromes (Cowden, Gorlin, and Bannaya n-Zonana) in association with developmental abnormalities, dysmorphic featu res, or extraintestinal tumours. Recently, some JPS families were shown to harbour germline mutations in the SMAD4 (DPC4) gene, providing further evid ence for the importance of the TGF beta signalling pathway in colorectal ca ncer. There remains, however, considerable, unexplained genetic heterogenei ty in JPS. Other members of the SMAD family are excellent candidates for JP S, especially SMAD2 (which, like SMAD4, is mutated somatically in colorecta l cancers), SMAD3 (which causes colorectal cancer when "knocked out" in mic e), SMAD5, and SMAD1. Methods-SMAD1, SMAD2, SMAD3, and SMAD5 were screened for germline mutations in 30 patients with JPS and without SMAD4 mutations. Results-No mutations were found in any of these genes. A G-A C89Y polymorph ism with possible effects on protein function was found in SMAD3, but the f requencies of the G and A alleles did not differ between patients with JPS and controls. Conclusions-It remains to be determined whether or not this polymorphism is involved in a minor predisposition to colorectal or other carcinomas. SMAD 4 may be the only member of the SMAD family which causes JPS when mutant in the germline. The other genes underlying JPS remain to be identified.