title: Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group.
abstract: BACKGROUND
  Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy. However, this SNP has not been assessed in a histologically homogeneous clinical trial cohort that has been treated with a uniform approach. In addition, whether germline DNA may serve as a surrogate for tumor genotype at this locus is unknown in this disease. Our objective was to assess this SNP in relation to the pathologic complete response (pCR) rate in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy in a multicenter clinical trial (Eastern Cooperative Oncology Group 1201). As a secondary aim, we investigated the rate of allelic imbalance between germline and tumor DNA.
  
  
  METHODS
  Eighty-one eligible treatment-naïve subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP.
  
  
  RESULTS
  The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs.
  
  
  CONCLUSIONS
  Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus.
authors.affiliation: Mayo Clinic, Rochester, MN 55905, USA. yoon.harry@mayo.edu
authors.forename: Harry H
authors.initials: HH
authors.lastname: Yoon
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Catalano
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.forename: Santosh
authors.initials: S
authors.lastname: Philips
authors.forename: Mark
authors.initials: M
authors.lastname: Powell
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Montgomery
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hafez
authors.forename: Steven M
authors.initials: SM
authors.lastname: Offer
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
authors.forename: Arlene A
authors.initials: AA
authors.lastname: Forastiere
authors.forename: Al B
authors.initials: AB
authors.lastname: Benson
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: Kleinberg
authors.forename: Michael K
authors.initials: MK
authors.lastname: Gibson
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D002945:Cisplatin