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Colin B Begg

Publications and source records attributed to Colin B Begg.

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

Properties of analysis methods that account for clustering in volume-outcome studies when the primary predictor is cluster size.

In recent years health services researchers have conducted 'volume-outcome' studies to evaluate whether providers (hospitals or surgeons) who treat many patients for a specialized condition have better outcomes than those that treat few patients. These studies and the inherent clustering of events by provider present an unusual statistical problem. The volume-outcome setting is unique in that 'volume' reflects both the primary factor under study and also the cluster size. Consequently, the assumptions inherent in the use of available methods that correct for clustering might be violated in this setting. To address this issue, we investigate via simulation the properties of three estimation procedures for the analysis of cluster correlated data, specifically in the context of volume-outcome studies. We examine and compare the validity and efficiency of widely-available statistical techniques that have been used in the context of volume-outcome studies: generalized estimating equations (GEE) using both the independence and exchangeable correlation structures; random effects models; and the weighted GEE approach proposed by Williamson et al. (Biometrics 2003; 59:36-42) to account for informative clustering. Using data generated either from an underlying true random effects model or a cluster correlated model we show that both the random effects and the GEE with an exchangeable correlation structure have generally good properties, with relatively low bias for estimating the volume parameter and its variance. By contrast, the cluster weighted GEE method is inefficient.

Aged↗
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

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

Cancer survivorship--genetic susceptibility and second primary cancers: research strategies and recommendations.

Cancer survivors constitute 3.5% of the United States population, but second primary malignancies among this high-risk group now account for 16% of all cancer incidence. Although few data currently exist regarding the molecular mechanisms for second primary cancers and other late outcomes after cancer treatment, the careful measurement and documentation of potentially carcinogenic treatments (chemotherapy and radiotherapy) provide a unique platform for in vivo research on gene-environment interactions in human carcinogenesis. We review research priorities identified during a National Cancer Institute (NCI)-sponsored workshop entitled "Cancer Survivorship--Genetic Susceptibility and Second Primary Cancers." These priorities include 1) development of a national research infrastructure for studies of cancer survivorship; 2) creation of a coordinated system for biospecimen collection; 3) development of new technology, bioinformatics, and biomarkers; 4) design of new epidemiologic methods; and 5) development of evidence-based clinical practice guidelines. Many of the infrastructure resources and design strategies that would facilitate research in this area also provide a foundation for the study of other important nonneoplastic late effects of treatment and psychosocial concerns among cancer survivors. These research areas warrant high priority to promote NCI's goal of eliminating pain and suffering related to cancer.

Antineoplastic Agents↗
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

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

The effect of changes in tumor size on breast carcinoma survival in the U.S.: 1975-1999.

BACKGROUND: Temporal comparisons of case survival are commonly used to assess improvement in cancer treatment at the population level. However, such comparisons may be confounded by secular trends in disease prognosis, even within conventional stage categories. The objective of the current study was to characterize within-stage migration of tumor size in breast carcinoma, and to estimate the effect of this shift on reported breast carcinoma survival. METHODS: Population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry data were used to evaluate secular trends in tumor size at the time of diagnosis and relative survival among localized and regional invasive breast carcinoma patients diagnosed between 1975-1999. Outcomes were stage-specific tumor size distribution, 5-year relative survival, relative survival standardized to the tumor size distribution of the cohort diagnosed between 1975-1979, and the percentage of improvement in relative survival attributable to shifts in tumor size distribution. RESULTS: Within each stage category, the proportion of smaller tumors increased significantly over time. Comparing patients diagnosed between 1995-1999 with those diagnosed between 1975-1979, within-stage migration of tumor size accounted for 61% and 28%, respectively, of the relative survival increases noted in localized and regional breast carcinoma. CONCLUSIONS: The tumor size distribution of incident breast carcinomas in SEER has shifted toward smaller tumors. A substantial fraction of the improvement in breast carcinoma survival noted since 1975 may be attributable to within-stage migration of tumor size.

Age Factors↗
PubMed2005

HER2 codon 655 polymorphism and breast cancer: results from kin-cohort and case-control analyses.

Several published epidemiologic studies show increased breast cancer risk for carriers of the Val-allele at codon 655 of the HER2 gene. We conducted additional analyses using data from three studies, including case-control analyses stratified on age and kin-cohort analyses using relatives of cases and controls. The results provide additional evidence that HER2 codon 655 genotype may predispose to early-onset breast cancer.

Adult↗
PubMed2005

Cystectomy for muscle-invasive bladder cancer: patterns and outcomes of care in the Medicare population.

OBJECTIVES: To describe the population-based patterns of care among patients with muscle-invasive bladder cancer. METHODS: A retrospective cohort study using the Surveillance, Epidemiology and End Results (SEER)-Medicare database identified 4664 patients aged 65 years or older with muscle-invasive bladder cancer diagnosed between 1991 and 1999. The use of particular treatment modalities was evaluated according to the clinical and demographic characteristics available in the SEER-Medicare database. RESULTS: Considerable variation was found in the treatments delivered to the cohort members. Overall, 39% had undergone cystectomy; 30% of Stage II, 57% of Stage III, and 38% of Stage IV patients underwent this operation within 6 months of diagnosis. The frequency of resection declined with age, such that 55% of patients aged 65 to 69 years and 27% of those aged 80 to 84 years underwent cystectomy. For 36% of Stage II, 18% of Stage III, and 27% of Stage IV patients, no evidence was found of surgery, chemotherapy, or radiotherapy within 6 months of diagnosis. Other management strategies included chemotherapy alone (14% Stage II, 6% Stage III, and 12% Stage IV), radiotherapy alone (11% for each stage), or combined modality chemoradiotherapy (10% Stage II, 8% Stage III, and 12% Stage IV). Multivariate analyses suggested that cystectomy conferred a survival advantage. CONCLUSIONS: A marked heterogeneity exists in the strategies used to treat muscle-invasive bladder cancer. The extent to which this variation can be attributed to the lack of informative clinical trials, the presence of comorbid illness, patient or physician preferences, or access to care warrants further evaluation.

Aged↗
PubMed2005

Variations among high volume surgeons in the rate of complications after radical prostatectomy: further evidence that technique matters.

PURPOSE: A strong association between surgeon, hospital volume and postoperative morbidity of radical prostatectomy has been demonstrated. While better outcomes are associated with high volume surgeons, the degree of variation in outcomes among surgeons has not been fully examined. MATERIALS AND METHODS: Using a linked database from Surveillance, Epidemiology and End Results registries and federal Medicare claims data, we analyzed outcomes of consecutive patients treated with radical prostatectomy between 1992 and 1996. We focused on variations in several measures of morbidity (perioperative complications, late urinary complications and long-term incontinence) among patients of high volume surgeons, defined as those with 20 or more patients in the study period. After adjusting for hospital, surgeon volume and case mix, we examined the extent to which variations in the rates of adverse outcomes differed among surgeons for all 3 end points. RESULTS: Of the 999 surgeons 16% (159) performed 48.7% (5,238) of the 10,737 radical prostatectomies during the study. The 30-day mortality rate was 0.5%, the major postoperative complication rate was 28.6%, late urinary complications 25.2% (major events 16%) and long-term incontinence 6.7%. For all 3 morbidity outcomes the variation among surgeons in the rate of complications was significantly greater than that expected by chance (p =0.001 for each) after adjustment of covariates. Furthermore, surgeons with better (or worse) than average results with regard to 1 outcome were likely to have better (or worse, respectively) results with regard to the other 2 outcome measures. CONCLUSIONS: Morbidity end points that directly affect quality of life showed significant variability among high volume providers. Surgeons who performed well in 1 area (eg postoperative complications) performed well in others. These results further suggest that variations in surgical technique and postoperative care lead to variations in outcomes after radical prostatectomy, indicating that outcomes of this operation are sensitive to small differences in performance.

Aged↗
PubMed2004

Resurrecting treatment histories of dead patients: a study design that should be laid to rest.

In this article we address whether studies of care rendered to patients prior to their death ("studies of decedents") produce an accurate portrait of care provided to patients who are dying. Studies of decedents typically analyze the care provided to patients over a defined interval antecedent to death. Studies of dying patients analyze care provided to patients subsequent to the time that their terminal status is perceived. We address whether 2 fundamental differences between studies of decedents and studies of the dying--the ways that subjects are identified and the time periods that are examined--lead to differences in interpretation of study results. Using examples from population-based cohorts of individuals with cancer, we show that both the differences in subject selection and time period introduce very substantial biases into studies of decedents. We conclude that studying care received prior to death can lead to invalid conclusions about the quality or type of care provided to dying patients.

Bias↗