Abstract 4673: Host genetic polymorphisms at TIMP3 are associated with survival of patients with adenocarcinoma of esophagus and gastoeophageal junction
Authors: Bashash Morteza , Shah Amil , Hislop T Greg , Le Nhu , Brooks-Wilson Angela , Bajdik Chris 
Published: June 2012

BACKGROUND: During the past two decades, several countries have experienced a dramatic increase in adenocarcinoma incidence for both the esophagus and gastroesophageal junction (GEJ). Because of this increase and generally poor survival, distal esophageal and GEJ adenocarcinomas are important in cancer research. Similarities and shared prognostic factors suggest these cancers can be considered a single neoplastic entity in many contexts. The American Joint Committee on Cancer (AJCC) Cancer Staging Manual uses “single-stage grouping” across the entire lower esophagus and GEJ area. The current study was conducted to examine the effect of polymorphism at TIMP and MMP genes as a host-related prognosis factor.

METHODS: This study used a prospective cohort of patients with adenocarcinoma of the esophagus and GEJ in British Columbia (BC) admitted to the BC Cancer Agency (BCCA). Germline DNA was extracted from patients’ blood or saliva. Selected SNPs were genotyped using Sequenom multiplex iPLEX Gold assays. Patient characteristics and clinical information were obtained from BCCA medical charts and preadmission questionnaires. Cox proportional hazards regression was used to estimate the effect of SNPs adjusted for patient age, tumour location, disease stage and treatment received. P-values less than 0.05 were considered statistically significant. The false discovery rate (FDR) method was applied to address multiple comparisons.

RESULTS: 4 genetic polymorphism at TIMP3 gene were associated with survival of patients. These associations were also observed after adjustment for patient age, tumour location, disease stage and treatment received. A SNP in the promoter region of TIMP3 (rs1962223) was associated with about a 3-fold increase in the HR for patients who carried the CG genotype. A tagSNP (rs130274) showed a more than 3-fold increased HR for the dominant and codominant models and 2-fold increased HR for the additive model. A tagSNP (rs715572) was associated with about a 3-fold increased HR for the dominant and codominant models and a 2-fold reduction in the HR for the additive model. Finally, a tagSNP (rs5754312) was associated with a 4-fold reduction in the HR in the recessive and codominant model, and a 2-fold reduction in the HR for the additive model, In haplotype analysis, a block including rs5754312 and rs715572 showed significant association with the patients’ survival (p=0.002).

CONCLUSION: Adenocarcinoma of the esophagus and GEJ are deadly diseases that are often diagnosed at a stage when the treatment options are limited and have limited effectiveness. Modeling survival based on host factors including genetic polymorphisms is an emerging field in cancer research. Compared to tumour, the patient's constitutional genetic material is relatively easy to obtain, and can be assessed before treatment is started.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2011-4673