4-Nitroquinoline-1-Oxide-Induced Mutagen Sensitivity and Risk of Nonmelanoma Skin Cancer: A Case–Control Analysis

Abstract

The UV radiation-mimetic chemical 4-nitroquinoline-1-oxide (4-NQO) is thought to induce squamous cell carcinoma (SCC) similar to those induced by UV radiation in animals. Therefore, we tested the hypothesis that cellular sensitivity to 4-NQO is associated with risk of developing skin cancer in a case-control study of 191 patients with nonmelanoma skin cancer (NMSC; 81 SCC and 110 basal cell carcinoma (BCC)) and 176 cancer-free controls. Short-term blood cultures were treated with 4-NQO at a final concentration of 10 microM for 24 hours and scored for chromatid breaks in 50 well-spread metaphases. We found that the mean frequency of chromatid breaks per cell (b/c) was significantly higher in the cases (mean+/-SD, 0.46+/-0.43 for SCC and 0.43+/-0.38 for BCC) than in the controls (0.25+/-0.25; P<0.001 for both comparisons) and were associated with more-than-twofold increased risk for both SCC and BCC after adjustment for known risk factors. Therefore, our findings support the notion that sensitivity to 4-NQO reflects susceptibility to UV-induced NMSC. However, there is a lack of correlation between UVB-induced b/c and 4-NQO-induced b/c in this study population. Therefore, these findings need to be verified by additional studies.

4-Nitroquinoline-1-oxide-induced mutagen sensitivity and risk of cutaneous melanoma

“…It was apparent that these risk factors, except for eye color and family history of skin cancer, were associated with a significantly increased risk of CM in this analysis (Table 1). Most of these known risk factors were statistically correlated with each other as expected, similar to what was reported previously for this study population [13]. For example, in 176 control participants, number of sunburns was highly correlated with hair color ( r = 0.191, P = 0.012), eye color ( r = 0.212, P = 0.005), skin color ( r = 0.227, P = 0.003), tanning ability ( r = 0.326, P < 0.001), and freckling in the sun ( r = 0.357, P < 0.001).…”

“…The mutagen sensitivity was expressed as the number of 4-NQO-induced chromatid b/c after cells were treated for 24 h [11–13]. Briefly, short-term cultures of 1 ml of fresh whole blood were established in 9 ml of RPMI 1640 medium supplemented with 20 v/v% fetal bovine serum and phytohemagglutinin (Remel, Lenexa, Kansas, USA) at a final concentration of 112.5 µg/ml to stimulate T-lymphocyte growth.…”

“…All statistical tests were two sided, and P less than 0.05 was considered statistically significant. We analyzed all data, except for additive models, using SAS software (version 9.2; SAS Institute, Cary, North Carolina, USA) [13,14]. …”

Chromosome Instability and Risk of Squamous Cell Carcinomas of Head and Neck

“…In a recent pilot study of the correlation between in vitro BPDE-induced DNA damage and repair (measured by the comet assay) and chromosomal aberrations in primary lymphocytes of 136 cancer-free controls, we found that there was a weak correlation (r = 0.163; P = 0.009) between measurements of Olive tail moment (single DNA strand breaks) and frequencies of chromatid breaks per cell (i.e., mutagen sensitivity) (ref. 25).…”

“…Because Dr. T. C. Hsu developed the mutagen sensitivity assay with bleomycin as an effective inducer of chromosomal aberrations in vitro, this assay has been widely used in epidemiologic studies to assess genetic susceptibility to various types of cancer. The assay has been modified with a variety of etiologically related challenge mutagens to evaluate cancer susceptibility in association studies, such as BPDE for tobacco-related cancers of the lung (4,(6)(7)(8) and SCCHN (9-11), g-radiation for glioma (22,23), and UV light or 4-nitroquinoline-1-oxide for skin cancer (24,25). These studies have consistently showed that in vitro induced mutagen sensitivity phenotype is a risk factor for developing cancers.…”