Risk Of Squamous Cell Carcinoma Of Head And Neck Research Articles

Associations between expression levels of nucleotide excision repair proteins in lymphoblastoid cells and risk of squamous cell carcinoma of the head and neck

Squamous cell carcinoma of head and neck (SCCHN) is one of the most common malignancies worldwide, and nucleotide excision repair (NER) is involved in SCCHN susceptibility. In this analysis of 349 newly diagnosed SCCHN patients and 295 cancer-free controls, we investigated whether expression levels of eight core NER proteins were associated with risk of SCCHN. We quantified NER protein expression levels in cultured peripheral lymphocytes using a reverse-phase protein microarray. Compared with the controls, SCCHN patients had statistically significantly lower expression levels of ERCC3 and XPA (P = 0.001 and 0.001, respectively). After dividing the subjects by controls' median values of expression levels, we found a dose-dependent association between an increased risk of SCCHN and low expression levels of ERCC3 (adjusted OR, 1.75, and 95% CI: 1.26-2.42; Ptrend = 0.008) and XPA (adjusted OR, 1.88; 95% CI, 1.35-2.60; Ptrend = 0.001). We also identified a significant multiplicative interaction between smoking status and ERCC3 expression levels (P = 0.014). Finally, after integrating demographic and clinical variables, we found that the addition of ERCC3 and XPA expression levels to the model significantly improved the sensitivity of the expanded model on SCCHN risk. In conclusion, reduced protein expression levels of ERCC3 and XPA were associated with an increased risk of SCCHN. However, these results need to be confirmed in additional large studies.

Modulation of risk of squamous cell carcinoma head and neck in North Indian population with polymorphisms in xeroderma pigmentosum complementation Group C gene.

Genetic variations in nucleotide excision repair genes can alter the risk of squamous cell carcinoma of head and neck (SCCHN). The present study has genotyped 334 subjects from North Indian population for xeroderma pigmentosum complementation Group C (XPC) rs2228001A>C, XPC rs77907221 polyadenylate (PAT) deletion/insertion (D/I), xeroderma pigmentosum complementation Group D - rs13181A>C, and xeroderma pigmentosum complementation Type G rs17655 G>C polymorphisms with polymerase chain reaction (PCR)-restriction-fragment length polymorphism or allele-specific PCR methods. Compared to D allele, I allele for XPC PAT D/I polymorphism was associated with significantly decreased the risk of SCCHN (odds ratios = 0.67, 95% confidence interval [CI] =0.48-0.94, P = 0.03). Haplotype CI constituted from XPC polymorphisms was also associated with decreased risk of SCCHN (P = 0.004). In contrast, haplotype Crohn's disease significantly increased the risk for SCCHN (P < 0.00). A significant early onset of SCCHN was observed in individuals with CC genotype for XPC A>C polymorphism (P = 0.004). Our results suggest a possible risk modulation for SCCHN with XPC polymorphisms in North Indian population.

Reduced mRNA expression of nucleotide excision repair genes in lymphocytes and risk of squamous cell carcinoma of the head and neck.

Nucleotide excision repair (NER) plays a critical role in the development of smoking-related cancers. We hypothesize that mRNA expression levels of NER genes are associated with risk of the squamous cell carcinoma of head and neck (SCCHN). To test this hypothesis, we conducted a case-control study of 260 SCCHN patients and 246 cancer-free controls by measuring the mRNA expression levels of eight core NER genes in cultured peripheral lymphocytes. Compared with the controls, cases had statistically significantly lower expression levels of DDB1 and ERCC3 (P = 0.015 and 0.041, respectively). Because DDB1 and ERCC3 expression levels were highly correlated, we used DDB1 for further multivariate analyses and modeling. After dividing the subjects by controls' quartiles of expression levels, we found an association between an increased risk of SCCHN and low DDB1 expression levels [adjusted ORs and 95% CIs: 1.92 and 1.11-3.32, 1.48 and 0.85-2.59, 2.00 and 1.15-3.45 for the 2nd-4th quartiles, respectively, compared with the 1st quartile; Ptrend = 0.026]. We also identified a multiplicative interaction between sex and DDB1 expression levels (P = 0.007). Finally, the expanded model with gene expression levels, in addition to demographic and clinical variables, on SCCHN risk was significantly improved, especially among men. In conclusion, reduced DDB1 expression levels were associated with an increased risk of SCCHN. However, these results need to be validated in larger studies.

Reduced expression of DNA repair genes (XRCC1, XPD, and OGG1) in squamous cell carcinoma of head and neck in North India

Squamous cell carcinoma of head and neck (SCCHN) is the sixth most common cancer globally, and in India, it accounts for 30% of all cancer cases. Epidemiological studies have shown a positive association between defective DNA repair capacity and SCCHN. The underlying mechanism of their involvement is not well understood. In the present study, we have analyzed the relationship between SCCHN and the expression of DNA repair genes namely X-ray repair cross-complementing group 1 (XRCC1), xeroderma pigmentosum group D (XPD), and 8-oxoguanine DNA glycosylase (OGG1) in 75 SCCHN cases and equal number of matched healthy controls. Additionally, levels of DNA adduct [8-hydroxyguanine (8-OHdG)] in 45 SCCHN cases and 45 healthy controls were also determined, to ascertain a link between mRNA expression of these three genes and DNA adducts. The relative expression of XRCC1, XPD, and OGG1 in head and neck cancer patients was found to be significantly low as compared to controls. The percent difference of mean relative expression between cases and controls demonstrated maximum lowering in OGG1 (47.3%) > XPD (30.7%) > XRCC1 (25.2%). A negative Spearmen correlation between XRCC1 vs. 8-OHdG in cases was observed. In multivariate logistic regression analysis (adjusting for age, gender, smoking status, and alcohol use), low expression of XRCC1, XPD, and OGG1 was associated with a statistically significant increased risk of SCCHN [crude odds ratios (ORs) (95%CI) OR 2.10; (1.06-4.17), OR 2.76; (1.39-5.49), and 5.24 (2.38-11.52), respectively]. In conclusion, our study demonstrated that reduced expression of XRCC1, XPD, and OGG1 is associated with more than twofold increased risk in SCCHN.

Role of OGG1 Ser326Cys polymorphism and 8-oxoguanine DNA damage in risk assessment of squamous cell carcinoma of head and neck in north Indian population

Squamous cell carcinoma of head and neck (SCCHN), one of the leading cancers worldwide, is most prevalent in Indian sub-continent. The major risk factors involved are smoking and consumption of alcohol, since they provide high free radical generating environment.We studied 8-oxoguanine DNA-glycosylase (OGG1) Ser326Cys polymorphism in 278 SCCHN cases and 278 matched controls by PCR-RFLP and observed that the variant genotype Ser/Cys exhibited an enhanced risk of ∼1.7 folds (OR=1.71, 95% CI=1.20–2.93) and Cys/Cys ∼2.5 folds (OR=2.55, 95% CI=1.29–5.00). Furthermore, we found a significant increase in salivary cell 8-OHdG with respect to Ser/Cys and Cys/Cys genotypes of OGG1 in SCCHN cases, when compared to Ser/Ser and Ser/Cys genotypes of the control population. Our results demonstrate that Ser326Cys variant genotype is associated with an increased risk of SCCHN in north India. Ser326Cys variant genotype was found to accumulate more of 8-OHdG, which may serve as a biomarker for early diagnosis of SCCHN.

Associated risk of XRCC1 and XPD cross talk and life style factors in progression of head and neck cancer in north Indian population

Effective DNA repair machinery ensures maintenance of genomic integrity. Environmental insults, ageing and replication errors necessitate the need for proper DNA repair systems. Any alteration in DNA repair efficacy would play a dominant role in progression of squamous cell carcinoma of head and neck (SCCHN).Genotypes of XRCC1 gene–Arg194Trp, Arg280His, Arg399Gln and XPD Lys751Gln, by PCR-RFLP were studied in 278 SCCHN patients and an equal number of matched healthy controls residing in north India.In XRCC1 polymorphisms, Arg194Trp and Arg399Gln variants showed a reduced risk, whereas, XPD Lys751Gln variants exhibited ∼2-fold increase in SCCHN risk. With XRCC1-Arg280His variants, there was no association with SCCHN risk. Arg399Gln of XRCC1 appears to have a protective role in people those consume alcohol, while XPD Lys751Gln variants indicated ∼2-fold increased risk of SCCHN in all the co-variate groups.Comparison of gene–gene interaction among XRCC1 Arg280His and XPD Lys751Gln suggested enhanced risk of SCCHN by ∼2.3-fold in group one and ∼6.1-fold in group two. In dichotomized groups of this combination, the risk was ∼2.4 times. Haplotype analysis revealed the frequency of C–G–G–G and C–A–G–G to be significantly associated with an increased risk of SCCHN. On the contrary, T–G–A–A significantly diminished the risk. CART analysis results showed that the terminal node that contains homozygous mutants of XPD Lys751Gln and XRCC1 Arg194Trp, wild type of XRCC1 Arg399Gln and homozygous mutant of XRCC1 Arg280His, represent the highest risk group.Our results demonstrate high degree of gene–gene interaction involving DNA repair genes of NER and BER pathways, namely XRCC1 and XPD. This study amply demonstrates positive association of XPD Arg751Gln polymorphism with an increased risk of SCCHN. Further, XRCC1 Arg280His variant though dormant individually, may also contribute to the development of cancer in combination with XPD Arg751Gln.

Modifying effect of MDM4 variants on risk of HPV16‐associated squamous cell carcinoma of oropharynx

The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16-associated squamous cell carcinoma of head and neck (SCCHN). Genotyping was conducted on 3 tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer-free controls that were frequency-matched by age, sex, smoking, and drinking status. None of 3 MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers. The risk of HPV16-associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings.

Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck

Both p53 tumor suppressor and murine double minute 2 (MDM2) oncoprotein are crucial in carcinogenesis. We hypothesized that MDM2 promoter single nucleotide polymorphisms (SNPs) SNP309 T > G, A2164G, and p53 codon 72 are associated with risk and age at onset of squamous cell carcinoma of head and neck (SCCHN). We genotyped these SNPs in a study of 1,083 Caucasian SCCHN cases and 1,090 cancer-free controls. Although none of these SNPs individually had a significant effect on risk of SCCHN, nor did their combined putative risk genotypes (i.e., MDM2 SNP309 GT + GG, 2164 AA, and p53 codon 72 CC), we found that individuals with two to three risk genotypes had significantly increased risk of non-oropharyngeal cancer (OR = 1.42; 95% CI = 1.07-1.88). This increased risk was more pronounced among young subjects, men, smokers, and drinkers. In addition, female patients carrying the MDM2 SNP309 GT and GG genotypes showed a 3-yr (56.7 yr) and 9-yr (51.2 yr) earlier age at onset of non-oropharyngeal cancer (P(trend) = 0.007), respectively, compared with those carrying the TT genotype (60.1 yr). The youngest age (42.5 yr) at onset of non-oropharyngeal cancer was observed in female patients with the combined MDM2 SNP309 GG and p53 codon 72 CC genotypes. The findings suggest that MDM2 SNP309, A2164G, and p53 codon 72 SNPs may collectively contribute to non-oropharyngeal cancer risk and that MDM2 SNP309 individually or in combination with p53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. Further studies with large sample sizes are warranted to validate these results.

Abstract 881: Polymorphisms of PUMA, a BH3-only pro-apoptotic gene, modify risk of squamous cell carcinoma of head and neck associated with HPV16 infection

Abstract PUMA (p53 upregulated modulator of apoptosis) and Noxa (Latin for damage), as well as their common target MCL-1 (myeloid cell leukemia 1), respond to human papillomavirus 16 (HPV16) oncoprotein E6-mediated p53 degradation or E7-mediated pRb inactivation, and therefore may alter cancer susceptibility through the PUMA (Noxa)-MCL1-apoptosis mechanism. In this case-control study of 380 cases and 335 cancer-free matched controls, we evaluated HPV16 seropositivity and two single nucleotide polymorphisms (SNPs) in the promoter region for each gene (rs3810294 and rs2032809 for PUMA, rs4558496 and rs9957673 for Noxa, rs9803935 and rs3738485 for MCL1) to examine their possible associations with risk of squamous cell carcinoma of head and neck (SCCHN). Of the 6 SNPs, both two SNPs of PUMA were significantly associated with 1.5-fold increased SCCHN risk in a dominant model. When we include the HPV16 seropositivity in the model, the risk of SCCHN was significantly increased in an allele-dose effect manner (Ptrend&amp;lt; 0.0001 for each SNP, respectively). Notably, in the site-stratified analysis, oropharyngeal cancer risk was dramatically increased, particularly among minor alleles carriers having the HPV16 L1 seropositivity with OR (95%CI) of 13.8 (5.4-35.5) for rs3810294 and 8.1 (4.3-15.0) for rs2032809 (both Ptrend &amp;lt; 0.0001). These data suggest some synergistic effects between PUMA variants and HPV16 seropositivity on susceptibility to SCCHN, especially in those cases with HPV-related oropharyngeal cancer. Additionally, the modifying effect of PUMA variants on oropharyngeal cancer associated with the HPV16 L1 seropositivity was more predominant in never-smokers, never-drinkers and young subjects. Our results suggest that PUMA promoter polymorphisms, synergistically interacting with HPV16 L1 seropositivity, modify risk of HPV-related oropharyngeal cancer. Further molecular and epidemiologic studies with larger samples are needed to validate our findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 881. doi:10.1158/1538-7445.AM2011-881

The functional IGFBP7 promoter −418G>A polymorphism and risk of head and neck cancer

Insulin-like growth factor binding protein 7 (IGFBP7) functions mostly independent of the IGF signaling pathway and acts as a tumor suppressor in multiple cancers, but roles of IGFBP7 genetic variants in cancer remains unknown. In a hospital-based study of 1065 patients with squamous cell carcinoma of head and neck (SCCHN) and 1112 cancer-free controls of non-Hispanic whites, we investigated associations between two putatively functional IGFBP7 promoter single nucleotide polymorphisms (SNPs) (−702G>C, rs11573014 and −418G>A, rs4075349) and SCCHN risk. A significantly lower SCCHN risk was observed in those subjects carrying −418AG (adjusted OR = 0.82, 95% CI = 0.67–0.99) and −418AG+AA (adjusted OR = 0.82, 95% CI = 0.69–0.99) genotypes than those carrying the −418GG genotype, but not for the −702G>C SNP. However, those subjects carrying two common homozygous genotypes of these two SNPs (−418GG and −702GG) had an increased risk (adjusted OR = 1.21, 95% CI = 1.00–1.46) than did those carrying variant genotypes (−418AG+AA and −702CG+CC). This increased risk was more evident in subgroups of never smokers and subjects with oral cancer. Further functional analysis showed that the IGFBP7 −418A allele had significantly higher promoter and DNA-protein binding activities than did the G allele, suggesting a tumor suppressor role of this allelic change in the SCCHN etiology. We conclude that the functional variant −418G>C in the IGFBP7 promoter is associated with reduced risk of SCCHN, likely by enhancing the IGFBP7 promoter and DNA-protein binding activities. Larger studies are needed to validate our findings.

850 The role of DNA repair gene polymorphisms in the development of radiation-induced late toxicity in prostate cancer patients

Effective DNA repair machinery ensures maintenance of genomic integrity. Environmental insults, ageing and replication errors necessitate the need for proper DNA repair systems. Any alteration in DNA repair efficacy would play a dominant role in progression of squamous cell carcinoma of head and neck (SCCHN).Genotypes of XRCC1 gene–Arg194Trp, Arg280His, Arg399Gln and XPD Lys751Gln, by PCR-RFLP were studied in 278 SCCHN patients and an equal number of matched healthy controls residing in north India.In XRCC1 polymorphisms, Arg194Trp and Arg399Gln variants showed a reduced risk, whereas, XPD Lys751Gln variants exhibited ∼2-fold increase in SCCHN risk. With XRCC1-Arg280His variants, there was no association with SCCHN risk. Arg399Gln of XRCC1 appears to have a protective role in people those consume alcohol, while XPD Lys751Gln variants indicated ∼2-fold increased risk of SCCHN in all the co-variate groups.Comparison of gene–gene interaction among XRCC1 Arg280His and XPD Lys751Gln suggested enhanced risk of SCCHN by ∼2.3-fold in group one and ∼6.1-fold in group two. In dichotomized groups of this combination, the risk was ∼2.4 times. Haplotype analysis revealed the frequency of C–G–G–G and C–A–G–G to be significantly associated with an increased risk of SCCHN. On the contrary, T–G–A–A significantly diminished the risk. CART analysis results showed that the terminal node that contains homozygous mutants of XPD Lys751Gln and XRCC1 Arg194Trp, wild type of XRCC1 Arg399Gln and homozygous mutant of XRCC1 Arg280His, represent the highest risk group.Our results demonstrate high degree of gene–gene interaction involving DNA repair genes of NER and BER pathways, namely XRCC1 and XPD. This study amply demonstrates positive association of XPD Arg751Gln polymorphism with an increased risk of SCCHN. Further, XRCC1 Arg280His variant though dormant individually, may also contribute to the development of cancer in combination with XPD Arg751Gln.

Reduced DNA Repair Capacity for Removing Tobacco Carcinogen–Induced DNA Adducts Contributes to Risk of Head and Neck Cancer but not Tumor Characteristics

Although cigarette smoking and alcohol use are known risk factors for squamous cell carcinoma of head and neck (SCCHN), only a few exposed individuals develop this disease, suggesting an individual susceptibility. In this study, we investigated the associations between genetically determined DNA repair capacity (DRC) for removing tobacco-induced DNA adducts and risk of SCCHN and tumor characteristics. We measured DRC in cultured T lymphocytes using the host-cell reactivation assay in a hospital-based case-control study of 744 SCCHN patients and 753 age-, sex-, and ethnicity-matched cancer-free controls recruited from The University of Texas M.D. Anderson Cancer Center. Patients with SCCHN had significantly lower mean DRC (8.84% +/- 2.68%) than controls (9.97% +/- 2.61%; P < 0.0001), and the difference accounted for approximately 2-fold increased risk of SCCHN [adjusted odds ratio (OR), 1.91; 95% confidence interval (CI), 1.52-2.40] after adjustment for other covariates. Compared with the highest DRC quartile of controls, this increased risk was dose dependent (second highest quartile: OR, 1.40; 95% CI, 0.99-1.98; third quartile: OR, 1.87; 95% CI, 1.34-2.62; and fourth quartile: OR, 2.76; 95% CI, 1.98-3.84, respectively; P(trend) < 0.0001). We also assessed the performance of DRC in risk prediction models by calculating the area of under the receiver operating characteristic curve. The addition of DRC to the model significantly improved the sensitivity of the expanded model. However, we did not find the association between DRC and tumor sites and stages. DRC is an independent susceptibility biomarker for SCCHN risk but not a tumor marker.

Oral health and risk for head and neck squamous cell carcinoma: the Carolina Head and Neck Cancer Study

Recent reports have linked oral health and periodontal disease indicators with increased risk of squamous cell carcinoma of head and neck (SCCHN). Thus far, evidence has been inconclusive; our objective was to study the association between oral health and SCCHN risk in the context of a large population-based study. A population-based case-control study of incident SCCHN, the Carolina Head and Neck Cancer Study was carried out in 2002-2006 in 46 counties in North Carolina. Controls (n = 1,361) were frequency matched with cases (n = 1,289) on age, race, and gender. Oral health was assessed using interview data on tooth loss and mobility, mouthwash use, and frequency of dental visits. Subjects were 26-80 years old (median age = 61). The distribution of tooth loss among controls was 0-5 teeth = 60%; 5-14 = 15%; and 16-28 = 25%. After controlling for covariates, tooth loss did not yield any notable association with SCCHN (16-28 vs. 0-5 lost teeth: OR: 1.21, 95% CI: 0.94, 1.56). Self-reported history of tooth mobility was moderately associated with increased SCCHN risk (OR: 1.33, 95% CI: 1.07, 1.65); however, the association did not persist among never smokers. Routine dental visits were associated with 30% risk reduction (OR: 0.68, 95% CI: 0.53, 0.87). These data provide support for a possible modest association of periodontal disease, as measured by self-reported tooth loss indicators, but not tooth loss per se, with SCCHN risk.

Polymorphisms in metabolizing enzymes and the risk of head and neck squamous cell carcinoma in the Slavic population of the central Europe

The question of susceptibility to squamous cell carcinoma of head and neck (SCCHN) in the environmental context was addressed by analysis of functional polymorphisms in enzymes metabolizing smoke constituents and/or alcohol (CYP2A13, CYP1B1, EPHX1, NQO1, GSTM1, GSTP1, GSTT1, ADH1B and ADH1C). Case-control study of 122 age- and sex-matched pairs of subjects was performed using so far unexplored Central European Slavic population with high level of tobacco and alcohol abuse. Age-, gender-, smoking- and alcohol-adjusted logistic regression failed to demonstrate any significant association of the analyzed polymorphisms with the SCCHN risk. When interactions between potential modifiers of effect, i.e. smoking and alcohol were tested, drinkers seemed to be at lower risk than nondrinkers when carrying the heterozygous genotype Ile/Val in codon 432 of CYP1B1 (OR=0.42; 95% CI=0.21-0.83; p=0.013 vs. OR=1.02; 95% CI=0.34-2.94; p=0.977). Similarly, drinkers were at lower risk than nondrinkers when carrying the heterozygous genotype Pro/Ser in codon 187 of NQO1 (OR=0.41; 95% CI=0.19-0.88; p=0.022 vs. OR=0.96; 95% CI=0.29-3.12; p=0.948). More interestingly, drinkers carrying the rare homozygous genotype Val/Val in codon 350 of ADH1C were at significantly higher risk than nondrinkers carrying this genotype (OR=4.01; 95% CI=1.61-10.01; p=0.003 vs. OR=0.93; 95% CI=0.25-3.57; p=0.919). This result confirmed findings of previously published studies. Smoking did not significantly modify the effect of genotypes. Our data thus demonstrate that genetic susceptibility to SCCHN shall be further followed on populations with different genetic background and lifestyle.

Thiazolidinedione (TZD) exposure and risk of squamous cell carcinoma of head and neck (SCCHN)

1511 Background: Peroxisome proliferator-activated receptor γ (PPARγ), a nucleic acid receptor, heterodimerizes with retinoic acid X receptor (RXR). Ligand activation of RXR leads to decreased proliferation of SCCHN cell lines. TZDs (syn: glitazones), used to treat diabetes mellitus (DM), are ligands for the RXR:PPARγ heterodimer. A retrospective study of diabetics attending the Veterans Affairs (VA) health care system was undertaken to assess the association between TZD exposure and the risk of developing SCCHN. Methods: Data were obtained from the electronic patient database VISN 16 (covering 10 VA institutions) for males aged ≥40 presenting with DM and no prior SCCHN between 10/01/96 and 12/31/03. DM and SCCHN diagnoses were identified using ICD9 codes. Subjects were followed until 12/31/05, and analyzed for SCCHN risk via Cox regression, using time-dependent covariates to model exposure to TZDs, insulin and other anti-DM agents. Results: 130,406 subjects met the study criteria. Median (quartiles) age at DM presentation was 64 (55–72).18.5% were African-American, 61.3% were Caucasian, and 20.2% were other/unknown. The table shows TZD exposure, SCCHN incidence and hazard ratios for SCCHN with exposure to TZD alone or in combination with insulin and other anti-DM agents after adjusting for age, race, BMI, and HbA1C. Conclusions: A 41%-55% reduction in the risk of SCCHN was observed in diabetic subjects treated with TZD alone, with insulin, and with other anti-DM agents. The decrease was statistically significant (P&lt;0.05) for TZD alone and TZD with other agents, but not for TZD with insulin. These findings suggest a protective effect of TZD on the development of SCCHN. The mechanism is not clearly known but possibly mediated through RXR:PPARγ pathway. [Table: see text] No significant financial relationships to disclose.

In vitro Benzo[a]pyrene Diol Epoxide–Induced DNA Adducts and Risk of Squamous Cell Carcinoma of Head and Neck

In this large confirmatory study of 803 patients with squamous cell carcinoma of head and neck (SCCHN) and 839 controls frequency matched by age, sex, and ethnicity, we further examined potential predictors of benzo[a]pyrene diol epoxide (BPDE)-induced adduct levels and their associations with SCCHN risk. BPDE-DNA adduct levels were determined by the (32)P-postlabeling method in peripheral lymphocytes after in vitro challenged by BPDE. We also genotyped for GSTM1 null, GSTT1 null, GSTP1 Ile(105)Val, and GSTP1 Ala(114)Val. Potential predictors of BPDE-DNA adducts were evaluated by stratification and multivariate linear regression analyses and the association between adduct levels and SCCHN risk by multivariate logistic regression analyses. We found that mean BPDE-DNA adduct levels (the relative adduct labeling x 10(7) +/- SD) were significantly higher in cases (77.6 +/- 111.8) than in controls (57.3 +/- 98.3; P < 0.001). Using the median control value (29.22) as a cutoff, 63% of the cases were distributed above this level (adjusted odds ratio, 1.71; 95% confidence interval, 1.39-2.10). A significant dose-response relationship was observed between adduct quartiles and SCCHN risk (P(trend) < 0.001). Multivariate linear regression analysis revealed that ethnicity and smoking were significant predictors of BPDE-DNA adduct levels in controls. In conclusion, we confirmed the previously reported association between in vitro BPDE-induced DNA adduct levels and SCCHN risk, and the assay may help identify individuals at high risk of developing smoking-related cancers.