MTNR1B polymorphisms with CDKN2A and MGMT methylation status are associated with poor prognosis of colorectal cancer in Taiwan

BACKGROUND Identifying novel colorectal cancer(CRC)prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions.Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours.AIM To explore the relationship between MTNR1B single-nucleotide polymorphism(SNPs)combined with gene hypermethylation and CRC prognosis.METHODS A total of 94 CRC tumour tissues were investigated.Genotyping for the four MTNR1B SNPs(rs1387153,rs2166706,rs10830963,and rs1447352)was performed using multiplex polymerase chain reaction.The relationships between the MTNR1B SNPs and CRC 5-year overall survival(OS)was assessed by calculating hazard ratios with 95%CIs.RESULTS All SNPs(rs1387153,rs2166706,rs10830963,and rs1447352)were correlated with decreased 5-year OS.In stratified analysis,rs1387153,rs10830963,and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS.A strong cumulative effect of the four polymorphisms on CRC prognosis was observed.Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS.MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival.CONCLUSION The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.

Methylation of IRAK3 is a novel prognostic marker in hepatocellular carcinoma

AIM: To examine the methylation levels of interleukin-1 receptor-associated kinase 3(IRAK3) and GLOXD1 and their potential clinical applications in hepatocellular carcinoma(HCC).METHODS: m RNA expression and promoter methylation of IRAK3 and GLOXD1 in HCC cells were analyzed by reverse transcription-polymerase chain reaction(RTPCR) and methylation-specific PCR(MSP), respectively. Using pyrosequencing results, we further established a quantitative MSP(Q-MSP) system for the evaluation of IRAK3 and GLOXD1 methylation in 29 normal controls and 160 paired HCC tissues and their adjacent nontumor tissues. We also calculated Kaplan-Meier survival curves to determine the applications of gene methylation in the prognosis of HCC.RESULTS: IRAK3 and GLOXD1 expression was partially restored in several HCC cell lines after treatment with 5-aza-2′-deoxycytidine(DNA methyltransferase inhibitor; 5DAC). A partial decrease in the methylated band was also observed in the HCC cell lines after 5DAC treatment. Using GLOXD1 as an example, we found a significant correlation between the data obtained from the methylation array and from pyrosequencing. The methylation frequency of IRAK3 and GLOXD1 in HCC tissues was 46.9% and 63.8%, respectively. Methylation of IRAK3 was statistically associated with tumor stage. Moreover, HCC patients with IRAK3 methylation had a trend toward poor 3-year disease-free survival(P < 0.05). CONCLUSION: IRAK3 and GLOXD1 were frequently methylated in HCC tissues compared to normal controls and nontumor tissues. IRAK3 methylation was associated with tumor stage and poor prognosis of patients. These data suggest that IRAK3 methylation is a novel prognostic marker in HCC.