Background: The TGF-β signal pathways play a key role in the development and promotion of squamous cell carcinoma (SCC). The pathway is mediated by the SMAD  family proteins that include SMAD3  and SMAD6 . Our study aimed to evaluate the relationship between single nucleotide polymorphism (SNP) of SMAD3/SMAD6  and susceptibility to esophageal squamous cell carcinoma (ESCC) in the Chinese population.
Patients and Methods: This was a hospital-based case–control study compromised of 1043 ESCC patients and 1315 non-cancer patients. Seven SMAD3/SMAD6  (rs8028147, rs3743343, rs3743342, rs8025774, rs8031440, rs803167, and rs34643453) SNPs were selected and used to evaluate their correlation with ESCC susceptibility. Genetic model tests, stratified analyses, linkage disequilibrium analyses, and haplotype analyses were performed in our study.
Results: Participants with SMAD3  rs3743342 C>T, rs8025774 C>T, rs8031440 G>A or rs8031627 G>A had a significantly higher risk of ESCC. This was more evident in males, older patients (> 63 years), smokers, and non-alcohol drinking participants. Linkage disequilibrium analyses further revealed that there were strong correlations between SMAD3  rs3743342 C>T, rs8025774 C>T, rs8031440 G>A, and rs8031627 G>A. In the same line, haplotype analyses revealed that SMAD3  ACCCGGSMAD6 A and SMAD3 AGCCGGSMAD6 A were associated with less susceptibility to ESCC while SMAD3 ATTTAASMAD6 A was associated with a higher risk of ESCC.
Conclusion: SNPs of SMAD3  were related to higher susceptibility to ESCC. As such, they may contribute to the development of viable strategies for early diagnosis and treatment of ESCC. However, more detailed association mechanisms between SMAD3/SMAD6  SNPs and ESCC need further experiments to prove.
Keywords: SMAD , single nucleotide polymorphism, esophageal squamous cell carcinoma