ABSTRACT
BACKGROUND: Genetic loci within the major histocompatibility complex (MHC) have been associated with nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-associated cancer, in several GWAS. Results outside this region have varied. METHODS: We conducted a meta-analysis of four NPC GWAS among Chinese individuals (2,152 cases; 3,740 controls). Forty-three noteworthy findings outside the MHC region were identified and targeted for replication in a pooled analysis of four independent case-control studies across three regions in Asia (4,716 cases; 5,379 controls). A meta-analysis that combined results from the initial GWA and replication studies was performed. RESULTS: In the combined meta-analysis, rs31489, located within the CLPTM1L/TERT region on chromosome 5p15.33, was strongly associated with NPC (OR = 0.81; P value 6.3 × 10(-13)). Our results also provide support for associations reported from published NPC GWAS-rs6774494 (P = 1.5 × 10(-12); located in the MECOM gene region), rs9510787 (P = 5.0 × 10(-10); located in the TNFRSF19 gene region), and rs1412829/rs4977756/rs1063192 (P = 2.8 × 10(-8), P = 7.0 × 10(-7), and P = 8.4 × 10(-7), respectively; located in the CDKN2A/B gene region). CONCLUSIONS: We have identified a novel association between genetic variation in the CLPTM1L/TERT region and NPC. Supporting our finding, rs31489 and other SNPs in this region have been reported to be associated with multiple cancer sites, candidate-based studies have reported associations between polymorphisms in this region and NPC, the TERT gene has been shown to be important for telomere maintenance and has been reported to be overexpressed in NPC, and an EBV protein expressed in NPC (LMP1) has been reported to modulate TERT expression/telomerase activity. IMPACT: Our finding suggests that factors involved in telomere length maintenance are involved in NPC pathogenesis.
Subject(s)
Genetic Loci , Genetic Predisposition to Disease , Membrane Proteins/genetics , Nasopharyngeal Neoplasms/genetics , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Telomerase/genetics , Asian People , Carcinoma , Case-Control Studies , Genome-Wide Association Study , Haplotypes , Humans , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/pathology , PrognosisABSTRACT
OBJECTIVE: To analyze the allelic loss of heterozygosity (LOH) in the region of chromosome 4p15.1-4q12 in nasopharyngeal carcinoma (NPC) patients with family history. METHODS: Tumor cells and lymphocytes were obtained from paraffin-embedded biopsied tissue section by microdissection. LOH detections were carried out on 25 NPC patients with family history by PCR-based microsatellite polymorphism analysis using 7 pairs of microsatellite markers primers. The microsatellite loci located in 4p15.1-4q12 region. Genescan software was used to analyse LOH at each locus. RESULTS: Ninety-two percent of NPC cases (23/25) with family history was showed at least one microsatellite marker of LOH. Higher frequencies of LOH were found at three loci: D4S238 (56%), D4S350 (50%), D4S1547 (50%). The minimal common region of deletion might be defined between D4S350 and D4S1547. CONCLUSION: The higher incidence of LOH at D4S350 and D4S1547 suggests that there may be a potential tumor suppressor gene located in the two regions.
