Showing papers by "Margaret R. Karagas published in 2008"

Use of photosensitising diuretics and risk of skin cancer: a population-based case–control study

Abstract: Diuretics have photosensitising properties. However, little is known about how these diuretics affect the risk of skin cancers. In North Jutland County, Denmark, we investigated whether the use of photosensitising diuretics was associated with an increased risk for developing basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). From the cancer registry, we identified primary cases of BCC, SCC and MM during the period of 1989–2003. We selected four population controls for each case from the Danish Civil Registration System, matched on age and gender. Prescriptions for photosensitising diuretics before cancer diagnosis were ascertained in the county's Prescription Database. We used conditional logistic regression to compute incidence rate ratio (IRR), controlling for the chronic medical conditions and for the previous use of oral glucocorticoids. We found an increased risk of SCC (IRR of 1.79 (95% confidence interval (CI): 1.45–2.21)) and MM (IRR of 1.43 (95% CI: 1.09–1.88)) among users of combined amiloride and hydrochlorothiazide therapy. An increased risk of MM (IRR of 3.30 (95% CI: 1.34–8.10)) was found among users of indapamide. We found little associations with risk of BCC. Our findings provide evidence that the use of some photosensitising diuretics is associated with an increased risk for SCC and MM.

Drinking-Water Arsenic Exposure Modulates Gene Expression in Human Lymphocytes from a U.S. Population

Abstract: Arsenic exposure impairs development and can lead to cancer, cardiovascular disease, and diabetes [International Agency for Research on Cancer (IARC) 2004]. The mechanism underlying these effects remains unknown. Primarily because of geologic sources of contamination, drinking-water arsenic levels are above the current recommended maximum contaminant level of 10 μg/L in several areas of the United States, including levels exceeding 20 μg/L in 12% of water supplies from surface water sources in the north central region, and ground-water sources in the West [Agency for Toxic Substances and Disease Registry (ATSDR) 2007; Mead 2005]. Approximately 40% of households in New Hampshire are served by unregulated private drinking-water wells, and 10% of these wells contain arsenic at levels > 10 μg/L (Karagas et al. 2002; Mead 2005). Although many laboratory-based animal or cell-culture studies have investigated the effects of arsenic exposure on gene expression using microarray analysis, many of these were conducted on arsenic exposures outside the normal range of U.S. contamination, and only a few have studied arsenic-exposed humans (Andrew et al. 2007; Argos et al. 2006; Lu et al. 2001; Wu MM et al. 2003). Progress in arsenic research has been hampered by the wide variations in its dose–response effects across different species and cell lines (IARC 2004). Humans are believed to be more sensitive to the toxic effects of arsenic than are model organisms; therefore it is important to understand the exposure implications on a genomewide scale (Mead 2005). The first two human studies of arsenic exposure employed smaller arrays representing < 1,000 genes to examine arsenic-exposed tissues. Lu et al. (2001) used liver biopsies from China (n = 6), whereas Wu MM et al. (2003) used peripheral blood lymphocytes from 24 subjects to compare the effects of low (0–46.4 μg/dL) versus high (46.4–465 μg/dL) blood arsenic levels [normal blood arsenic levels are around 70 μg/dL (ATSDR 2007)]. Recently, Argos et al. (2006) used peripheral blood lymphocytes from a population of highly exposed individuals from Bangladesh with skin lesions and the Affymetrix GeneChip microarray platform to investigate differentially expressed genes associated with arsenic exposure. Mean well-water levels of arsenic in the Bangladesh study were 342.7 μg/L for the high-exposure group (n = 11) and 39.6 μg/L for the low-exposure group (n = 5), which is well above the current maximum contaminant level of 10 μg/L. Thus, the objective of the present study was to investigate the effects of arsenic exposure at levels relevant to North American populations. We chose high- versus low-arsenic-exposed groups from a population in New Hampshire, where the rural landscape results in 40% of the population consuming drinking water from unregulated private wells (Karagas et al. 2002, 2004). We conducted a microarray-based genome-wide analysis of expression patterns associated with internal biomarkers of arsenic exposure in peripheral blood lymphocytes from the high-versus low-exposure groups for this population. Our analysis characterizes the major biologic functional classes of genes differentially expressed in arsenic-exposed individuals. Understanding the affected biologic pathways will guide investigations of carcinogenic and pathogenic mechanisms and assist in the development of remediation techniques and chemo-preventive agents for exposed individuals.

DNA repair polymorphisms modify bladder cancer risk: a multi-factor analytic strategy.

Abstract: Objectives: A number of common non-synonymous single nucleotide polymorphisms (SNPs) in DNA repair genes have been reported to modify bladder cancer risk. These include: AP

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

Abstract: 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.

Cutaneous human papillomavirus infection, the EVER2 gene and incidence of squamous cell carcinoma: a case-control study.

Abstract: The initial link between HPV and skin cancers was a rare autosomal inherited disease called Epidermodysplasia Verruciformis (EV) first described nearly a century ago.1 The disease is characterized by cutaneous lesions that display a high rate of progression to squamous cell carcinomas (SCCs) beginning in the second decade of life. Furthermore, EV patients experience diminished cell-mediated immunity possibly resulting in an observed susceptibility to infection by specific HPV types falling into the genus β, with HPV5 and HPV8 the most prevalent infections in this patient population.2 Genome-wide linkage studies were performed to map two EV loci3,4 and to identify the EVER genes (EVER1 or EVER2, also referred to as TMC6 and TMC8, respectively) in one of these loci.5 The identification of EVER1 and EVER2 expressed sequence tags and cDNA from lymphoid tissue is consistent with a model in which EV mutations exert their direct effects in the immune system. It was recently discovered that 75% of EV patients studied have rare mutations in either of these adjacent, related, novel genes. To date, 10 truncating, loss of function mutations have been identified, 4 in EVER1 and 6 in EVER2 and were identified in EV patients from Algeria, Columbia, Poland and Japan.5 More recently, 5 additional mutations have been detected in the EVER genes supporting the hypothesis that EVER1 and EVER2 are the molecular basis of EV.6–8 β-HPV DNA has been detected in up to 50% of SCC tumors from immunocompetent individuals and in up to 90% of lesions from immunocompromised individuals,9,10 further emphasizing the role of host susceptibility in infection with these viruses. Recently, we reported that the presence of antibodies to viral proteins of HPV types in the genus β, particularly HPV5, was associated with risk of SCC.11 We hypothesize that a common nonsynonymous single nucleotide polymorphism in the EVER2 gene also may be related to infection with β-HPVs. Here we report that this particular SNP (rs7208422), located in the most highly conserved region of the gene, is not only associated with SCC of the skin but also with the presence of antibodies to genus β-HPVs in control subjects.

Mortality in Danish patients with nonmelanoma skin cancer, 1978–2001

Abstract: Recently, we reported a 10% reduced mortality among patients with basal cell carcinoma (BCC), and a 60% increased mortality among patients with squamous cell carcinoma (SCC) during a 10-year follow-up in a cohort of Danish patients with nonmelanoma skin cancer (NMSC).1 The results were based on a comparison of patients with NMSC diagnosed with a first primary NMSC at private or public outpatient dermatology clinics in 1995 with age-, gender- and residence-matched population controls. Another Danish study, examining patients registered in the Danish Cancer Registry (DCR) from 1981 to 1997, reported a similar increased survival rate among patients with NMSC compared with the general population.2 They did not separate the type of NMSC and the result probably reflects the survival rate for patients with BCC because of the higher proportion of patients with BCC compared with those with SCC in the study population. However, one Finnish3 and one U.S. study4 showed no differences in mortality between patients with BCC and NMSC and the general population. The Finnish study identified all patients with BCC and SCC cases registered in the Finnish Cancer Registry from 1974 to 1981 and followed them for an average of 10 years. The U.S. study followed 35 062 patients with NMSC (identified through 1982) for an average period of 12 years. The study did not stratify by type of NMSC but adjusted for multiple risk factors of mortality such as age, gender, education, smoking and health-related factors (body mass index, alcohol use and exercise level). The differences in calendar periods, settings, adjustments for covariates and type of NMSC studied may explain the disagreement between the various studies. Therefore, the effects of a NMSC diagnosis on mortality remain to be established. Such data are important because they provide further insight into the clinical course, and foster our understanding, of NMSC and diseases associated with NMSC. As NMSC is the most common of all cancers among Caucasians,5 these findings will have a significant public health interest. We examined the total and cause-specific mortality of all Danish patients with NMSC stratified by gender and type of NMSC over a 23-year period and compared them with the general Danish population. In supplementary analyses, we evaluated the potential impact of surveillance and selection bias on the results. We also addressed a potential ‘healthy patient effect’ (similar to the ‘healthy worker effect’6,7) among, in particular, patients with BCC.

Histological classification and stage of newly diagnosed bladder cancer in a population-based study from the Northeastern United States

Abstract: Objective. There are limited data on the distribution of bladder cancers in the general population, classified by World Health Organization (WHO)/International Society of Urological Pathology (ISUP) criteria. This study evaluated the classification and stage of bladder cancers as part of a population-based epidemiological study of bladder cancer in the Northeastern United States. Material and methods. All New Hampshire residents with bladder cancer newly diagnosed from 1998 to 2000 were identified through the state cancer registry. All slides were reviewed by a single pathologist. Tumors were classified by two sets of standard criteria. Results. The retrieval rate for cases was over 90%. Of 342 cases reviewed, 15 were excluded for technical reasons or because malignancy was not definitively diagnosed. According to WHO/ISUP criteria, 25.7% of tumors were papillary urothelial neoplasms of low malignant potential (PUNLMP), 34.3% low-grade papillary carcinomas, 22.6% high-grade papillary carcinomas, 10.1% non...

Disinfection byproducts in drinking water and skin cancer? A hypothesis.

Abstract: Recent evidence suggests possible carcinogenic effects of exposure to disinfection byproducts (DBPs) via non-ingestion routes (i.e., bathing, showering or swimming) [1]. In light of these findings and the accumulating data that dermal absorption represents an important human exposure pathway for trihalomethanes (a major component of DBPs) [2] we conducted an exploratory analysis of the hypothesis that exposure to DBPs may enhance risk of cancers of skin. Our hypothesis is supported by experimental evidence that some genes that metabolize DBPs into reactive intermediates (CYP2E1 and GSTT1) are expressed in the skin [3] and are involved in the genetic susceptibility of skin cancer [4]. In a preliminary analysis, we used data accrued in a completed population-based case–control study of keratinocyte-derived malignancies (basal cell carcinomas (BCC) and squamous cell carcinomas (SCC)) from New Hampshire originally designed to examine the effects of drinking water arsenic [5]. Newly diagnosed cases of BCC and SCC were identified through a state-wide network of dermatologists, dermatopathologists and pathologists, and age- and sex-matched controls were selected from population lists. The study comprised 293 SCC cases, 603 BCC cases and 540 controls (response rates of 83% of cases and 69% of controls confirmed as eligible) [5]. Participants completed a self-administered work and residential history calendar and structured interview regarding water supply at lifetime residences along with other risk factors (e.g., sun exposure, smoking history etc.). Total trihalomethane (THM) levels, based on the four regulated THMs (chloroform, bromodichloromethane, dibromochloromethane, bromoform), were obtained from routine monitoring data of public water systems maintained by the New Hampshire Department of Environmental Services. Average THM levels were computed from samples taken from public water systems between 1984 and 1994 and assigned by subject’s residence at their reference date (date of diagnosis of the cases and a comparable date for controls). Residents of towns or cities with multiple water systems were assigned the average THM value weighted by the proportion of the population served by these systems. Grouping according to maximum THM levels produced essentially the same categories. Among individuals who reported using public water systems, the odds ratio for those with levels above 40 mcg/L were 2.4 (95% CI = 0.9–6.7) for BCC and 2.1 (95% CI = 0.7–7.0) for SCC (Table 1). Users of public water systems with either trace or no THMs served as the reference group; estimates based on other reference groups (i.e., private wells) did not materially change the results. Presented odds ratios were adjusted for age, gender and skin sensitivity to the sun (i.e., tendency to sunburn) using unconditional logistic regression. Further adjustment for toenail arsenic concentrations did not affect the results. Based on this preliminary analysis, we think the hypothesis that DBP exposure might affect the pathogenesis of skin cancer warrants further exploration.

Analysis of High-throughput DNA Methylation Bead Arrays Utilizing Bayesian Genotyping Algorithms

Abstract: We present a statistical framework, MAMS-M, for determining the methylation status of hundreds of cancer related CpG sites. MAMS-M extends and adapts our previous SNP genotyping algorithm, MAMS, to methylation bead array data, exploiting the similarities in data structure between the two platforms. MAMS-M employs a multi-site, multi-array model-based clustering approach to derive initial methylation calls, and then recalibrate these calls and associated confidence measures using site-specific adjustments. We demonstrate the performance of MAMS-M using a real-life data set with cancer applications.