Editor—Transforming growth factor-β (TGF-β) family members are known to be involved in the regulation of cell proliferation, differentiation, and apoptosis.1Members of the TGF-β family include TGF-βs, activins, and bone morphogenetic proteins (BMPs). Their signals are mediated to the cell nucleus by a network of transmembrane serine/threonine kinase receptors and their downstream effectors, the SMAD proteins.2 SMAD proteins play a key role in intracellular TGF-β signalling and inactivating mutations of SMADs, such asSMAD2, SMAD3, andSMAD4, provide resistance of cells to TGF-β induced growth inhibition.

To date, eight human SMADs have been identified. Two of them, SMAD2 andSMAD4, have been reported to be mutated in a subset of colorectal carcinomas.3-6 Germline mutations ofSMAD4 have been found in patients with juvenile polyposis, a condition predisposing to colorectal cancer.7-10

SMAD3 mutations have not been reported in human cancers. In a recent study by Arai et al,11 SMAD3 mutations were analysed in 35 sporadic colorectal and 15 HNPCC cancers and no mutations were found. Targeted disruption of the SMAD3 gene in mice has been reported to lead to development of colorectal cancer,12 though other studies have not detected a clear association.13 14 No genetic alterations in otherSMADs have been reported in malignancy.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer susceptibility syndrome, associated with germline mutations in five DNA mismatch repair genes:MLH1, PMS1, PMS2, MSH2, and MSH6.15-19Inactivation of both alleles of a mismatch repair gene results in microsatellite instability (MSI) that is a hallmark of HNPCC tumours.20-23 The genes responsible for microsatellite stable (MSS) HNPCC are still unknown.

Loss of growth inhibition by TGF-β is an important step in colon tumorigenesis and in …