Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer

Xifeng Wu, Jian Gu, Tsung Teh Wu, Stephen G. Swisher, Zhongxin Liao, Arlene M. Correa, Jun Liu, Carol J. Etzel, Christopher I. Amos, Maosheng Huang, Silvia S. Chiang, Luke Milas, Walter N. Hittelman, Jaffer A. Ajani

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Purpose: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. Methods: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. Results: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). Conclusion: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

Original languageEnglish (US)
Pages (from-to)3789-3798
Number of pages10
JournalJournal of Clinical Oncology
Volume24
Issue number23
DOIs
StatePublished - Aug 10 2006
Externally publishedYes

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Critical Pathways
Esophageal Neoplasms
Alleles
Radiation
Drug Therapy
Survival
Genotype
Recurrence
Fluorouracil
DNA Repair
Pharmaceutical Preparations
Odds Ratio
Genes
Genetic Polymorphisms
Platinum
Proportional Hazards Models
Single Nucleotide Polymorphism
Survival Rate
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. / Wu, Xifeng; Gu, Jian; Wu, Tsung Teh; Swisher, Stephen G.; Liao, Zhongxin; Correa, Arlene M.; Liu, Jun; Etzel, Carol J.; Amos, Christopher I.; Huang, Maosheng; Chiang, Silvia S.; Milas, Luke; Hittelman, Walter N.; Ajani, Jaffer A.

In: Journal of Clinical Oncology, Vol. 24, No. 23, 10.08.2006, p. 3789-3798.

Research output: Contribution to journalArticle

Wu, X, Gu, J, Wu, TT, Swisher, SG, Liao, Z, Correa, AM, Liu, J, Etzel, CJ, Amos, CI, Huang, M, Chiang, SS, Milas, L, Hittelman, WN & Ajani, JA 2006, 'Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer', Journal of Clinical Oncology, vol. 24, no. 23, pp. 3789-3798. https://doi.org/10.1200/JCO.2005.03.6640
Wu, Xifeng ; Gu, Jian ; Wu, Tsung Teh ; Swisher, Stephen G. ; Liao, Zhongxin ; Correa, Arlene M. ; Liu, Jun ; Etzel, Carol J. ; Amos, Christopher I. ; Huang, Maosheng ; Chiang, Silvia S. ; Milas, Luke ; Hittelman, Walter N. ; Ajani, Jaffer A. / Genetic variations in radiation and chemotherapy drug action pathways predict clinical outcomes in esophageal cancer. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 23. pp. 3789-3798.
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abstract = "Purpose: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. Methods: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. Results: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95{\%} CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26{\%} and 46.43{\%}, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95{\%} CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95{\%} CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95{\%} CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95{\%} CI, 1.00 to 3.72). Conclusion: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.",
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AU - Gu, Jian

AU - Wu, Tsung Teh

AU - Swisher, Stephen G.

AU - Liao, Zhongxin

AU - Correa, Arlene M.

AU - Liu, Jun

AU - Etzel, Carol J.

AU - Amos, Christopher I.

AU - Huang, Maosheng

AU - Chiang, Silvia S.

AU - Milas, Luke

AU - Hittelman, Walter N.

AU - Ajani, Jaffer A.

PY - 2006/8/10

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N2 - Purpose: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. Methods: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. Results: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). Conclusion: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

AB - Purpose: Understanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy. Methods: We applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients. Results: In the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72). Conclusion: Several biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

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