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Background  The development and progression of colorectal cancer has been extensively studied and the genes responsible have been well characterized. However the correlation between the  SMAD4  gene mutations with  KRAS  mutant status has not been explored by many studies so far. Here, in this study we aimed to investigate the role of  SMAD4  gene aberrations in the pathogenesis of CRC in Kashmir valley and to correlate it with various clinicopathological variables and  KRAS  mutant genotype.    Methods  We examined the paired tumor and normal tissue specimens of 86 CRC patients for the occurrence of aberrations in MCR region of  SMAD4  and exon 1 of  KRAS  by PCR-SSCP and/or PCR-Direct sequencing.    Results  The overall mutation rate of mutation cluster region (MCR) region of  SMAD4  gene among 86 patients was 18.6% (16 of 86). 68.75% (11/16) of the  SMAD4  gene mutants were found to have mutations in  KRAS  gene as well. The association between the  KRAS  mutant genotype with  SMAD4  mutants was found to be significant (P =< 0.05). Further more, we found a significant association of tumor location, tumor grade, node status, occupational exposure to pesticides and bleeding PR/Constipation with the mutation status of the  SMAD4  gene (P =< 0.05).    Conclusion  Our study suggests that  SMAD4  gene aberrations are the common event in CRC development but play a differential role in the progression of CRC in higher tumor grade (C+D) and its association with the  KRAS  mutant status suggest that these two molecules together are responsible for the progression of the tumor to higher/advanced stage.

bmc cancer

SMAD4 - Molecular gladiator of the TGF-β signaling is trampled upon by mutational insufficiency in colorectal carcinoma of Kashmiri population: an analysis with relation to KRASproto-oncogene