Cutaneous alpha, beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: a population-based study.

Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta-analysis of the available literature. In a population-based case-control study from New Hampshire, USA (n = 1,408), histologically confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2-5, 7-10, 15, 17, 20, 23, 24, 27b, 36, 38, 48-50, 57, 65, 75-77, 88, 92, 95, 96, 101, 103 and 107 using multiplex serology. An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (p for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07-3.56) for four or more beta types positive. In a meta-analysis of six case-control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies (meta odds ratio = 1.45, CI = 1.27-1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.

Analgesic and nonsteroidal anti-inflammatory use in relation to nonmelanoma skin cancer: a population-based case-control study.

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.

A role for ultraviolet radiation immunosuppression in non-melanoma skin cancer as evidenced by gene-environment interactions.

The genotoxic effects of ultraviolet (UV) radiation are well-known causes of skin cancers; however, UV radiation also suppresses the immune system, decreasing the body's surveillance for tumor cells. In experimental systems, UV radiation immunosuppression is at least partially mediated through urocanic acid (UCA), an UV radiation-absorbing molecule in the stratum corneum. We tested the hypothesis that genetic variation in the histidase gene (HAL), which catalyzes the formation of UCA in the skin, modifies risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in a population-based study (914 BCC, 702 SCC and 848 controls). We observed no evidence of a main gene effect for the HAL I439V polymorphism (rs7297245) and BCC or SCC. However, we found a HAL genotype-sunburn interaction in association with BCC (P for interaction = 0.040) and SCC (P for interaction = 0.018). A HAL genotype-SCC association was observed primarily among women (odds ratio = 1.5, 95% confidence interval 1.1-2.2), and among women, we found an interaction between HAL genotype and oral contraceptive use on SCC risk (P = 0.040). The variant HAL allele likewise appeared to modify the SCC risk associated with glucocorticoid steroid usage (P for interaction = 0.0004). In conclusion, our findings are a first step in determining the genetic underpinnings of UV immune suppression and have identified important new genetic interactions contributing to the etiology of skin cancer.

Tea consumption and basal cell and squamous cell skin cancer: results of a case-control study.

BACKGROUND: Tea constituents, including polyphenols, are hypothesized to have chemopreventive properties, and inhibit the induction of skin cancers in animal models. OBJECTIVE: To explore the association between regular tea consumption (>or=1 cup/d for >or=1 month) and the incidence of squamous cell (SCC) and basal cell (BCC) carcinomas. METHODS: A population-based case-control study of 770 individuals with BCC, 696 with SCC, and 715 age- and sex-matched control subjects. RESULTS: After adjustment for age, sex, and lifetime history of painful sunburns, ever having consumed tea regularly was associated with a significantly lower risk of SCC (odds ratio [OR] = 0.70; 95% confidence interval [CI] 0.53-0.92), especially among long-term drinkers (>or=47 years consumption: SCC, OR = 0.49; 95% CI 0.29-0.83; P for trend = .008) and among those consuming >or=2 cups/d (OR = 0.65; 95% CI 0.44-0.96; P for trend = 0.013). After adjustment for age and sex, ever having consumed tea regularly was weakly associated with BCC risk (OR = 0.79; 95% CI 0.63-0.98). LIMITATIONS: Our case-control study was susceptible to recall bias and to confounding by unknown cancer risk factors associated with tea consumption. CONCLUSIONS: Our findings support the existence of an inverse association between tea consumption and skin carcinogenesis.

Multiple primary melanoma: two-year results from a population-based study.

OBJECTIVE: To assess the frequency of occurrence and risk factors for multiple primary melanoma. DESIGN: Population-based, case-control study. SETTING: New Hampshire. PARTICIPANTS: Three-hundred fifty-four New Hampshire residents with a confirmed first diagnosis of cutaneous melanoma. MAIN OUTCOME MEASURE: Diagnosis of a subsequent primary cutaneous melanoma. RESULTS: An additional melanoma occurred in 27 individuals (8%) within 2 years of their initial diagnosis, including 20 (6%) within the first postdiagnosis year. In 9 (33%) of these 27 cases, at least 1 subsequent melanoma was deeper than the first tumor. The 27 individuals with a subsequent melanoma diagnosis were classified as "cases" and were compared on the basis of risk factors to the 327 "controls" with a single melanoma diagnosis. The data indicate an inverse relation of risk of multiple primary melanomas with multiple blistering sunburns (P = .01 for the trend); the odds ratio (OR) was 0.32 (95% confidence interval [CI], 0.11-0.93) for 2 or more sunburns compared with none. The number of atypical moles was significantly related to increased risk (P = .004 for the trend). The presence of 3 or more atypical moles compared with none was associated with more than a 4-fold risk of multiple primary melanomas (OR, 4.29; 95% CI, 1.51-12.16). CONCLUSIONS: Additional melanomas occur more frequently than previously shown. Our study confirms that atypical moles are strongly associated with risk of multiple primary melanomas but provides little evidence that risk is influenced by pigmentary characteristics, hours of sun exposure, or benign moles. The inverse association with blistering sunburn may reflect the influence of an unmeasured covariate.

Use of tanning devices and risk of basal cell and squamous cell skin cancers.

Use of artificial tanning devices that emit UV radiation, such as tanning lamps and tanning beds, has become increasingly popular in the United States. Although an excess risk of nonmelanoma skin cancers might be predicted from this exposure, little epidemiologic data exist. We conducted a population-based, case-control study that included 603 basal cell carcinoma (BCC) case patients, 293 squamous cell carcinoma (SCC) case patients, and 540 control subjects. Study participants were interviewed in person to obtain information on tanning device use, sun exposure history, sun sensitivity, and other risk factors for skin cancer. Overall, any use of tanning devices was associated with odds ratios of 2.5 (95% confidence interval [CI] = 1.7 to 3.8) for SCC and 1.5 (95% CI = 1.1 to 2.1) for BCC. Adjustment for history of sunburns, sunbathing, and sun exposure did not affect our results. Our findings suggest that the use of tanning devices may contribute to the incidence of nonmelanoma skin cancers. They highlight the need to further evaluate the potential risks of BCC and SCC that are associated with tanning lamp exposure and the appropriate public health response.

Early-onset basal cell carcinoma and indoor tanning: a population-based study.

OBJECTIVE: Indoor tanning with UV radiation-emitting lamps is common among adolescents and young adults. Rising incidence rates of basal cell carcinoma (BCC) have been reported for the United States and elsewhere, particularly among those diagnosed at younger ages. Recent epidemiologic studies have raised concerns that indoor tanning may be contributing to early occurrence of BCC, and younger people may be especially vulnerable to cancer risk associated with this exposure. Therefore, we sought to address these issues in a population-based case-control study from New Hampshire. METHODS: Data on indoor tanning were obtained on 657 cases of BCC and 452 controls ≤50 years of age. RESULTS: Early-onset BCC was related to indoor tanning, with an adjusted odds ratio (OR) of 1.6 (95% confidence interval, 1.3-2.1). The strongest association was observed for first exposure as an adolescent or young adult, with a 10% increase in the OR with each age younger at first exposure (OR per year of age ≤23 = 1.1; 95% confidence interval, 1.0-1.2). Associations were present for each type of device examined (ie, sunlamps, tanning beds, and tanning booths). CONCLUSIONS: Our findings suggest early exposure to indoor tanning increases the risk of early development of BCC. They also underscore the importance of counseling adolescents and young adults about the risks of indoor tanning and for discouraging parents from consenting minors to this practice.

Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case-control study.

It is well-known that UV light exposure and a sun-sensitive phenotype are risk factors for the development of non-melanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). In this New Hampshire population-based case-control study, we collected data from 5,072 individuals, including histologically confirmed cases of BCC and SCC, and controls via a personal interview to investigate possible associations between photosensitizing medication use and NMSC. After adjustment for potentially confounding factors (e.g., lifetime number of painful sunburns), we found a modest increase in risk of SCC (odds ratio (OR)=1.2, 95% confidence interval (CI)=1.0-1.4) and BCC (OR=1.2, 95% CI=0.9-1.5), in particular early-onset BCC, (≤ 50 years of age) (OR=1.5, 95% CI=1.1-2.1) associated with photosensitizing medication use. For SCC the association was strongest among those with tendency to sunburn rather than tan. We also specifically found associations with BCC, and especially early-onset BCC, and photosensitizing antimicrobials. In conclusion, certain commonly prescribed photosensitizing medications may enhance the risk of developing SCC, especially in individuals with a sun-sensitive phenotype, and may increase the risk of developing BCC and incidence of BCC at a younger age.

A population-based case-control study of urinary arsenic species and squamous cell carcinoma in New Hampshire, USA.

BACKGROUND: Chronic high arsenic exposure is associated with squamous cell carcinoma (SCC) of the skin, and inorganic arsenic (iAs) metabolites may play an important role in this association. However, little is known about the carcinogenicity of arsenic at levels commonly observed in the United States. OBJECTIVE: We estimated associations between total urinary arsenic and arsenic species and SCC in a U.S. population. METHODS: We conducted a population-based case-control SCC study (470 cases, 447 controls) in a U.S. region with moderate arsenic exposure through private well water and diet. We measured urinary iAs, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), and summed these arsenic species (ΣAs). Because seafood contains arsenolipids and arsenosugars that metabolize into DMA through alternate pathways, participants who reported seafood consumption within 2 days before urine collection were excluded from the analyses. RESULTS: In adjusted logistic regression analyses (323 cases, 319 controls), the SCC odds ratio (OR) was 1.37 for each ln-transformed microgram per liter increase in ln-transformed ΣAs concentration [ln(ΣAs)] (95% CI: 1.04, 1.80). Urinary ln(MMA) and ln(DMA) also were positively associated with SCC (OR = 1.34; 95% CI: 1.04, 1.71 and OR = 1.34; 95% CI: 1.03, 1.74, respectively). A similar trend was observed for ln(iAs) (OR = 1.20; 95% CI: 0.97, 1.49). Percent iAs, MMA, and DMA were not associated with SCC. CONCLUSIONS: These results suggest that arsenic exposure at levels common in the United States relates to SCC and that arsenic metabolism ability does not modify the association.

Genetic determinants of UV-susceptibility in non-melanoma skin cancer.

A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC). Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL). The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing number of variant IL10 haplotypes (BCC: p(trend) = 0.0048; SCC: p(trend) = 0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (OR(BCC) = 1.5, 95% CI 1.1-1.9; OR(SCC) = 1.4, 95% CI 1.0-1.9), and these associations were largely confined to women (OR(BCC) = 2.2, 95% CI 1.4-3.4; SCC: OR(SCC) = 1.8, 95% CI 1.1-3.0). To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR) and classification and regression trees (CART). Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender.

Genus beta human papillomaviruses and incidence of basal cell and squamous cell carcinomas of skin: population based case-control study.

OBJECTIVE: To investigate the association between genus beta human papillomaviruses and the incidence of non-melanocytic skin cancer in the general population. DESIGN: Population based case-control study. SETTING: New Hampshire, USA. PARTICIPANTS: 2366 skin cancer cases and controls from the general population aged 25 to 74 years (663 squamous cell carcinoma, 898 basal cell carcinoma, 805 controls), with plasma samples tested for L1 antibodies to 16 genus beta human papillomaviruses by multiplex serology. MAIN OUTCOME MEASURES: Odds ratios for squamous cell carcinoma and basal cell carcinoma associated with seropositivity to beta human papillomaviruses. RESULTS: Squamous cell carcinoma, but not basal cell carcinoma, cases had a higher prevalence of each of the individual beta human papillomaviruses assayed compared with controls. The odds ratios for squamous cell carcinoma increased with the number of beta types positive (odds ratio for one type positive 0.99 (95% confidence interval 0.74 to 1.33); two to three types positive 1.44 (1.03 to 2.01); four to eight types positive 1.51 (1.03 to 2.20); more than eight types positive 1.71 (1.12 to 2.62); P for trend (categorical)<0.001; P for trend (continuous)=0.003). With limited statistical power, the association was stronger among long term users of systemic glucocorticoids (odds ratio 3.21, 1.22 to 8.44) than among non-users (1.23, 0.97 to 1.55). CONCLUSIONS: These findings support a relation between genus beta human papillomavirus infection and the incidence of squamous cell carcinoma of the skin in the general population, as well as potential enhancement of risk by immunosuppression.

Oral contraceptives: a risk factor for squamous cell carcinoma?

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 > or =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 < or =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 > or =7 years, 2.7; 95% CI: 0.9-8.5, P(trend)=0.01). Furthermore, the XPD Lys751Gln polymorphism was a significant modifier of the OC-SCC association (P(interaction)=0.03). These findings lead us to hypothesize a potential relationship between OCs and SCC risk, and that this could involve DNA repair pathways.

CTLA4 variants, UV-induced tolerance, and risk of non-melanoma skin cancer.

Although skin tumors are highly immunogenic, exposure to UV radiation is known to suppress immune responses via regulatory T cells. Specifically, the activity of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is integral in regulating the development of UV-induced tolerance and, concomitantly, skin cancers. Due to the inverse relationship between tumor surveillance and autoimmunity, we hypothesize that the same genetic variant in the CTLA4 locus that increases risk for autoimmune diseases is associated with decreased risk of non-melanoma skin cancer (NMSC). We analyzed whether the polymorphism CT60 or haplotypes of CTLA4 influence odds of developing the major types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), in a population-based case-control study of Caucasians in New Hampshire (849 controls, 930 BCC, and 713 SCC). The CTLA4 CT60 GG genotype was associated with decreased odds for BCC and SCC, controlling for age, sex, lifetime number of severe sunburns, and skin type [BCC: odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-0.9; SCC: OR, 0.7; 95% CI, 0.5-1.0]. For BCC, this decrease was apparent largely among those with a higher lifetime number of severe sunburns (P(interaction) = 0.0074). There were significantly decreased odds of disease associated with two haplotypes, which possess the CT60 G allele. Additionally, lifetime number of severe sunburns modestly altered the effects of the CTLA4 haplotypes in BCC, and the association seemed driven by the CT60 single nucleotide polymorphism. In conclusion, genetic variation at the CTLA4 locus may be etiologically important in NMSC, the most prevalent malignancy in the United States.

Exposure to sunlamps, tanning beds, and melanoma risk.

OBJECTIVE: To estimate the separate effects of sunlamp and tanning bed device use on melanoma risk. METHODS: Population-based case-control study of 423 cases of melanoma and 678 controls in the state of New Hampshire. Exposure data, including sunlamp and tanning bed use, were collected by telephone interview. Associations were evaluated using logistic regression analyses. RESULTS: About 17% of participants ever used a sunlamp, and most use (89%) occurred before 1980. The OR was 1.39 (95% CI 1.00-1.96) for ever using a sunlamp, 1.23 (95% CI 0.81-1.88) for those starting sunlamp use <20 years, and 1.71 (95% CI 1.00-2.92) for those starting >/=20 years. Data suggested increasing risk with number of sunlamp uses and with duration of use (tests of trend p = 0.02). The overall prevalence of tanning bed use was 22% and most use (83%) occurred after 1980. The OR was 1.14 (95% CI 0.80-1.61) for ever using a tanning bed; there was no evidence that risk increased with frequency or duration of use. The OR was 1.96 (95% CI 1.06-3.61) for having used both devices. CONCLUSION: Results suggest a modest association between sunlamp use and melanoma risk, and increasing risk with greater frequency and duration of use. No association with tanning bed use was found, but sufficient lag time may not have elapsed to assess a potential effect.

Factors associated with atypical moles in New Hampshire, USA.

Only a few studies, conducted in Sweden, assessed factors associated with the presence of atypical moles in the general population. We conducted a population-based, case-control study in New Hampshire, USA, to identify factors associated with atypical moles. In our study, atypical moles affected 14% of the study population. The adjusted odds ratio (OR) was 0.34 (95% confidence interval (CI) = 0.14-0.80) for those with the highest adulthood recreational sun exposure, relative to the lowest. The OR for any freckles, compared to none, was 2.24 (95% CI = 1.18-4.25). We found a linear relationship between the number of benign moles and the presence of atypical moles (p for trend = 0.0001). The OR was 7.34 (95% CI = 3.03-17.80) for > 15 benign moles, relative to 0-4. Our data indicate that freckles and benign moles, which may reflect melanocytic inducibility, are strongly associated with atypical moles. The inverse association with sun exposure should be considered with caution.

Gene-drug interaction at the glucocorticoid receptor increases risk of squamous cell skin cancer.

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.

Occupation and keratinocyte cancer risk: a population-based case-control study.

OBJECTIVE: The aim of our study was to identify occupations associated with increased risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). METHODS: We conducted a population-based case-control study of BCC and SCC in New Hampshire. Cases (n = 599 BCC, n = 290 SCC) and controls (n = 524) completed a self-administered residence and work history questionnaire and personal interview regarding major risk factors for skin cancer. Reported jobs were coded using the Standardized Occupational Classification system (SOC). Odds ratios (ORs) and confidence intervals (CIs) for BCC and SCC were calculated for men and women separately using unconditional logistic regression models taking into account age, education, skin reaction to sun, history of painful sunburns, time spent outdoors, and for SCC, smoking. RESULTS: Among men, we observed elevated risks of both BCC and SCC among groundskeepers and gardeners, except farm (SOC 5622). We also found that garage and service station-related occupations (SOCs 873) and to some extent food/beverage preparation/service occupations (SOC 521) were associated with BCC risk among men. Women in health services occupations (SOC 523) had elevated risks for both tumors, especially for BCC. Additionally, administrative support (SOC 46/47) occupations were related to BCC risk among women. Other occupations were associated with excess risks, but without consistent trends by duration of employment. CONCLUSION: We observed several occupations associated with elevated BCC and SCC risk. These results resemble reported findings for cutaneous melanoma and are generally consistent with the few available studies on keratinocyte cancers.

Pigmentary characteristics and moles in relation to melanoma risk.

Although benign and atypical moles are considered key melanoma risk factors, previous studies of their influence were small and/or institution-based. We conducted a population-based case-control study in the state of New Hampshire. Individuals of ages 20-69 with an incident diagnosis of first primary cutaneous melanoma were ascertained through the New Hampshire State Cancer Registry. Controls were identified through New Hampshire driver's license lists and frequency-matched by age and gender to cases. We interviewed 423 eligible cases and 678 eligible controls. Host characteristics, including mole counts, were evaluated using logistic regression analyses. Our results showed that pigmentary factors, including eye color (OR = 1.57 for blue eyes compared to brown), hair color (OR = 1.85 for blonde/red hair color compared to brown/black), freckles before age 15 (OR = 2.39 for freckles present compared to absent) and sun sensitivity (OR = 2.25 for peeling sunburn followed by no tan or a light tan and 2.42 for sunburn followed by tan compared to tanning immediately), were related to melanoma risk; these associations held after adjustment for sun-related factors and for moles. In analyses confined to skin examination participants, the covariate-adjusted effects of benign and atypical moles were moderately strong. Compared to 0-4 benign moles, risk increased steadily for 5-14 moles (OR = 1.71), 15-24 moles (OR = 3.55) and >or= 25 moles (OR = 4.33). Risk also increased with the number of atypical moles; compared to none, the ORs for having 1, 2-3, or >or= 4 atypical moles were 2.08, 1.84 and 3.80, respectively. Although risk was highest for those with multiple benign and atypical moles, the interaction was not of statistical significance. Our findings, arising from the first population- and incidence-based study to evaluate atypical moles in relation to melanoma risk, confirm the importance of host susceptibility, represented by pigmentary factors and the tendency to develop benign or atypical moles, in the etiology of this disease.