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Open Access Research article

Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: a retrospective cohort study of the Eastern Cooperative Oncology Group

Harry H Yoon1*, Paul J Catalano2, Kathleen M Murphy3, Todd C Skaar4, Santosh Philips4, Mark Powell2, Elizabeth A Montgomery3, Michael J Hafez3, Steven M Offer1, Geoffrey Liu5, Stephen J Meltzer3, Xifeng Wu6, Arlene A Forastiere3, Al B Benson7, Lawrence R Kleinberg3 and Michael K Gibson8

Author Affiliations

1 Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

2 Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA, 02115, USA

3 Johns Hopkins University, 3400 North Charles Street, Baltimore, MD, 21218, USA

4 Indiana University, 420 University Boulevard, Indianapolis, IN, 46202, USA

5 Princess Margaret Hospital, 190 Elizabeth Street, Toronto, ON, M5G 2C4, Canada

6 MD Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

7 Northwestern University, 710 North Lake Shore Drive, Chicago, IL, 60611, USA

8 University of Pittsburgh Medical Center, 5150 Centre Avenue, 5thfloor, Pittsburgh, PA, 15232, USA

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BMC Cancer 2011, 11:176  doi:10.1186/1471-2407-11-176

Published: 17 May 2011

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.