Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

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

Yoon, HH and Catalano, PJ and Murphy, KM and Skaar, TC and Philips, S and Powell, M and Montgomery, EA and Hafez, MJ and Offer, SM and Liu, G and Meltzer, SJ and Wu, X and Forastiere, AA and Benson, AB and Kleinberg, LR and Gibson, MK (2011) Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma: A retrospective cohort study of the Eastern Cooperative Oncology Group. BMC Cancer, 11.

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (349kB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

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. © 2011 Yoon et al; licensee BioMed Central Ltd.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Yoon, HH
Catalano, PJ
Murphy, KM
Skaar, TC
Philips, S
Powell, M
Montgomery, EA
Hafez, MJ
Offer, SM
Liu, G
Meltzer, SJ
Wu, X
Forastiere, AA
Benson, AB
Kleinberg, LR
Gibson, MK
Date: 17 May 2011
Date Type: Publication
Journal or Publication Title: BMC Cancer
Volume: 11
DOI or Unique Handle: 10.1186/1471-2407-11-176
Schools and Programs: School of Medicine > Radiation Oncology
Refereed: Yes
Date Deposited: 28 Oct 2016 17:55
Last Modified: 29 Jan 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/30062

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item