AIM: To investigate the correlation of HOXA4 and HOXA5 promoter DNA hypermethylation with imatinib resistance among CML patients.

METHODS AND RESULTS: Samples from 175 Philadelphia positive CML patients (83 good response and 92 BCR-ABL non-mutated imatinib resistant patients) were subjected to Methylation Specific High Resolution Melt Analysis for methylation levels quantification of the HOXA4 and HOXA5 promoter regions. Receiver operating characteristic curve analysis was done to elucidate the optimal methylation cut-off point followed by multiple logistic regression analysis. Log-Rank analysis was done to measure the overall survival difference between CML groups. The optimal methylation cut-off point was found to be at 62.5% for both HOXA4 and HOXA5. Chronic myeloid leukemia patients with ≥63% HOXA4 and HOXA5 methylation level were shown to have 3.78 and 3.95 times the odds, respectively, to acquire resistance to imatinib. However, overall survival of CML patients that have ≤62% and ≥ 63% methylation levels of HOXA4 and HOXA5 genes were found to be not significant (P-value = 0.126 for HOXA4; P-value = 0.217 for HOXA5).

MATERIALS AND METHODS: We performed genotyping for both SNPs for 250 GIC patients and 572 healthy volunteers using a polymerase chain reaction- restriction fragment length polymorphism approach. We validated heterozygosity and homozygosity for both SNPs using direct sequencing.

RESULTS: The presence of a variant 194Trp allele in the Arg194Trp SNP was significantly associated with a higher risk of GIC, especially with gastric and colorectal cancers. We additionally found that the variant 399Gln allele in Arg399Gln SNP was associated with a greater risk of developing gastric cancer. Our combined analysis revealed that inheritance of variant alleles in both SNPs increased the GIC risk in Sabah population. Based on our etiological analysis, we found that subjects ≥50 years and males who carrying the variant 194Trp allele, and Bajau subjects carrying the 399Gln allele had a significantly increased risk of GIC.

MATERIALS AND METHODS: cDNAs from 41 OSCC samples with and without risk habits were included in this study. Quantitative real-time PCR was used to analyze KRT13, FAIM2 and CYP2W1 in OSCC. The housekeeping gene (GAPDH) was used as an endogenous control.

RESULTS: Of the 41 OSCC samples, KRT13 was down-regulated in 40 samples (97.6%), while FAIM2 and CYP2W1 were down-regulated in 61.0% and 48.8%, respectively. Overall, there were no associations between KRT13, FAIM2 and CYP2W1 expression with risk habits, selected socio-demographic and clinico-pathological parameters and patient survival.

AIMS: To determine the usefulness of immunohistochemical techniques and FISH of the tumour suppressor TP 53 gene to identify microinvasion in marginal tissue sections and to relate the possible correlation between protein expression and genetic aberrations in OSCC cases in Malaysia.

METHODS: Immunohistochemistry and FISH of TP 53 genes were applied on 26 OSCC formalin fixed paraffin embed (FFEP) blocks selected from two oral cancer referral centers in Malaysia.

RESULTS: For p53 protein immunohistochemistry, 96% of the 26 OSCC studied showed positive immunostaining at the excision margins. In FISH assay, 48.9±9.7% of the cancerous cells were monoploid for p53 probe signals, 41.0±9.5 % were diploid, and 10.2±7.8 % were polyploid. A correlation between p53 immunostaining and TP53 gene aberrations was noted (p< 0.05).

METHODS: Using multi-region sampled RNA-seq data of 90 patients, we performed patient-specific differential expression testing, together with the patients' matched adjacent normal samples.

RESULTS: Comparing the results from conventional DE analysis and patient-specific DE analyses, we show that the conventional DE analysis omits some genes due to high inter-individual variability present in both tumour and normal tissues. Dysregulated genes shared in small subgroup of patients were useful in stratifying patients, and presented differential prognosis. We also showed that the target genes of some of the current targeted agents used in HCC exhibited highly individualistic dysregulation pattern, which may explain the poor response rate.

METHODS: In this study, plasma miRNA profiles from eight early-stage breast cancer patients and nine age-matched (± 2 years) healthy controls were characterized by miRNA array-based approach, followed by differential gene expression analysis, Independent T-test and construction of Receiver Operating Characteristic (ROC) curve to determine the capability of the assays to discriminate between breast cancer and the healthy control.

RESULTS: Based on the 372-miRNAs microarray profiling, a set of 40 differential miRNAs was extracted regarding to the fold change value at 2 and above. We further sub grouped 40 miRNAs of breast cancer patients that were significantly expressed at 2-fold change and higher. In this set, we discovered that 24 miRNAs were significantly upregulated and 16 miRNAs were significantly downregulated in breast cancer patients, as compared to the miRNA expression of healthy subjects. ROC curve analysis revealed that seven miRNAs (miR-125b-5p, miR-142-3p, miR-145-5p, miR-193a-5p, miR-27b-3p, miR-22-5p and miR-423-5p) had area under curve (AUC) value > 0.7 (AUC p-value < 0.05). Overlapping findings from differential gene expression analysis, ROC analysis, and Independent T-Test resulted in three miRNAs (miR-27b-3p, miR-22-5p, miR-145-5p). Cohen's effect size for these three miRNAs was large with d value are more than 0.95.

MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.