title: Genetic polymorphisms at TIMP3 are associated with survival of adenocarcinoma of the gastroesophageal junction.
abstract: The poor survival of adenocarcinomas of the gastroesophageal junction (GEJ) makes them clinically important. Discovery of host genetic factors that affect outcome may guide more individualized treatment. This study tests whether constitutional genetic variants in matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) genes are associated with outcome of GEJ adenocarcinoma. Single nucleotide polymorphisms (SNPs) at four TIMP (TIMP1-4) and three MMP genes (MMP2, MMP7 and MMP9) were genotyped in DNA samples from a prospective cohort of patients with primary adenocarcinoma of the GEJ admitted to the British Columbia Cancer Agency. Cox proportional hazards regression, with adjustment for patient, disease and treatment variables, was used to estimate the association of SNPs with survival. Genotypes for 85 samples and 48 SNPs were analyzed. Four SNPs across TIMP3, (rs130274, rs715572, rs1962223 and rs5754312) were associated with survival. Interaction analyses revealed that the survival associations with rs715572 and rs5754312 are specific and significant for 5FU+cisplatin treated patients. Sanger sequencing of the TIMP3 coding and promoter regions revealed an additional SNP, rs9862, also associated with survival. TIMP3 genetic variants are associated with survival and may be potentially useful in optimizing treatment strategies for individual patients.
authors.affiliation: Cancer Control Research Program, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Morteza
authors.initials: M
authors.lastname: Bashash
authors.forename: Amil
authors.initials: A
authors.lastname: Shah
authors.forename: Greg
authors.initials: G
authors.lastname: Hislop
authors.forename: Martin
authors.initials: M
authors.lastname: Treml
authors.forename: Karla
authors.initials: K
authors.lastname: Bretherick
authors.forename: Rozmin
authors.initials: R
authors.lastname: Janoo-Gilani
authors.forename: Stephen
authors.initials: S
authors.lastname: Leach
authors.forename: Nhu
authors.initials: N
authors.lastname: Le
authors.forename: Chris
authors.initials: C
authors.lastname: Bajdik
authors.forename: Angela
authors.initials: A
authors.lastname: Brooks-Wilson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D023061:Gene Order; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000737:chemistry / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3