title: Genetic and epigenetic alterations of WWOX in the development of gastric cardia adenocarcinoma.
abstract: WWOX is a tumor suppressor gene that maps to the common fragile site FRA16D and is involved in carcinogenesis and cancer progression in many different carcinomas. Reduced WWOX expression is associated with more aggressive phenotypes and poor patient outcomes in several cancers. The present study was conducted in order to elucidate more precisely the genetic and epigenetic alterations of WWOX that play a role in gastric cardia adenocarcinoma (GCA) carcinogenesis in a population from Northern China. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), PCR-simple sequence length polymorphism (PCR-SSLP), and methylation specific PCR (MSP) methods were used to characterize polymorphisms in the rs3764340, rs2548861, and rs1079635 loci, the level of loss of heterozygosity (LOH), and methylation status of WWOX, respectively. Protein and mRNA expression of WWOX in GCA tissues was quantified by immunohistochemistry and reverse transcription-PCR (RT-PCR). Family history of upper gastrointestinal cancer (UGIC) significantly increased the risk of developing GCA. The CG+GG genotype of rs3764340 and GT or TT genotype of rs2548861 significantly elevated the risk of developing GCA. LOH at the WWOX locus was observed in 45.6% tumors. The promoter and exon 1 methylation frequency of WWOX in GCA tissues was significantly higher than in corresponding normal tissues and was associated with UGIC family history. Protein and mRNA expression of WWOX was reduced in GCA tumor tissues and was associated with LOH and methylation of the gene. These results indicate that WWOX may play an important role in GCA especially in individuals with UGIC family history.
authors.affiliation: Department of Laboratory of pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Dong
authors.forename: Yuran
authors.initials: Y
authors.lastname: Dong
authors.forename: Yanli
authors.initials: Y
authors.lastname: Guo
authors.forename: Gang
authors.initials: G
authors.lastname: Kuang
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yang
mesh_terms: D002299:Cardia / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002681:China / Q000453:epidemiology; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D019656:Loss of Heterozygosity; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D012150:Polymorphism, Restriction Fragment Length; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human