Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group
Year: 2011
Type: article
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.
Source: BMC Cancer
Institutions: Mayo Clinic, Dana-Farber Cancer Institute, Johns Hopkins University, Indiana University Indianapolis, Indiana University, Princess Margaret Cancer Centre, Princess Margaret Hospital, The University of Texas MD Anderson Cancer Center, Northwestern University, University of Pittsburgh, University of Pittsburgh Medical Center
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,390
Awards: Eastern Cooperative Oncology Group, ECOG Statistical Office Data Management Grant, Eastern Cooperative Oncology Group (Main Institution), Eastern Cooperative Oncology Group, G3895727354, ECOG Clinical Trials, G613628225, Eastern Cooperative Oncology Group, ECOG Specimen Banking, Multidisciplinary Clinical and Translational Science (MCTS) Program (UL1), ECOG Statistical Office, Eastern Cooperative Oncology Group Operations Office, Paul Calabresi Program in Clinical/Translational Research at Mayo Clinic
OpenAlex ID: W2015599354