Submitted May 9, 2006
Accepted December 21, 2006
Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials
Nataliya Kuptsova, Kenneth J. Kopecky, John Godwin, Jeanne Anderson, Ashraful Hoque, Cheryl L. Willman, Marilyn L. Slovak, and Christine B. Ambrosone*
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, United States
Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Southern Illinois University School of Medicine, Springfield, IL, United States
Katmai Oncology Group, Anchorage, AK, United States
UT MD Anderson Cancer Center, Houston, TX, United States
University of New Mexico, Albuquerque, NM, United States
Department of Cytogenetics, City of Hope National Medical Center, Duarte, CA, United States
* Corresponding author; email: christine.ambrosone{at}roswellpark.org.
Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD and XRCC3, in predicting therapeutic outcomes of older adult AML patients from two Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (OR=3.06 (95% CI: 1.44-6.70)) and less likely to have resistant disease (OR=0.32 (95%CI: 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P=.037) and metabolic (P=.041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (odds ratio [OR]=0.32, 95%CI: 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may impact both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.
