Further more, we also found the SMAD4 mutant status associated with occupational exposure to pesticides, signifying that pesticides serves as the important risk factor in the development of CRC like other cancers [Table 3], as has been previously reported in various studies [ 51- 53].
However, low DI tumours independently associated with PgR-positive status (P=0.012, BLR), intermediate DI tumours associated with p53 mutant status (P=0.001, BLR), and high DI tumours independently associated with HER2-positive status (P=0.004, BLR) (Table 3; Figure 4).
Accumulation in M-phase was the most prominent phenotype and notably, was also correlated with TP53 mutant status.
However the correlation between the SMAD4 gene mutations with KRAS mutant status has not been explored by many studies so far.
Examining the 5q and 6q status of the patients in Figure 2F, either alone or in combination with SPOP mutant status would be informative and provide a clearer understanding of the contributions of these genes to the DNA damage phenotype (BRCA1 mutant gene set) of this subtype.
We have also observed a statistically significant association of SMAD4 gene aberrations with KRAS mutant status suggesting the involvement of at least two molecules in the advanced tumor grade in colorectal cancers; in other words, in case of high grade advanced tumor, aberration in more than one molecular gate keeper of several signal transduction pathways may be involved.
Another study showed that among patients with the T/T genotype, mutant status of TP53 and aberrant p53 protein expression were associated with poor survival, suggesting an interaction between MDM2 SNP309 and tumor TP53 status [ 25].
The correlation between M-phase accumulation and TP53 mutant status that we observed is consistent with this overall model: Destabilization of mutant p53 combined with the corresponding loss of p21 activity and the subsequent weakening of G1/S and G2/M checkpoint surveillance could permit cells to inappropriately enter M, as would destabilization of WEE1 and CHK1.
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.
