SMAD4 Mutations Identified in Iranian Patients with Colorectal Cancer and Polyp

Aim: Search for SMAD4 mutations in Colorectal cancer (CRC) or polyp in Iran.

Background: Colorectal cancer is one of the five prevalent cancers among the Iranian population; however, its molecular mechanisms are not fully understood. The vast majority of CRCs arise from neoplastic polyp.

Methods: Colorectal cancer and polyp lesions with matched normal tissues from patients who had undergone colonoscopy in Taleghani Hospital (January 2009 - November 2010) were included in the study. DNA extraction and PCR-sequencing for exons 5-11 of the SMAD-4 gene were carried out on 39 and 30 specimens of polyp and adenocarcinoma, respectively.

Results: Of cancer and polyp specimens, 33.3% and 28.2%, respectively, were mutated in the Smad-4 gene. The majority of SMAD4 mutations, especially in the MH domain were missense mutations (63.6% and 68.75, respectively). In cancer, codon 435 and in polyp, codons 435 and 399 were the most common alterations. Unlike cancer specimens, transversion was found frequently in the polyp (56.25% vs. 35.7%). CG>TA transition was about 18.75% and 14.3% in cancer and polyp samples, respectively. Mutations of codon 264 and C.483-4 were seen both in cancer and neoplastic polyps.

Conclusion: As frequent alterations, missense mutations are presumably selected during tumorigenesis and polyposis due to their structural impacts on SMAD4 functions and TGF-ß signaling pathway. The lower frequency of CG>TA can be attributed to global genome hypomethylation. Presumably, SMAD4 mutations had occurred in the primary polyps, and some of these mutated cells then developed into carcinoma. On the other hand, polyp-specific mutations may lower the risk of CRC.