الفهرس 
Title : Relationship between TNF alpha gene polymorphisms and the Pathogenesis of cachexia in cancer patients treated with chemotherapy
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Abstract
Background: Cachexia is a frequent syndrome in pancreatic and non-small cell lung (NSCL)
cancer patients. The storm of cancer-induced inflammatory cytokines, in particular TNF-α, is a
crucial pathogenic mechanism. Among the molecular alterations accused of cancer-induced
cachexia, TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) are single-nucleotide
polymorphisms (SNPs) within the gene encoding this pro-inflammatory cytokine. Recent studies
have demonstrated the crucial role of noncoding micro RNAs (miRNAs) in pathogenesis of different
diseases including cachexia. Moreover, the mechanistic cytokine signaling pathway of miR-155, as
a TNF-α regulator, supports the involvement of SOCS1, TAB2 and FOXP3, which are direct targets
of TNF-α gene.
Aim: A case-control study (NCT04131478) was conducted primarily to determine the incidence of
TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) gene polymorphism in adult Egyptian
patients with local/advanced or metastatic pancreatic or NSCL cancer and investigate both as
cachexia risk factors. The association of gene polymorphism with cachexia severity and the
expression of miR-155 in cachectic patients were analyzed. A mechanistic investigation of the
cytokine signaling pathway, involving SOCS1, TAB2 and FOXP3, was also performed.
Results: In both pancreatic and NSCL cancer cohorts, the mutant TNF-α variant of 308 G/A was
positively associated with cachexia, on the contrary that of 1031T/C was negatively associated with
cachexia in NSCL cancer patients. miR-155 was higher in cachexia and in alignment with its
severity in cachectic group as compared to non-cachectic group in both pancreatic and NSCL
cancer patients. Though TAB2 did not change to any significant extent in cachectic patients, the
levels of SOCS1 and FOXP3 were significantly lower in cachectic group as compared to noncachectic
group.
Conclusion: Carriers of the A allele 308 G/A gene and high miR-155 are at greater risk of cachexia
in both pancreatic and NSCL cancer patients; however, the mutant variant of 1031T/C gene is
protective against cachexia in NSCL cancer patients. Finally, high levels of miR-155 in the
cachectic group lead to negative feedback inhibition of both SOCS1 and FOXP3 in both the
pancreatic and NSCL cancer patients.