Significant effect of homologous recombination DNA repair gene polymorphisms on pancreatic cancer survival.
Genetic variation in DNA repair may affect the clinical response to cytotoxic therapies. We investigated the effect of six single nucleotide polymorphisms of the RecQ1, RAD54L, XRCC2, and XRCC3 genes on overall survival of 378 patients with pancreatic adenocarcinoma who were treated at University of Texas M.D. Anderson Cancer Center during February 1999 to October 2004 and were followed up to October 2005. Genotypes were determined using the MassCode method. Survival was determined from pathologic diagnosis to death. Patients who were alive at the last follow-up evaluation were censored at that time. Kaplan-Meier plot, log-rank test, and Cox regression were used to compare overall survival by genotypes. A significant effect on survival of all patients was observed for RecQ1 and RAD54L genes. The median survival time was 19.2, 14.7, and 13.2 months for the RecQ1 159 AA, AC, and CC genotypes, and 16.4, 13.3, and 10.3 months for RAD54L 157 CC, CT, and TT genotypes, respectively. A significantly reduced survival was associated with the variant alleles of XRCC2 R188H and XRCC3 A17893G in subgroup analysis. When the four genes were analyzed in combination, an increasing number of adverse alleles were associated with a significantly decreased survival. Subgroup analyses have shown that the genotype effect on survival was present among patients without metastatic disease or among patients who receive radiotherapy. These observations suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly affect the clinical outcome of patients with pancreatic cancer.
Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1402, USA. dli@mdanderson.org
Donghui
D
Li
Hui
H
Liu
Li
L
Jiao
David Z
DZ
Chang
Garth
G
Beinart
Robert A
RA
Wolff
Douglas B
DB
Evans
Manal M
MM
Hassan
James L
JL
Abbruzzese
D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D004265:DNA Helicases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D053484:RecQ Helicases; D011995:Recombination, Genetic; D015996:Survival Rate
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C110901:X-ray repair cross complementing protein 3; C113187:XRCC2 protein, human; D000251:Adenosine Triphosphatases; C506725:RECQL protein, human; D004265:DNA Helicases; C103532:RAD54L protein, human; D053484:RecQ Helicases