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. Yoon*, Paul J. Catalano, Kathleen M. Murphy, Todd C. Skaar, Santosh Philips, Mark Powell, Elizabeth A. Montgomery, Michael J. Hafez, Steven M. Offer, Geoffrey Liu, Stephen J. Meltzer, Xifeng Wu, Arlene A. Forastiere, Al B. Benson, Lawrence R. Kleinberg, Michael K. Gibson

*Corresponding author for this work

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number176
JournalBMC cancer
Volume11
DOIs
StatePublished - May 17 2011

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Chemoradiotherapy
DNA Repair
Single Nucleotide Polymorphism
Adenocarcinoma
Cohort Studies
Retrospective Studies
Genotype
Allelic Imbalance
Alleles
Neoplasms
Cisplatin
DNA
Clinical Trials
Esophageal Neoplasms
Multicenter Studies
Radiotherapy
Nucleotides
Odds Ratio
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Yoon, Harry H. ; Catalano, Paul J. ; Murphy, Kathleen M. ; Skaar, Todd C. ; Philips, Santosh ; Powell, Mark ; Montgomery, Elizabeth A. ; Hafez, Michael J. ; Offer, Steven M. ; Liu, Geoffrey ; Meltzer, Stephen J. ; Wu, Xifeng ; Forastiere, Arlene A. ; Benson, Al B. ; Kleinberg, Lawrence R. ; Gibson, Michael K. / Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma : A retrospective cohort study of the Eastern Cooperative Oncology Group. In: BMC cancer. 2011 ; Vol. 11.
@article{92a1da0898fc4bb18cb043fec705d4be,
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-na{\"i}ve 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.",
author = "Yoon, {Harry H.} and Catalano, {Paul J.} and Murphy, {Kathleen M.} and Skaar, {Todd C.} and Santosh Philips and Mark Powell and Montgomery, {Elizabeth A.} and Hafez, {Michael J.} and Offer, {Steven M.} and Geoffrey Liu and Meltzer, {Stephen J.} and Xifeng Wu and Forastiere, {Arlene A.} and Benson, {Al B.} and Kleinberg, {Lawrence R.} and Gibson, {Michael K.}",
year = "2011",
month = "5",
day = "17",
doi = "10.1186/1471-2407-11-176",
language = "English (US)",
volume = "11",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central",

}

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 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, vol. 11, 176. https://doi.org/10.1186/1471-2407-11-176

Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma : A retrospective cohort study of the Eastern Cooperative Oncology Group. / Yoon, Harry H.; Catalano, Paul J.; Murphy, Kathleen M.; Skaar, Todd C.; Philips, Santosh; Powell, Mark; Montgomery, Elizabeth A.; Hafez, Michael J.; Offer, Steven M.; Liu, Geoffrey; Meltzer, Stephen J.; Wu, Xifeng; Forastiere, Arlene A.; Benson, Al B.; Kleinberg, Lawrence R.; Gibson, Michael K.

In: BMC cancer, Vol. 11, 176, 17.05.2011.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic variation in DNA-repair pathways and response to radiochemotherapy in esophageal adenocarcinoma

T2 - A retrospective cohort study of the Eastern Cooperative Oncology Group

AU - Yoon, Harry H.

AU - Catalano, Paul J.

AU - Murphy, Kathleen M.

AU - Skaar, Todd C.

AU - Philips, Santosh

AU - Powell, Mark

AU - Montgomery, Elizabeth A.

AU - Hafez, Michael J.

AU - Offer, Steven M.

AU - Liu, Geoffrey

AU - Meltzer, Stephen J.

AU - Wu, Xifeng

AU - Forastiere, Arlene A.

AU - Benson, Al B.

AU - Kleinberg, Lawrence R.

AU - Gibson, Michael K.

PY - 2011/5/17

Y1 - 2011/5/17

N2 - 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.

AB - 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.

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