Association of gene polymorphisms and XPD expression on risk of nasopharyngeal carcinoma and survival among Malaysians

Nasopharyngeal carcinoma (NPC) is a rare form of cancer across the world except in certain areas such as Southern China, Hong Kong and Malaysia. NPC is the 4th most common cancer in Malaysia and the incidence rate for Malaysian Chinese is exceptionally high compared to other races. NPC is considered as a relatively radiosensitive tumor and patients diagnosed at early stages tend to survive longer compared to those who with advanced disease. Given that early symptoms of NPC are non-specific and that the nasopharynx is relatively inaccessible, less invasive screening methods such as biomarker screening might be the key to improve NPC survival and management. A matched case-control study was conducted to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T, TNF-α -308G>A and XPD Lys751Gln polymorphisms on the risk of nasopharyngeal carcinoma and all-cause survival. The association of XPD Lys751Gln polymorphism with XPD mRNA expression was investigated in order to substantiate the finding of significant association between XPD Lys751Gln polymorphism with NPC risk. A number of genes with their respective polymorphisms were shown in past studies to be associated with various cancers. hOGG1 and XPD genes encode for a DNA glycosylase and a DNA helicase respectively; both are proteins that are involved in DNA repair. ITGA2 is the alpha subunit of the transmembrane receptor integrin and is mainly responsible for cell-cell and cellextracellular matrix interaction. TNF-α is a cytokine that is released by immune cells during inflammation. In the present study, NPC cases and controls were matched by age, gender and ethnicity. Restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was used to process DNA genotyping studies involving all aforementioned gene polymorphisms. Conditional logistic regression was used for the analysis of NPC risk on gene polymorphisms, controlling for cigarette smoking, salted fish and alcohol consumption. Quantitative real-time PCR was utilized to process the XPD expression. 2-ΔΔCt relative expression fold-change method was chosen for the analysis of expression study. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations arising from all aforementioned gene polymorphisms with NPC risk. Kaplan-Meier survival function, log-rank test, and Cox regression were used to investigate the effect of gene polymorphisms on the all-cause survival of NPC. XPD homozygous wildtype Lys/Lys genotype was associated with increased NPC risk (adjusted OR=1.65, 95% CI=1.09- 2.50). No association was found between ITGA2 and TNF-α polymorphism on NPC risk. Lys/Lys genotype of XPD polymorphism was associated with reduced XPD expression. Interaction between gene polymorphisms showed that Ser/Gln (hOGG1- Ser326/XPD-Gln751) (adjusted OR=2.18, 95% CI=1.00-4.75), Ser/T (hOGG1- Ser326/ITGA2-T807) (adjusted OR=1.48, 95% CI=1.02-2.16) and G/Gln (TNF-α- G308/XPD-Gln751) (adjusted OR=1.59, 95% CI=1.07-2.35) allelic combinations conferred higher risk of NPC. 5-year survival rates for ITGA2 807 C/C, C/T and T/T carriers were 55 %, 50 % and 43 %, respectively. The application of XPD Lys751Gln and ITGA2 C807T polymorphisms in early NPC detection and prognostic prediction for NPC survival is not warranted at the current moment and the finding should be subjected to further validation and testing involving studies with larger sample size.

Preview Text FPSK(p) 2017 43 IR.pdf Download (1MB) | Preview

Actions (login required)

View Item