ABSTRACT
BACKGROUND: Nasopharyngeal carcinoma (NPC) is a neoplasm of the epithelial lining of the nasopharynx. Despite various reports linking genomic variants to NPC predisposition, very few reports were done on copy number variations (CNV). CNV is an inherent structural variation that has been found to be involved in cancer predisposition. METHODS: A discovery cohort of Malaysian Chinese descent (NPC patients, n = 140; Healthy controls, n = 256) were genotyped using Illumina® HumanOmniExpress BeadChip. PennCNV and cnvPartition calling algorithms were applied for CNV calling. Taqman CNV assays and digital PCR were used to validate CNV calls and replicate candidate copy number variant region (CNVR) associations in a follow-up Malaysian Chinese (NPC cases, n = 465; and Healthy controls, n = 677) and Malay cohort (NPC cases, n = 114; Healthy controls, n = 124). RESULTS: Six putative CNVRs overlapping GRM5, MICA/HCP5/HCG26, LILRB3/LILRA6, DPY19L2, RNase3/RNase2 and GOLPH3 genes were jointly identified by PennCNV and cnvPartition. CNVs overlapping GRM5 and MICA/HCP5/HCG26 were subjected to further validation by Taqman CNV assays and digital PCR. Combined analysis in Malaysian Chinese cohort revealed a strong association at CNVR on chromosome 11q14.3 (Pcombined = 1.54x10-5; odds ratio (OR) = 7.27; 95% CI = 2.96-17.88) overlapping GRM5 and a suggestive association at CNVR on chromosome 6p21.3 (Pcombined = 1.29x10-3; OR = 4.21; 95% CI = 1.75-10.11) overlapping MICA/HCP5/HCG26 genes. CONCLUSION: Our results demonstrated the association of CNVs towards NPC susceptibility, implicating a possible role of CNVs in NPC development.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 6/genetics , DNA Copy Number Variations , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Nasopharyngeal Neoplasms/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Asian People/genetics , Carcinoma , China/ethnology , Cohort Studies , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genotype , Humans , Malaysia , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/ethnology , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Young AdultABSTRACT
BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr Virus (EBV)-associated cancer that is the fifth most common cancer in Malaysia. Early and accurate diagnoses are critical for patient prognosis. Unfortunately, early detection of NPC is still a challenge and the cost of more accurate imaging protocols is prohibitive in developing countries like Malaysia. OBJECTIVES: To evaluate the clinical values of pre-treatment plasma EBV DNA levels in Malaysian NPC patients. STUDY DESIGN: Plasma EBV DNA levels were measured by quantitative PCR (Q-PCR) in a large and multi-ethnic cohort of Malaysian patients with NPC (n=459) and 72 control subjects. RESULTS: We show for the first time that, compared to controls, NPC patients with stage I disease had significantly higher levels of EBV DNA (p<0.001). Further, the median level of plasma EBV DNA in stage IV patients with distant metastasis was >9-fold higher than those without systemic spread (p=0.001), suggesting plasma EBV DNA measurement could aid in the diagnosis of metastatic disease in advanced cases. Further, using a cut-off value of 8000 copies/mL, we demonstrate that EBV DNA level is a strong predictor for overall survival of NPC patients. CONCLUSIONS: Our data show that pre-treatment plasma EBV DNA is a potential biomarker for early stage and metastatic NPC. We conclude that the quantification of plasma EBV DNA is a useful tool in developing countries to stratify patients for MRI or PET/CT scans where such imaging protocol is not routinely applied.
Subject(s)
DNA, Viral/blood , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/genetics , Nasopharyngeal Neoplasms/virology , Adolescent , Adult , Aged , Carcinoma , Case-Control Studies , Epstein-Barr Virus Infections/blood , Epstein-Barr Virus Infections/epidemiology , Female , Humans , Kaplan-Meier Estimate , Malaysia/epidemiology , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/epidemiology , Neoplasm Metastasis , Retrospective Studies , Statistics, NonparametricABSTRACT
BACKGROUND: Ribosomal proteins are traditionally associated with protein biosynthesis until recent studies that implicated their extraribosomal functions in human diseases and cancers. Our previous studies using GeneFishing™ DEG method and microarray revealed underexpression of three ribosomal protein genes, RPS26, RPS27, and RPL32 in cancer of the nasopharynx. Herein, we investigated the expression pattern and nucleotide sequence integrity of these genes in nasopharyngeal carcinoma to further delineate their involvement in tumourigenesis. The relationship of expression level with clinicopathologic factors was also statistically studied. METHODS: Quantitative Polymerase Chain Reaction was performed on nasopharyngeal carcinoma and their paired normal tissues. Expression and sequence of these three genes were analysed. RESULTS: All three ribosomal protein genes showed no significant difference in transcript expressions and no association could be established with clinicopathologic factors studied. No nucleotide aberrancy was detected in the coding regions of these genes. CONCLUSION: There is no early evidence to substantiate possible involvement of RPS26, RPS27, and RPL32 genes in NPC tumourigenesis.
