Polymorphisms in genes related to oxidative stress (CAT, MnSOD, MPO, and eNOS) and acute toxicities from radiation therapy following lumpectomy for breast cancer.
OBJECTIVE
Because radiotherapy exerts cytotoxic effects via generation of massive oxidative stress, we hypothesized that catalase, manganese superoxide dismutase, myeloperoxidase (MPO), and endothelial nitric oxide synthase (eNOS) genotypes might result in greater risk of radiotoxicity.


METHODS
Cases (n = 446) were Caucasian women with breast cancer who received radiotherapy following lumpectomy. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight. The development of acute reactions (moist desquamation) associated with genotypes was modeled using the Cox proportional hazards model, accounting for cumulative biologically effective radiation dose.


RESULTS
Genotypes associated with higher levels of reactive oxygen species (ROS) were not associated with risk of radiotoxicity. However, relationships between overweight/obesity [body mass index (BMI), >25] and radiotoxicity risk seemed to be modified by eNOS and MPO genotypes associated with higher generation of nitric oxide and ROS, respectively. Women with high BMI (>25) and eNOS GG genotypes were at more than a 6-fold increase in risk (hazard ratio, 6.39; 95% confidence interval, 2.53-16.15) compared with those with BMI <25, and for MPO, those with high BMI (>25) and GG genotypes also had greater risk of radiotoxicity (hazard ratio, 3.61; 95% confidence interval, 1.78-7.35) compared with those with BMI <25. Overweight/obesity was not a strong risk factor among women with other eNOS and MPO genotypes. Exploratory analysis using classification and regression trees indicated that total number of risk alleles contributed, in part, to acute toxicity outcomes among a subgroup of women.


CONCLUSIONS
Associations between BMI and radiotoxicity risk may be most apparent among women with genotypes related to higher levels of oxidative stress. Regression trees may be useful in future studies to examine the contributions of multiple factors to individual susceptibility to adverse effects of cancer treatment.
Ahn
Jiyoung
J
Division of Cancer Prevention and Population Science, Department of Epidemiology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Ambrosone
Christine B
CB
Kanetsky
Peter A
PA
Tian
Chunqiao
C
Lehman
Teresa A
TA
Kropp
Silke
S
Helmbold
Irmgard
I
von Fournier
Dietrich
D
Haase
Wulf
W
Sautter-Bihl
Marie Luise
ML
Wenz
Frederik
F
Chang-Claude
Jenny
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D002374:Catalase / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005838:Genotype; D006801:Humans; D015412:Mastectomy, Segmental / Q000379:methods; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D018384:Oxidative Stress; D009195:Peroxidase / Q000235:genetics*; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011878:Radiotherapy / Q000009:adverse effects*; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000235:genetics*
D002374:Catalase; D009195:Peroxidase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase