title: DNA repair gene and MTHFR gene polymorphisms as prognostic markers in locally advanced adenocarcinoma of the esophagus or stomach treated with cisplatin and 5-fluorouracil-based neoadjuvant chemotherapy.
abstract: BACKGROUND
  DNA repair plays an important role in chemoresistance to platinum-based therapy, and therefore polymorphisms in the genes may modulate therapeutic response. We assessed 12 polymorphisms in 7 DNA repair genes and 2 polymorphisms in the MTHFR gene for association with disease response and prognosis.
  
  
  METHODS
  A total of 258 patients included in the study had adenocarcinoma of the esophagus (n = 114) or gastric cancer (n = 144), at stage cT3/4 and cM0, and had been treated with platinum-based neoadjuvant polychemotherapy. The patients were genotyped for polymorphisms in the XPC, XPD, XPG, APEX, XRCC1, NBS1, XRCC3, and MTHFR genes by the allelic discrimination method and the data correlated with various clinical parameters.
  
  
  RESULTS
  None of the investigated polymorphisms was associated with histopathological response. XRCC3 polymorphisms rs861539 (P = 0.02) and rs861530 (P = 0.05) showed association with clinical response in gastric cancer. The variants in XRCC3 (rs861539, P = 0.05; rs1799794, P = 0.03) and MTHFR (rs1801131, P = 0.02) were associated with survival in esophageal and gastric cancer, respectively. In R0 resected patients, XRCC3 variants (rs861539, P = 0.04; rs861530, P = 0.02) in esophageal cancer, and XRCC3 (rs1799794, P = 0.02) and MTHFR (rs1801131, P = 0.005) in gastric cancer predicted survival. Cox regression revealed ypT category (P = 0.001) and lymphatic vessel invasion (P = 0.03) to be independent prognostic factors for esophageal cancer, and histopathological response (P = 0.01), MTHFR variant (rs1801131, P = 0.002), and ypN category (P = 0.02) to be prognostic factors for gastric cancer.
  
  
  CONCLUSIONS
  In gastric cancer patients, MTHFR variant (rs1801131) could serve as a potential prognostic marker. In esophageal cancer patients, none of the polymorphisms studied had conclusive results in multivariate analysis, although XRCC3 variant (rs861539) showed an effect on survival in Kaplan-Meier univariate analysis.
authors.affiliation: Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Ott
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.forename: Benjamin
authors.initials: B
authors.lastname: Panzram
authors.forename: Gisela
authors.initials: G
authors.lastname: Keller
authors.forename: Florian
authors.initials: F
authors.lastname: Lordick
authors.forename: Karen
authors.initials: K
authors.lastname: Becker
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Markus
authors.initials: M
authors.lastname: Buechler
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D017322:Clinical Trials, Phase II as Topic; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D004273:DNA, Neoplasm; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002945:Cisplatin; D005472:Fluorouracil