In the last decade, it has been established that tumors display different abilities in order to grow, survive and proliferate, of which we highlight here resistance to cell death, including apoptosis . However, there is still a lot to discover about these mechanisms.
Apoptosis is a complex process that involves the protein action of several different genes, such as BCL2, CASP3, CASP8, CASP9, FADD, FAS and TP53. Dysfunction in these genes may lead to deregulation of cell death and, thus, tumor development. Therefore, in this study, we investigated whether nine INDEL variants in the mentioned genes might influence gastric carcinogenesis, by comparing their distribution in GC patients and cancer-free individuals.
Regarding the observed deviation from HWE in the distribution of rs4197 and rs4645982 in case group, no previous studies were found with these markers, but their genotype distribution varies greatly between different populations in 1000 Genomes Project database . Curiously, their distribution also presented a deviation from HWE in most populations in that database, suggesting that there could be a selective advantage leading to this pattern and/or that the deviation observed here could be due to population substructure, especially considering the relatively recent admixture process in Brazil, as previously observed for other markers in this population [7, 22]. As such, it is an expected process in admixed populations, and it could even highlight the potential of these markers. In fact, it has been suggested that HWE deviation only in patient’s group could support possible locus-disease associations .
Then, we carried on to the analyses performed for each genotype (carriers of a genotype vs. non-carriers of such genotype as a reference group) in cases and controls. In these analyses, our results suggest that individuals carrying INS/DEL of rs4197 have about 2-fold chances of developing GC than non-carriers (P = 0.046; OR = 1.940; 95%CI = 1.011–3.725).
To the best of our knowledge, this is the first study investigating variant rs4197. It is a 3-bp INDEL in the 3′ UTR of FADD gene, a key adaptor molecule that transmits death signals from death receptors during extrinsic apoptosis, thus being crucial to a variety of processes . In fact, it seems that it could affect protein features due to the importance of 3′-UTR . Depletion of FADD protein action may lead to failure of apoptosis and, thus, to tumor development. Absence of FADD expression has been suggested as marker of tumor development in mice and cancer prognosis in humans, due to the involvement of this protein with cell apoptosis, survival and proliferation . Therefore, investigation of FADD gene should help the understanding of cancer development, including gastric carcinogenesis.
As for the variants that did not present a statistical association here, this may suggest that they either do not play a role in gastric carcinogenesis or it is a population-specific treat. Indeed, some of these variants have been associated cancer development in a few studies, but not in others. For instance, one of these variants (rs3834129 in CASP8) has been previously studied by our research group in other sampling of the same region: we have associated INS/INS genotype of this variant to reduced chances of developing B-cell acute lymphoblastic leukemia , but have not found any association of this variant with GC or colorectal cancer , so that our study corroborates the findings in the latter. Thus, the association of such variants to GC and other types of cancer is still a matter of great discussion.