SMAD4 mutations identified in Iranian patients with colorectal cancer and polyp.
Gastroenterology and Hepatology from Bed to Bench,
30 December 2021
Background: Colorectal cancer is one of the five prevalent cancers among the Iranian population. However, its molecular mechanisms is not fully understood, while 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 was carried out on 39 and 30 specimens of polyp and adenocarcinoma.
Results: 33.3% of cancer and 28.2% of polyp specimens were mutated for Smad-4. Missense mutations, especially in the MH2 domain (63.6% and 68.75) were the prominent alterations. In cancer, codon 435 and in polyp, codons 435 and 399 were the most prevalent mutations. Unlike cancer specimens, in polyp, transversion was the most frequent substitutions (56.25 vs. 35.7%). CG>TA transition was about 18.75 and 14.3% in cancer and polyp samples. Mutations of codon 264 and C.483-4 were seen both in cancer and neoplastic polyps.
Conclusion: As the 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 the global genome hypomethylation. Presumably, SMAD4 mutations had occurred in the primary polyps, and some of these mutated cells then developed to carcinoma. On the other hand, polyp-specific mutations may lower the risk of CRC.
- colorectal cancer
- MH2 domain
- neoplastic polyp
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