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Background: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are potentially chemopreventive.Objective: We examined the relation between NSAID use and nonmelanoma skin cancer in a population-based case-control study.Methods: NSAID and analgesic use was analyzed in 1484 participants: 535 with squamous cell carcinoma (SCC), 487 with basal cell carcinoma (BCC), and 462 control subjects.Results: Use of NSAIDs, particularly aspirin, was associated with a reduced odds ratio (OR) of SCC, especially tumors positive for p53 (OR 0.29; 95% confidence interval 0.11-0.79) or with PTCH loss of heterozygosity (OR 0.35; 95% confidence interval 0.13-0.96). Although not considered a NSAID, decreased ORs of both basal cell carcinoma and SCC were observed in relation to use of paracetamol (acetaminophen). Risk of BCC was unrelated to NSAID use.Limitations: Self-reported drug use was a limitation.Conclusions: This study supports the hypothesis that NSAIDs, aspirin in particular, may reduce risk of SCC and may affect specific molecular subtypes of SCC. [ABSTRACT FROM AUTHOR]

Oral contraceptives (OCs) affect the risk of several cancers in women, but have been virtually unstudied for squamous cell carcinoma (SCC). We examined the hypothesis that OCs influence SCC risk in a case–control study among women and also examined whether polymorphisms in the DNA repair gene, Xeroderma pigmentosum group D (XPD), modified the risk. Incident cases of SCC were identified by a network of dermatologists and pathology laboratories. Population-based controls were frequency matched to cases by age and gender (n=261 SCC cases, 298 controls). Overall, OC use was associated with a 60% higher risk of SCC (odds ratio (OR), 1.6; 95% confidence interval (95% CI): 1.0–2.5). ORs for SCC were higher among those who last used OCs 25 years before diagnosis (OR: 2.1; 95% CI: 1.2–3.7), and among these women, SCC risk increased with duration of use (OR for 2 years, 1.7; 95% CI: 0.9–3.5; OR for 3–6 years, 2.6; 95% CI: 1.0–6.5; OR for 7 years, 2.7; 95% CI: 0.9–8.5, Ptrend=0.01). Furthermore, the XPD Lys751Gln polymorphism was a significant modifier of the OC-SCC association (Pinteraction=0.03). These findings lead us to hypothesize a potential relationship between OCs and SCC risk, and that this could involve DNA repair pathways. [ABSTRACT FROM AUTHOR]

Summary: The tumor suppressor PTEN encodes a lipid phosphatase that negatively regulates the phosphatidylinositol 3-kinase/AKT cell survival pathway. Mutations of this gene are common in brain, prostate, endometrial, and gastric cancers but occur rarely in non–small-cell lung cancer (NSCLC), although the PTEN protein is often lost in lung tumors. We have studied hypermethylation of the PTEN promoter, loss of heterozygosity (LOH) at microsatellites in chromosome 10q23 (surrounding and intragenic to the PTEN locus), and hypermethylation of PTEN''s highly homologous pseudogene, PTENP1, and their association with PTEN protein loss in a surgical case series study of primary NSCLC. PTEN protein expression was reduced or lost in 74% (86/117) of tumors, with loss occurring more often in well to moderately differentiated tumors. In squamous cell carcinomas, PTEN loss occurred significantly more often in early-stage (stage I or II) disease. PTEN protein loss also occurred more frequently in tumors with low to no aberrant TP53 staining. Methylation of PTEN occurred in 26% (39/151) of tumors, and LOH at 10q23 was rare, occurring in only 19% (17/90) of informative tumors. Neither methylation nor LOH was a significant predictor of PTEN protein expression, although LOH occurred exclusively in early-stage disease. In NSCLC, loss of PTEN protein expression occurs frequently, although the mechanism responsible for loss is not clearly attributable to deletion or epigenetic silencing. PTEN loss may also be a favorable prognostic marker, although further studies are needed to confirm this finding. [Copyright &y& Elsevier]

Abstract: Signature UV-DNA lesions, cyclobutane dimers and 6–4 photoproducts, are repaired via the nucleotide excision repair pathway. NER may be subdivided into transcription-coupled repair and global genome repair, and the XPC protein is specific to this latter repair pathway recognizing helix distorting lesions and initiating their repair. Inactivating XPC mutations are associated with xeroderma pigmentosa and an extremely high risk of skin cancer. A common polymorphism in intron 9 of the XPC gene has been associated with both reduced repair of UV-DNA damage (using the host-cell reactivation assay) and increased risk of squamous cell head and neck cancer. Here, we have tested the hypothesis that the XPC PAT+ polymorphism is associated with non-melanoma skin cancer using a population-based case control study of skin cancer in New Hampshire (n=1917). Overall, there was a modest decreased risk of squamous cell carcinoma (SCC) among those with the homozygous variant PAT+/+ genotype (OR 0.8, 95% CI 0.5–1.1) that was most evident among tanners (OR 0.4, 95% CI 0.1–1.1), however, these trends failed to reach statistical significance. There was no association of the PAT+/+ genotype and basal cell carcinoma (OR 1.0, 95% CO 0.7–1.3), however there was a modest, non-statistically significant, decreased risk among those with the heterozygous genotype (OR 0.8, 95% CI 0.7–1.1). We did not detect gene environment interactions for either SCC or BCC between the XPC PAT genotype and average hours of UV exposure per week, painful sunburn history, nor ionizing radiation therapy. These results suggest that the XPC PAT+polymorphism does not play a major role in non-melanoma skin cancer, but that it may slightly modify the risk of SCC among individuals with a phenotype which results in low UV-DNA adduct burdens. These results require further confirmation. [Copyright &y& Elsevier]

Abstract: Tobacco smoke is well recognized as the major etiological contributor to lung cancer, yet the relationship between tobacco smoke exposure and a specific pattern of molecular abnormalities at somatic loci is less well characterized. We analyzed 100 primary tumors from patients undergoing surgical resection of squamous cell carcinoma and adenocarcinoma of the lung for loss of heterozygosity (LOH) and homozygous deletions at two microsatellite markers in a recombinogenic region of 9p13. We describe the relationship of alterations at these markers with tumor characteristics (both clinical and molecular), patient demographics, survival, and measures of tobacco-smoke exposure. Homozygous deletions in this region occurred in 25% (21/85) and LOH in 33% (28/85) of informative tumors examined. These alterations occurred more often in tumors with intense TP53 protein staining by immunohistochemistry, suggesting that inactivation of the TP53 pathway may contribute to these LOH events. Duration of smoking was greatest in patients with the homozygous deletion, intermediate in patients with LOH, and shortest in patients whose tumor did not demonstrate loss in these markers. Unexpectedly, LOH at 9p13 was a significant predictor of improved survival in patients, while the homozygous deletion was associated with the poorest patient survival. Together, these results suggest that TP53 alteration and long-term tobacco smoke exposure may contribute to genetic alterations at 9p13, and that the mechanism and biologic consequences of allele loss reflect individual biologic differences that determine the extent of loss (LOH or homozygous deletion), such that those patients with the deletion of this region face a more aggressive and deadly disease. [Copyright &y& Elsevier]

Abstract: Functional variants in the methylenetetrahydrofolate reductase (MTHFR) gene, including the 677C>T and 1298A>C polymorphisms, have been associated with a moderately reduced risk of several cancers, including colorectal cancers. While recent studies have investigated the role of these polymorphisms on bladder cancer susceptibility, results have been mixed. To clarify the role of MTHFR polymorphisms on bladder cancer risk, we genotyped MTHFR 677C>T and MTHFR 1298A>C in a population-based study of bladder cancer of 352 patients and 551 controls from New Hampshire, USA. The allelic frequency was 35.6% for MTHFR 677C>T and 40.4% for MTHFR 1298A>C among controls. We found no evidence of a main gene effect for either polymorphism (adjusted OR for MTHFR 677C>T variants versus the reference genotype=1.1; 95% CI, 0.8–1.4 and adjusted OR for MTHFR 1298A>C variants versus the reference genotype=1.0; 95% CI, 0.7–1.4). Odds ratios did not appear to differ by smoking status or gender. We observed differences in the risk estimates for the MTHFR polymorphisms by arsenic exposure, but they were not statistically significant ( for MTHFR 677C>T and for MTHFR 1298A>C). Thus, our findings do not support the presence of a main gene effect. The possibility that MTHFR polymorphism affects susceptibility to environmental exposures warrants further consideration. [Copyright &y& Elsevier]

Metabolites of tobacco smoke constituents can be quantified in urine and other body fluids providing a realistic measure of carcinogen and toxicant dose in a smoker. Many previous studies have demonstrated that these metabolites - referred to as biomarkers in this paper - are related to tobacco smoke exposure. The studies reviewed here were designed to answer another question: are these substances also biomarkers of cancer risk? Using a prospective study design comparing biomarker levels in cancer cases and controls, all of whom were smokers, the results demonstrate that several of these biomarkers - total cotinine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), and total N'-nitrosonornicotine (NNN) - are biomarkers of cancer risk. Therefore, these biomarkers have the potential to become part of a cancer risk prediction algorithm for smokers. [ABSTRACT FROM AUTHOR]

Abstract: Drinking water arsenic exposure has been associated with increased bladder cancer susceptibility. Epidemiologic and experimental data suggest a co-carcinogenic effect of arsenic with exposure to DNA damaging agents, such as cigarette smoke. Recent evidence further supports the hypothesis that genetic variation in DNA repair genes can modify the arsenic–cancer relationship, possibly because arsenic impairs DNA repair capacity. We tested this hypothesis in a population-based study of bladder cancer with XRCC3, ERCC2 genotype/haplotype and arsenic exposure data on 549 controls and 342 cases. Individual exposure to arsenic was determined in toenail samples by neutron activation. Gene–environment interaction with arsenic exposure was observed in relation to bladder cancer risk for a variant allele of the double-strand break repair gene XRCC3 T241M (adjusted OR 2.8 (1.1–7.3)) comparing to homozygous wild type among those in the top arsenic exposure decile (interaction p-value 0.01). Haplotype analysis confirmed the association of the XRCC3 241. Thus, double-strand break repair genotype may enhance arsenic associated bladder cancer susceptibility in the U.S. population. [Copyright &y& Elsevier]

An increasing number of studies report that genus β human papillomaviruses (HPVs) are associated with skin cancer, with suggestions of specificity for squamous cell carcinoma (SCC) of the skin. We have conducted a systematic examination of HPV DNA in tumors from immunocompetent hosts, including SCC and basal cell carcinoma (BCC), using a highly sensitive methodology and population-based samples to test the hypothesis that a differential prevalence of β-HPVs exists between SCC (n=101) and BCC (n=101) tumors. When testing for all known β-HPV types, we found no significant difference in HPV prevalence between the two histologies. However, SCC lesions were significantly more likely to be infected with HPV genus β-species 1 (includes types 5 and 8), than BCC samples (P=0.01); this difference was not observed for any other species. A histologic difference was also observed for those HPV types previously reported to be important in skin cancer (P=0.003). SCC samples showed a higher rate of infectivity (that is, were positive for multiple types) than BCC tumors (P=0.02). These data highlight the potential importance of various genus β-HPV types, in particular genus β-species 1 in SCC, and support the hypothesis of a behavioral difference of the virus within the two major histological skin cancers.Journal of Investigative Dermatology (2008) 128, 2888–2893; doi:10.1038/jid.2008.162; published online 12 June 2008 [ABSTRACT FROM AUTHOR]

The human homolog of the Drosophila Patched gene (PTCH), located at chromosome 9q22.3, is frequently altered in both nevoid basal cell carcinoma syndrome, and sporadic basal cell carcinomas (BCCs). However, alteration of the PTCH gene locus has been poorly studied in squamous cell carcinoma (SCC). We analyzed loss of heterozygosity (LOH) at five markers in and around the PTCH gene in 276 keratinocyte tumors from a population-based study in New Hampshire. We found a high prevalence of any 9q22.3 LOH in both BCC (75.5%) and SCC (60.8%), with BCC being significantly more likely to have LOH than SCC (P<0.009). The PTCH gene was specifically lost in 60% of BCC, and 50% of SCC tumors. Among SCC tumors, 9q22 LOH was significantly more likely to occur in those who tend to burn (P<0.05), and this association was strongest for tumors that occurred on sun-exposed areas of the body (P<0.04). Additionally, 9q22 LOH occurred more frequently in SCC tumors associated with a history of severe sunburns (P<0.08). Thus, in our large, population-based sample, 9q22 loss, including PTCH, was highly prevalent in both BCC and SCC. Overall, these data support the hypothesis that PTCH loss is a common, early lesion for SCC and BCC.Journal of Investigative Dermatology (2006) 126, 1152–1158. doi:10.1038/sj.jid.5700209; published online 16 February 2006 [ABSTRACT FROM AUTHOR]

Abstract: Objective. Male gender, tobacco smoking and occupational exposure to arylamines and polycyclic aromatic hydrocarbons are the primary risk factors for bladder cancer. Emerging, and consistent data indicate that risk may be modified by polymorphisms in carcinogen metabolism genes, including those involving the glutathione-S-transferases. Recent work further suggests that susceptibility to the carcinogenic effects of tobacco on the bladder may differ among men and women. Method. We investigated the gender specific risk of bladder cancer associated with glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms in a population-based case-control study of 354 bladder cancer cases and 542 controls. Results. We found an increased risk of bladder cancer associated with GSTM1 null genotype among women (OR 1.7; 95% CI 1.0–3.0), but not men (OR 0.9; 95% CI 0.7–1.3). Among women, the GSTM1 null genotype was associated with an elevated bladder cancer risk only among smokers (OR 2.3; 95% CI 1.1–4.5 in ever smokers versus OR 0.9; 95% CI 0.3–2.5 in never smokers). There was no apparent association between bladder cancer and the GSTT1 null polymorphism in either men or women, and we did not detect evidence of any GSTT1–smoking or GSTT1–GSTM1 gene–gene interaction. Conclusion. Our data suggest that a subset of women may be particularly susceptible to tobacco-induced bladder cancer. [Copyright &y& Elsevier]

A letter to the editor is presented about the results of a population-based case-control research about the reported use of photosensitizing medications and basal cell carcinoma of the skin.

Non-melanoma skin cancers (NMSCs) are the most common malignancy among US Caucasians. Using a population-based study of NMSC we found that oral steroid use is associated with nearly 6-fold elevated risk of squamous cell carcinoma among individuals with a common genetic variant in the steroid receptor (NR3C1) gene. Given the large numbers of individuals on immunosuppressive drug therapy for inflammatory disease, these findings have important implications for NMSC screening and prevention.Journal of Investigative Dermatology (2007) 127, 1868–1870; doi:10.1038/sj.jid.5700798; published online 29 March 2007 [ABSTRACT FROM AUTHOR]

Purpose: To evaluate cancer incidence among Minnesota taconite mining workers.Methods: We evaluated cancer incidence between 1988 and 2010 in a cohort of 40,720 Minnesota taconite mining workers used between 1937 and 1983. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated by comparing numbers of incident cancers with frequencies in the Minnesota Cancer Surveillance System. SIRs for lung cancer by histologic subtypes were also estimated. We adjusted for out-of-state migration and conducted a probabilistic bias analysis for smoking-related cancers.Results: A total of 5700 cancers were identified, including 51 mesotheliomas and 973 lung cancers. The SIRs for lung cancer and mesothelioma were 1.3 (95% CI = 1.2-1.4) and 2.4 (95% CI = 1.8-3.2), respectively. Stomach, laryngeal, and bladder cancers were also elevated. However, adjusting for potential confounding by smoking attenuated the estimates for lung (SIR = 1.1, 95% CI = 1.0-1.3), laryngeal (SIR = 1.2, 95% CI = 0.8-1.6), oral (SIR = 0.9, 95% CI = 0.7-1.2), and bladder cancers (SIR = 1.0, 95% CI = 0.8-1.1).Conclusions: Taconite workers may have an increased risk for certain cancers. Lifestyle and work-related factors may play a role in elevated morbidity. The extent to which mining-related exposures contribute to disease burden is being investigated. [ABSTRACT FROM AUTHOR]