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Richard P Gallagher

Publications and source records attributed to Richard P Gallagher.

At least 19 recordsLinked to original sources
PubMed2016

Variants in autophagy-related genes and clinical characteristics in melanoma: a population-based study.

Autophagy has been linked with melanoma risk and survival, but no polymorphisms in autophagy-related (ATG) genes have been investigated in relation to melanoma progression. We examined five single-nucleotide polymorphisms (SNPs) in three ATG genes (ATG5; ATG10; and ATG16L) with known or suspected impact on autophagic flux in an international population-based case-control study of melanoma. DNA from 911 melanoma patients was genotyped. An association was identified between (GG) (rs2241880) and earlier stage at diagnosis (OR 0.47; 95% Confidence Intervals (CI) = 0.27-0.81, P = 0.02) and a decrease in Breslow thickness (P = 0.03). The ATG16L heterozygous genotype (AG) (rs2241880) was associated with younger age at diagnosis (P = 0.02). Two SNPs in ATG5 were found to be associated with increased stage (rs2245214 CG, OR 1.47; 95% CI = 1.11-1.94, P = 0.03; rs510432 CC, OR 1.84; 95% CI = 1.12-3.02, P = 0.05). Finally, we identified inverse associations between ATG5 (GG rs2245214) and melanomas on the scalp or neck (OR 0.20, 95% CI = 0.05-0.86, P = 0.03); ATG10 (CC) (rs1864182) and brisk tumor infiltrating lymphocytes (TILs) (OR 0.42; 95% CI = 0.21-0.88, P = 0.02), and ATG5 (CC) (rs510432) with nonbrisk TILs (OR 0.55; 95% CI = 0.34-0.87, P = 0.01). Our data suggest that ATG SNPs might be differentially associated with specific host and tumor characteristics including age at diagnosis, TILs, and stage. These associations may be critical to understanding the role of autophagy in cancer, and further investigation will help characterize the contribution of these variants to melanoma progression.

Adult↗
PubMed2007

CDKN2A germline mutations in individuals with cutaneous malignant melanoma.

Cyclin-dependent kinase inhibitor type 2A (CDKN2A) has been identified as a major melanoma susceptibility gene based on the presence of germline mutations in high-risk melanoma families. In this study, we sought to identify and characterize the spectrum of CDKN2A mutations affecting p16 inhibitor of cyclin-dependent kinase type 4 (INK4a) in individuals with melanoma using a population-based study design. DNA samples from 1189 individuals with incident multiple primary melanoma (MPM) and 2424 with incident single primary melanoma unselected for family history of melanoma were available for screening of CDKN2A (p16INK4a) mutations. Variants were classified for functional impact based on intragenic position, existing functional data, sequence, and structural analysis. The impact of individual mutations and functional groupings was assessed by comparing frequencies in cases of MPM versus cases with a single first primary melanoma, and by comparing the reported incidence rates in first-degree relatives. Our results show that mutations occur infrequently in these high-risk groups, and that they occur mainly in exons 1alpha and 2. Rare coding variants with putative functional impact are observed to increase substantially the risk of melanoma. With the exception of the variant in position -34 of CDKN2A of known functional consequence, the remaining rare variants in the non-coding region have no apparent impact on risk.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed2007

Ambient UV, personal sun exposure and risk of multiple primary melanomas.

OBJECTIVE: Sun exposure is the main cause of melanoma in populations of European origin. No previous study has examined the effect of sun exposure on risk of multiple primary melanomas compared with people who have one melanoma. METHODS: We identified and enrolled 2,023 people with a first primary melanoma (controls) and 1,125 with multiple primary melanomas (cases) in seven centers in four countries, recorded their residential history to assign ambient UV and interviewed them about their sun exposure. RESULTS: Risk of multiple primary melanomas increased significantly (P<0.05) to OR=2.10 for the highest exposure quarter of ambient UV irradiance at birth and 10 years of age, to OR=1.38 for lifetime recreational sun exposure, to OR=1.85 for beach and waterside activities, to OR=1.57 for vacations in a sunnier climate, to OR=1.50 for sunburns. Occupational sun exposure did not increase risk (OR=1.03 for highest exposure). Recreational exposure at any age increased risk and appeared to add to risk from ambient UV in early life. CONCLUSIONS: People who have had a melanoma can expect to reduce their risk of a further melanoma by reducing recreational sun exposure whatever their age. The same is probably true for a person who has never had a melanoma.

Adolescent↗
PubMed2006

Identifying related cancer types based on their incidence among people with multiple cancers.

BACKGROUND: There are several reasons that someone might be diagnosed with more than one primary cancer. The aim of this analysis was to determine combinations of cancer types that occur more often than expected. The expected values in previous analyses are based on age-and-gender-adjusted risks in the population. However, if cancer in people with multiple primaries is somehow different than cancer in people with a single primary, then the expected numbers should not be based on all diagnoses in the population. METHODS: In people with two or more cancer types, the probability that a specific type is diagnosed was determined as the number of diagnoses for that cancer type divided by the total number of cancer diagnoses. If two types of cancer occur independently of one another, then the probability that someone will develop both cancers by chance is the product of the individual probabilities for each type. The expected number of people with both cancers is the number of people at risk multiplied by the separate probabilities for each cancer. We performed the analysis on records of cancer diagnoses in British Columbia, Canada between 1970 and 2004. RESULTS: There were 28,159 people with records of multiple primary cancers between 1970 and 2004, including 1,492 people with between three and seven diagnoses. Among both men and women, the combinations of esophageal cancer with melanoma, and kidney cancer with oral cancer, are observed more than twice as often as expected. CONCLUSION: Our analysis suggests there are several pairs of primary cancers that might be related by a shared etiological factor. We think that our method is more appropriate than others when multiple diagnoses of primary cancer are unlikely to be the result of therapeutic or diagnostic procedures.

Journal Article↗
PubMed2006

Population-based study of natural variation in the melanocortin-1 receptor gene and melanoma.

Natural variation in the coding region of the melanocortin-1 receptor (MC1R) gene is associated with constitutive pigmentation phenotypes and development of melanoma and nonmelanoma skin cancers. We investigated the effect of MC1R variants on melanoma using a large, international population-based study design with complete determination of all MC1R coding region variants. Direct sequencing was completed for 2,202 subjects with a single primary melanoma (controls) and 1,099 subjects with second or higher-order primary melanomas (cases) from Australia, the United States, Canada, and Italy. We observed 85 different MC1R variants, 10 of which occurred at a frequency >1%. Compared with controls, cases were more likely to carry two previously identified red hair ("R") variants [D84E, R151C, R160W, and D294H; odds ratio (OR), 1.6; 95% confidence interval (95% CI), 1.1-2.2]. This effect was similar among individuals carrying one R variant and one r variant (defined as any non-R MC1R variant; OR, 1.6; 95% CI, 1.3-2.2) and among those carrying only one R variant (OR, 1.5; 95% CI, 1.1-1.9). There was no statistically significant association among those carrying only one or two r variants. Effects were similar across geographic regions and categories of pigmentation characteristics or number of moles. Our results confirm that MC1R is a low-penetrance susceptibility locus for melanoma, show that pigmentation characteristics may not modify the relationship of MC1R variants and melanoma risk, and suggest that associations may be smaller than previously reported in part due to the study design.

Adult↗
PubMed2006

A design for cancer case-control studies using only incident cases: experience with the GEM study of melanoma.

BACKGROUND: The population-based case-control study is not suited to the evaluation of rare genetic (or environmental) factors. The use of a novel case-control design in which cases have second primaries and controls are cancer survivors has been proposed for this purpose. METHODS: We report results from an international study of melanoma that involved population-based ascertainment of incident cases of second or subsequent primary melanoma as the 'case' group and incident cases of first primary melanoma as the 'control' group. We evaluate the validity of the study design by comparing the results obtained for phenotypic factors that have been shown consistently to be associated with melanoma in previous conventional studies with the results from a conventional case-control study conducted in Connecticut and from literature reviews. RESULTS: All but one of the known risk factors for melanoma were shown to be significantly associated with melanoma in our study, though the individual odds ratios appear to be somewhat attenuated relative to the magnitudes typically observed in the literature. CONCLUSIONS: Patients with a second or subsequent primary cancer of a single type represent a potentially valuable and under-utilized resource for the study of cancer aetiology.

Adult↗
PubMed2006

Adverse effects of ultraviolet radiation: a brief review.

Solar ultraviolet radiation (UVR) has always been part of the environment of man. UVB is required for the conversion of 7-deoxycholesterol to vitamin D, which is critically important in the maintenance of healthy bones and research is making clear that it has other potential roles in maintenance of human health. Exposure to UVR, whether of solar or artificial origin, also carries potential risks to human health. UVR is a known carcinogen and excessive exposure-at least to solar radiation in sunlight-increases risk of cancer of the lip, basal cell, and squamous cell carcinoma of the skin and cutaneous melanoma, particularly in fair skin populations. There is also evidence that solar UVR increases risk of several diseases of the eye, including cortical cataract, some conjunctival neoplasms, and perhaps ocular melanoma. Solar UVR may also be involved in autoimmune and viral diseases although more research is needed in these areas. Artificial UVR from tanning beds, welding torches, and other sources, may contribute to the burden of disease from UVR. This brief review will assess the human evidence for adverse health effects from solar and artificial UVR and will attempt to assign a degree of certainty to the major disease-exposure relationships based on the weight of available scientific evidence.

Comorbidity↗
PubMed2006

Cancer risk in aluminum reduction plant workers (Canada).

A 14-year update to a previously published historical cohort study of aluminum reduction plant workers was conducted [1]. All men with three or more years at an aluminum reduction plant in British Columbia (BC), Canada between the years 1954 and 1997 were included; a total of 6,423 workers. A total of 662 men were diagnosed with cancer, representing a 400% increase from the original study. Standardized mortality and incidence ratios were used to compare the cancer mortality and incidence of the cohort to that of the BC population. Poisson regression was used to examine risk by cumulative exposure to coal tar pitch volatiles (CTPV) measured as benzene soluble materials (BSM) and benzo(a)pyrene (BaP). The risk for bladder cancer was related to cumulative exposure to CTPV measured as BSM and BaP (p trends <0.001), and the risk for stomach cancer was related to exposure measured by BaP (p trend BaP <0.05). The risks for lung cancer (p trend <0.001), non-Hodgkin lymphoma (p trend <0.001), and kidney cancer (p trend <0.01) also increased with increasing exposure, although the overall rates were similar to that of the general population. Analysis of the joint effect of smoking and CTPV exposure on cancer showed the observed dose-response relationships to be independent of smoking.

Air Pollutants, Occupational↗
PubMed2006

Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium.

BACKGROUND: Common genetic variants in immune and inflammatory response genes can affect the risk of developing non-Hodgkin lymphoma. We aimed to test this hypothesis using previously unpublished data from eight European, Canadian, and US case-control studies of the International Lymphoma Epidemiology Consortium (InterLymph). METHODS: We selected 12 single-nucleotide polymorphisms for analysis, on the basis of previous functional or association data, in nine genes that have important roles in lymphoid development, Th1/Th2 balance, and proinflammatory or anti-inflammatory pathways (IL1A, IL1RN, IL1B, IL2, IL6, IL10, TNF, LTA, and CARD15). Genotype data for one or more single-nucleotide polymorphisms were available for 3586 cases of non-Hodgkin lymphoma and for 4018 controls, and were assessed in a pooled analysis by use of a random-effects logistic regression model. FINDINGS: The tumour necrosis factor (TNF) -308G-->A polymorphism was associated with increased risk of non-Hodgkin lymphoma (p for trend=0.005), particularly for diffuse large B-cell lymphoma, the main histological subtype (odds ratio 1.29 [95% CI 1.10-1.51] for GA and 1.65 [1.16-2.34] for AA, p for trend <0.0001), but not for follicular lymphoma. The interleukin 10 (IL10) -3575T-->A polymorphism was also associated with increased risk of non-Hodgkin lymphoma (p for trend=0.02), again particularly for diffuse large B-cell lymphoma (p for trend=0.006). For individuals homozygous for the TNF -308A allele and carrying at least one IL10 -3575A allele, risk of diffuse large B-cell lymphoma doubled (2.13 [1.37-3.32], p=0.00083). INTERPRETATION: Common polymorphisms in TNF and IL10, key cytokines for the inflammatory response and Th1/Th2 balance, could be susceptibility loci for non-Hodgkin lymphoma. Moreover, our results underscore the importance of consortia for investigating the genetic basis of chronic diseases like cancer.

Case-Control Studies↗
PubMed2006

The prevalence of CDKN2A germ-line mutations and relative risk for cutaneous malignant melanoma: an international population-based study.

Germ-line mutations of CDKN2A have been identified as strong risk factors for melanoma in studies of multiple-case families. However, an assessment of their relative risk for melanoma in the general population has been difficult because they occur infrequently. We addressed this issue using a novel population-based case-control study design in which "cases" have incident second- or higher-order melanomas [multiple primary melanoma (MPM)] and "controls" have incident first primary melanoma [single primary melanoma (SPM)]. Participants were ascertained from nine geographic regions in Australia, Canada, Italy, and United States. In the 1,189 MPM cases and 2,424 SPM controls who were eligible and available for analysis, the relative risk of a subsequent melanoma among patients with functional mutations who have an existing diagnosis of melanoma, after adjustments for age, sex, center, and known phenotypic risk factors, is estimated to be 4.3 (95% confidence interval, 2.3-7.7). The odds ratio varied significantly depending on the type of mutation involved. The results suggest that the relative risk of mutation carriers in the population may be lower than currently believed and that different mutations on the CDKN2A gene may confer substantially different risks of melanoma.

Aged↗
PubMed2005

Etiologic factors associated with p53 immunostaining in cutaneousmalignant melanoma.

Findings from a case-control study of cutaneous malignant melanoma (CMM) in Queensland, Australia, suggest that melanomas exhibiting p53 immunostaining possess different risk factors from those of other melanomas. To further explore this hypothesis, a case-only analysis of risk factors for p53 immunostaining with anti-p53 MAb DO-7 was undertaken in 523 people diagnosed with CMM in Canada and Australia. Phenotypic factors and past sun exposure were measured using a self-administered questionnaire and telephone interview. The presence of strong p53 staining (>10% of cell nuclei positively stained vs. <1% staining) was positively associated with some indicators of high cumulative sun exposure: lentigo maligna melanoma subtype (OR = 3.2 vs. superficial spreading subtype), melanoma location on the head and neck (OR = 2.8 vs. back), histopathologic evidence of solar elastosis (OR = 2.1) and previous diagnosis of nonmelanoma skin cancer (OR = 2.4). Strong staining was negatively associated with high nevus density on the back (OR = 0.2 for >25 nevi vs. 0-3 nevi) and histologic evidence of a coexisting nevus (OR = 0.3). Other factors associated with strong p53 immunostaining include greater Breslow thickness (OR = 7.4 for >4.00 vs. <0.76 mm), male sex (OR = 2.2) and dense freckling (OR = 6.6 vs. few freckles). Of these, thickness, male sex, dense freckling, low nevus density on the back, histologic subtype and history of nonmelanoma skin cancer appeared to be independently associated with strong p53 staining. Our findings are consistent with the Queensland study in suggesting that variables indicating high accumulated sun exposure are positively associated with p53 staining and that an increased number of nevi is positively associated with its absence; they may reflect etiologic and pathogenetic heterogeneity in melanoma.

Adult↗
PubMed2005

Polymorphisms in nucleotide excision repair genes and risk of multiple primary melanoma: the Genes Environment and Melanoma Study.

Polymorphisms in six genes involved in nucleotide excision repair of DNA were examined in a large population-based case-control study of melanoma. Genotyping was conducted for 2485 patients with a single primary melanoma (controls) and 1238 patients with second or higher order primary melanomas (cases). Patients were ascertained from nine geographic regions in Australia, Canada, Italy and the United States. Positive associations were observed for XPD 312 Asn/Asn versus Asp/Asp [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.2-1.9] and XPD 751 Gln/Gln versus Lys/Lys (OR = 1.4, 95% CI 1.1-1.7) genotypes and melanoma. The combined XPD Asn (A) 312 + Gln (C) 751 haplotype was significantly more frequent in cases (32%) compared with controls (29%) (P = 0.003) and risk of melanoma increased significantly with one and two copies of the haplotype (ORs 1.2, 95% CI 1.0-1.4, and 1.6, 95% CI 1.2-2.0, trend P = 0.002). No significant associations were observed for HR23B codon 249, XPG codon 1104, XPC codon 939, XPF codon 415, XPF nt 2063, ERCC6 codon 1213 or ERCC6 codon 1230. ORs for XPD and XPC genotypes were stronger for melanoma diagnosed at an early age, but tests for interaction were not statistically significant. The results provide further evidence for a role of XPD in the etiology of melanoma.

Adolescent↗
PubMed2005

Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample.

BACKGROUND: Germline mutations in the CDKN2A gene have been linked to melanoma incidence in many families with multiple cases of the disease. Previous studies of multiple-case families have indicated that the lifetime risk (i.e., penetrance) of melanoma in CDKN2A mutation carriers is very high, ranging from 58% in Europe to 91% in Australia by age 80 years. In this study, we examined lifetime melanoma risk among CDKN2A mutation carriers using carriers who were identified in a population-based study of melanoma. METHODS: Probands for the study were incident case patients with either first or subsequent melanoma who were identified in nine geographic regions in Australia, Canada, the United States, and Italy. A total of 3626 probands (53% participation rate) with adequate DNA for analysis were recruited and genotyped for CDKN2A mutations. From the 3550 probands whose DNA could be amplified by polymerase chain reaction of CDKN2A exons 1alpha, 2, and 3 and surrounding regions, 65 mutation carriers were identified. Melanoma histories in first-degree relatives of these probands were used to calculate the lifetime risk in CDKN2A mutation carriers using the kin-cohort method. RESULTS: The risk of melanoma in CDKN2A mutation carriers was approximately 14% (95% CI = 8% to 22%) by age 50 years, 24% (95% CI = 15% to 34%) by age 70 years, and 28% (95% CI = 18% to 40%) by age 80 years. Eighteen probands had three or more first-degree relatives with melanoma, but only one was a carrier of a CDKN2A mutation. CONCLUSIONS: CDKN2A mutation carriers in the general population have a much lower risk of melanoma than that suggested by estimates obtained from multiple-case families. The preponderance of familial clustering of melanoma occurs in families without identifiable mutations in CDKN2A.

Adult↗
PubMed2005

Site-specific protective effect of broad-spectrum sunscreen on nevus development among white schoolchildren in a randomized trial.

BACKGROUND: Melanocytic nevus density is a strong risk factor for cutaneous malignant melanoma. Reducing the number of nevi in children may reduce the risk of their developing melanoma as adults. OBJECTIVE: We sought to assess the effect of sunscreen use on nevus development by anatomic sites and by nevi of different sizes for white schoolchildren in a randomized trial. METHODS: We compared the new nevus count between the sunscreen intervention group (n = 145) and the control group (n = 164) by anatomic site. RESULTS: Children randomized to the sunscreen group had significantly fewer new nevi on the trunk than children in the control group. The differences were more pronounced among the freckled children than children with no freckles. LIMITATIONS: Potential limitations to this study include relatively small numbers of enrolled children, and a follow-up period of only 3 years. CONCLUSION: Sunscreen use attenuated new nevus development on intermittently sun-exposed body sites for white schoolchildren, particularly among the freckled children.

Age Factors↗
PubMed2005

Identification of occupational cancer risks in British Columbia: a population-based case-control study of 1129 cases of bladder cancer.

OBJECTIVE: We collected information on lifetime occupational histories, smoking, and alcohol consumption from 15,463 incident cancer cases. Occupational risk factors for bladder cancer are presented in this report. METHOD: A matched case-control design was used. All cases were diagnosed with bladder cancers, with controls being internal controls consisting of all other cancer sites, excluding lung and unknown primary. Data were analyzed using conditional logistic regression for matched sets data and the likelihood ratio test. RESULTS: Excess bladder cancer risks was observed in a number of occupation and industries, particularly those involving exposure to metals, including aluminum, paint and solvents, polycyclic aromatic hydrocarbons, diesel engine emissions, and textiles. CONCLUSIONS: The results of our study are in line with those from the literature and further suggest that exposure to silica and to electromagnetic fields may carry an increased risk of bladder cancer.

Adult↗
PubMed2005

Twenty-four-hour light exposure and melatonin levels among shift workers.

OBJECTIVES: We sought to measure melatonin levels and 24-hour light intensity exposure in health care workers over a 7-day period in natural occupational and residential settings. METHODS: Five office workers and 17 nurses working either days or rotating night and day shifts wore a device to record light intensity exposure for one or two 7-day periods, completed a questionnaire, and provided three saliva samples for melatonin. RESULTS: Rotating shift workers had irregular light exposure patterns and abnormal melatonin levels compared with those working days. In addition to lower-than-normal melatonin levels during sleep periods, rotating shift workers exhibited higher-than-normal melatonin levels on arising and during work. Self-reported years of shift work were correlated with measured melatonin and light. CONCLUSIONS: Rotating shift work is supported as a surrogate for exposure to light-at-night and circadian disruption.

Adult↗