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.

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.

Measures of cumulative exposure from a standardized sun exposure history questionnaire: a comparison with histologic assessment of solar skin damage.

Ultraviolet radiation exposure is the dominant environmental determinant of all major forms of skin cancer; however, the nature of the association is incompletely understood. Existing instruments to capture sun exposure history tend to yield reproducible results, but the validity of these responses is unknown. To address this question, the authors examined the relation between responses to a standardized sun exposure instrument and histologic evidence of actinic damage in a population-based study of keratinocyte cancers from New Hampshire diagnosed from July 1, 1997, through March 31, 2000.

Carcinogen exposure and epigenetic silencing in bladder cancer.

Tobacco smoking, certain occupational exposures, and exposure to inorganic arsenic in drinking water have been associated with the occurrence of bladder cancer. However, in these tumors the exposure-associated pattern of somatic alterations in genes in the causal pathway for disease has been poorly characterized. Animal and in vitro studies have suggested that arsenic, tobacco carcinogens, and other exposures may act through epigenetic mechanisms.

Examination of a CpG island methylator phenotype and implications of methylation profiles in solid tumors.

The CpG island methylator phenotype (CIMP), thoroughly described in colorectal cancer and to a lesser extent in other solid tumors, is important in understanding epigenetics in carcinogenesis and may be clinically useful for classification of neoplastic disease. Therefore, we investigated whether this putative phenotype exists in exposure-related solid tumors, where somatic gene alterations and enhanced clonal growth are selected for by carcinogens, and examined the ability of methylation profiles to classify malignant disease. We studied promoter hypermethylation of 16 tumor suppressor genes and 3 MINT loci (acknowledged classifiers of CIMP) in 344 bladder cancers, 346 head and neck squamous cell carcinomas (HNSCC), 146 non-small-cell lung cancer (NSCLC), and 71 malignant pleural mesotheliomas (MPM).

Toenail mercury and dietary fish consumption.

New England is one of three areas in the United States with the highest annual deposition of mercury, an established environmental pollutant with a variety of health effects. We measured the mercury content in toenails of 27 individuals in New Hampshire who participated as controls in a health study in 1994-95. The mean total toenail mercury concentration was 0.

Arsenic exposure is associated with decreased DNA repair in vitro and in individuals exposed to drinking water arsenic.

The mechanism(s) by which arsenic exposure contributes to human cancer risk is unknown ; however, several indirect cocarcinogenesis mechanisms have been proposed. Many studies support the role of As in altering one or more DNA repair processes. In the present study we used individual-level exposure data and biologic samples to investigate the effects of As exposure on nucleotide excision repair in two study populations, focusing on the excision repair cross-complement 1 (ERCC1) component.

XRCC3 and XPD/ERCC2 single nucleotide polymorphisms and the risk of cancer: a HuGE review.

Hundreds of polymorphisms in DNA repair genes have been identified; however, for many of these polymorphisms, the impact on repair phenotype and cancer susceptibility remains uncertain. In this review, the authors focused on the x-ray repair cross-complementing protein group 3 (XRCC3) and xeroderma pigmentosum group D (XPD)/excision repair cross-complementing rodent repair deficiency (ERCC2) genes, because they are among the most extensively studied but no final conclusion has yet been drawn about their role in cancer occurrence. XRCC3 participates in DNA double-strand break/recombinational repair through homologous recombination to maintain chromosome stability.

Human papillomavirus infection and incidence of squamous cell and basal cell carcinomas of the skin.

Background: Although infection with human papillomaviruses (HPVs) is a major risk factor for several epithelial cancers, an etiologic relationship between HPV and keratinocyte cancers, such as squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), remains unclear.

Methods: In a population-based case-control study of 252 SCC case patients, 525 BCC case patients, and 461 control subjects, we used multiplex serology to detect antibodies in plasma samples against 16 HPV types from phylogenetic genera alpha, beta, and mu. Multiplex serology is a new method that is based on fluorescent bead technology and allows simultaneous detection of antibodies against up to 100 different in situ affinity-purified recombinant HPV proteins.

XPA, haplotypes, and risk of basal and squamous cell carcinoma.

Nucleotide excision repair (NER) is instrumental in removing DNA lesions caused by ultraviolet (UV) radiation, the dominant risk factor for keratinocyte carcinoma, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). We evaluated whether BCC or SCC risk was influenced by the A23G single nucleotide polymorphism (SNP) in Xeroderma pigmentosum group A (XPA), which codes for an essential protein in NER. We also investigated whether haplotypes of XPA, determined by seven haplotype-tagging SNPs, better define susceptibility to keratinocyte carcinoma.

Allelic loss at Drosophila patched gene is highly prevalent in Basal and squamous cell carcinomas of the skin.

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).

Pregnancy history and incidence of melanoma in women: a pooled analysis.

There is evidence that pregnancy history including age at first birth and parity may play a role in risk of cutaneous melanoma in women, although, epidemiological findings are inconsistent. We conducted a collaborative analysis of these factors using the original data from ten completed case-control studies (2391 cases and 3199 controls), and assessed the potential confounding effects of socioeconomic, pigmentary, and sun exposure-related factors. We found no overall association with ever having a live birth (pooled odds ratio (pOR) 0.

Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility.

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis.

Environmental exposure and fingernail analysis of arsenic and mercury in children and adults in a Nicaraguan gold mining community.

Gold mining can release contaminants, including mercury, into the environment, and may increase exposure to naturally occurring elements such as arsenic. The authors investigated environmental and human tissue concentrations of arsenic and mercury in the gold mining town of Siuna, Nicaragua. The study involved 49 randomly selected households in Siuna, from whom a questionnaire along with environmental and fingernail samples were collected.

Methylenetetrahydrofolate reductase (MTHFR) variants and bladder cancer: a population-based case-control study.

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 association of physical activity and body mass index with the risk of large bowel polyps.

Purpose And Method: Several studies have suggested that physical inactivity and obesity increase the risk for colorectal neoplasia. In this study, we investigated the association of physical activity and body mass index (BMI) with the risk of different types of large bowel polyps. We did an observational analysis nested within a randomized double-blind placebo-controlled chemoprevention trial among patients with one or more recently resected histologically confirmed colorectal adenoma.

Loss of heterozygosity on chromosome 9q and p53 alterations in human bladder cancer.

Background: Somatic loss of the 9q allele as well as alteration of the tumor suppressor p53 occurs commonly in bladder cancers. Although alteration of p53 has been strongly associated with invasive stage disease, the prognostic significance of 9q loss of heterozygosity (LOH) and the relations between these alterations are less well defined.

Methods: The 9q LOH was examined at five microsatellites and p53 alterations (mutation and persistent immunohistochemical staining) in a population-based case series of 271 newly diagnosed bladder cancer patients.

Epigenetic inactivation of SFRP genes and TP53 alteration act jointly as markers of invasive bladder cancer.

In the United States each year, almost 13,000 deaths are attributable to bladder cancer, with the majority of these deaths related to higher stage, muscle-invasive solid tumors. Epigenetic silencing of the secreted frizzled receptor proteins (SFRP), antagonists of the WNT pathway, leads to constitutive WNT signaling, altering cell morphology and motility. Identifying alterations in this pathway in bladder cancer may prove useful for defining the invasive phenotype and provide targets for guiding therapy.

Carcinogen exposure and gene promoter hypermethylation in bladder cancer.

Tobacco smoking, certain occupational exposures, and exposure to inorganic arsenic in drinking water have been associated with the occurrence of bladder cancer. However, in these tumors the exposure-associated pattern of somatic alterations in genes in the causal pathway for disease has been poorly characterized. In particular, the mechanism by which arsenic induces bladder cancer and the effects of lower environmental levels of exposure remain uncertain.

The XPC poly-AT polymorphism in non-melanoma skin cancer.

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.

Gender, smoking, glutathione-S-transferase variants and bladder cancer incidence: a population-based study.

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.

Selenium and colorectal adenoma: results of a pooled analysis.

Background: Secondary analyses of data from a large randomized clinical trial have suggested that intake of the trace element selenium reduces risk of colorectal neoplasia, but epidemiologic studies have not shown a consistent protective association.

Methods: We conducted a combined analysis of data from three randomized trials--the Wheat Bran Fiber Trial, the Polyp Prevention Trial, and the Polyp Prevention Study--which tested the effects of various nutritional interventions for colorectal adenoma prevention among participants who recently had an adenoma removed during colonoscopy. Selenium concentrations were measured from blood specimens from a total of 1763 trial participants, and quartiles of baseline selenium were established from the pooled data.

A population-based case-control study of the XRCC1 Arg399Gln polymorphism and susceptibility to bladder cancer.

Cigarette smoking is the major cause of bladder cancer. Constituents in tobacco smoke can induce oxidative DNA damage requiring base excision repair. The Arg399Gln polymorphism in the DNA base excision repair gene XRCC1 is associated with several phenotypic markers of reduced DNA repair capacity.

Incidence of transitional cell carcinoma of the bladder and arsenic exposure in New Hampshire.

Objective: Arsenic is a known bladder carcinogen and populations exposed to high arsenic levels in their water supply have reported elevated bladder cancer mortality and incidence rates. To examine the effects of lower levels of arsenic exposure on bladder cancer incidence, we conducted a case-control study in New Hampshire, USA where levels above 10 micro/l are commonly found in private wells.

Methods: We studied 383 cases of transitional cell carcinoma of the bladder cancer, newly diagnosed between July 1, 1994 and June 30, 1998 and 641 general population controls.

Effect of calcium supplementation on the risk of large bowel polyps.

Background: Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas. However, few studies have examined the effect of calcium on the risk of different types of colorectal lesions or dietary determinants of this effect.

Methods: Our analysis used patients from the Calcium Polyp Prevention Study, a randomized, double-blind, placebo-controlled chemoprevention trial among patients with a recent colorectal adenoma.