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Biomedical subjects

Peter Boyle

Publications and source records attributed to Peter Boyle.

At least 19 recordsLinked to original sources
PubMed2007

5alpha-Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia.

Controversy exists over the significance of associations between the SRD5A2 (5alpha-reductase type 2) polymorphisms, A49T and V89L, and risk of prostate cancer. These potentially functional polymorphisms may alter life-long exposure to androgens with subsequent effects on male health and aging. The aim of this study was to examine the association of these variants with prostate cancer risk, plasma hormone levels and androgenetic alopecia. Subjects include 827 cases and 736 controls from an Australian population-based case-control study of prostate cancer. Information on prostate cancer risk factors and patterns of balding were collected. Plasma levels of testosterone, 3alpha-diol glucuronide (3alpha-diolG), dehydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and estradiol were measured for controls. No associations with the V89L polymorphism were found. Carriers of the rarer A49T A allele were at a 60% higher risk of prostate cancer (OR = 1.60; 95% CI 1.09-2.36; p = 0.02) and 50% lower risk of vertex and frontal balding (p = 0.03) compared with men homozygous for the more common G allele. Although we found little evidence of association between this variant and plasma levels of 5 measured androgens, circulating 3alpha-diolG levels were 34% lower in A49T A allele carriers (p < 0.0001). Our study provides evidence that the SRD5A2 A49T A variant is associated with an increased risk of prostate cancer, lower levels of circulating 3alpha-diolG and decreased risk of baldness. These findings raise important questions with respect to previous assumptions concerning hormonal influences on prostate cancer risk in ageing males.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2007

Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma.

Circadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non-Hodgkin's lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer-related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population-based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51-0.85, p = 0.001), especially B-cell lymphoma (OR = 0.61, 95% CI: 0.47-0.80, p <or= 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation.

Aged↗
PubMed2007

Family history of hematopoietic and non-hematopoietic malignancies and risk of non-Hodgkin lymphoma.

BACKGROUND: Family history of hematopoietic malignancies has been linked to the risk of non-Hodgkin lymphoma (NHL). The relationship between family history of specific hematopoietic and non-hematopoietic malignancies and the risk of NHL and by NHL subtypes are unclear. METHODS: We analyzed data from a population-based case-control study in Connecticut women. A total of 601 histologically confirmed NHL incident cases and 717 randomly selected controls were included in the study. Unconditional logistic regression was used to estimate the association between family cancer history and risk of NHL overall and by NHL subtypes. RESULTS: Compared to women who reported to have no family history of any malignancies in first-degree relatives, those who reported to have a family history of lymphoma (OR = 2.2, 95%CI: 1.1-4.5) or leukemia (OR = 2.5, 95%CI: 1.2-5.2) had an increased risk of NHL. The risk was higher among women who had a sibling with lymphoma or leukemia than those who had parents with lymphoma or leukemia. Several non-hematopoietic malignancies in first-degree relatives, including cancer of the lung (OR = 1.7, 95%CI: 1.1-2.6) in first-degree relatives, stomach (OR = 2.2, 95%CI: 0.8-5.9) and pancreas (OR = 2.6, 95%CI: 0.9-7.1) in parents, as well as liver (OR = 5.0, 95%CI: 1.0-24.6), breast (OR = 2.2, 95%CI: 1.3-3.9), cervix (OR = 7.5, 95%CI: 0.9-64.9), and ovary (OR = 3.5, 95%CI: 1.1-11.5) in siblings were also associated with an increased risk of NHL. CONCLUSIONS: The risk associated with a family history of malignancies in first degree-relatives appears to vary by type of first-degree relatives.

Case-Control Studies↗
PubMed2006

Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma.

Oxidative damage caused by reactive oxygen species (ROS) and other free radicals is involved in a number of pathological conditions including cancer. In a population-based case-control study of non-Hodgkin lymphoma (NHL) (n = 518 cases, 597 controls) among women in Connecticut, we analyzed one or more single nucleotide polymorphisms (SNPs) in ten candidate genes (AKR1A1, AKR1C1, AKR1C3, CYBA, GPX1, MPO, NOS2A, NOS3, OGG1, and SOD2) that mediate oxidative stress directly or indirectly in the NADPH oxidase-dependent respiratory burst. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and race. Polymorphisms in AKR1A1 and CYBA were significantly associated with increased risk of NHL. There was a 1.7-fold (95% CI = 1.2-2.4, P = 0.0047) increased risk of NHL for individuals who were variant homozygous for the AKR1A1 (IVS5 + 282T > C) SNP. The effect was most pronounced for risk of diffuse large B-cell lymphoma, but risk estimates were non-significantly elevated for other common B-cell histologies and T-cell lymphomas as well. In addition, individuals variant homozygous for the CYBA (Ex4 + 11C > T) SNP had a 1.6-fold (95% CI = 1.1-2.4, P = 0.019) increased risk of NHL that was particularly pronounced for T-cell lymphoma (OR = 3.5, 95% CI = 1.3-9.6, P = 0.013), but was also associated with non-significant increased risks for each of the common B-cell histologies. These results suggest that SNPs in genes related to the oxidative stress pathway may be associated with increased risk of NHL.

Adult↗
PubMed2006

Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma.

The caspase proteins are essential for the regulation of normal B cell development and regulation of apoptosis. We investigated five single nucleotide polymorphisms in four key caspase genes, CASP3 [Ex8-280C>A (rs6948) and Ex8+567T>C (rs1049216)], CASP8 Ex14-271A>T (rs13113), CASP9 Ex5+32G>A (rs1052576) and CASP10 Ex3-171A>G (rs3900115) to determine whether they alter risk for non-Hodgkin lymphoma (NHL) in a population-based case-control study of women in Connecticut (461 cases and 535 controls). Variants in CASP3 and CASP9 were significantly associated with a decreased risk for NHL, particularly follicular lymphoma [e.g. CASP3 Ex8+567T>C odds ratio (OR)(CC+TC) = 0.4, 95% confidence interval (CI) = 0.3-0.7; and CASP9 Ex5+32G>A OR(AA+AG) = 0.6, 95% CI = 0.4-1.0]. Further, variants in CASP3, CASP8 and CASP10 were associated with a decreased risk of marginal zone lymphoma and variants in CASP3 and CASP10 were associated with a lower risk of chronic lymphocytic leukemia and related subtypes. The striking protective associations observed for polymorphisms in all four genes for NHL and/or one or more subtypes suggest that genetic variation in CASP genes may play an important role in the etiology of NHL.

Adult↗
PubMed2006

Estimates of the cancer burden in Europe from radioactive fallout from the Chernobyl accident.

The Chernobyl accident, which occurred April 26, 1986, resulted in a large release of radionuclides, which were deposited over a very wide area, particularly in Europe. Although an increased risk of thyroid cancer in exposed children has been clearly demonstrated in the most contaminated regions, the impact of the accident on the risk of other cancers as well as elsewhere in Europe is less clear. The objective of the present study was to evaluate the human cancer burden in Europe as a whole from radioactive fallout from the accident. Average country- and region-specific whole-body and thyroid doses from Chernobyl were estimated using new dosimetric models and radiological data. Numbers of cancer cases and deaths possibly attributable to radiation from Chernobyl were estimated, applying state-of-the-art risk models derived from studies of other irradiated populations. Simultaneously, trends in cancer incidence and mortality were examined over time and by dose level. The risk projections suggest that by now Chernobyl may have caused about 1,000 cases of thyroid cancer and 4,000 cases of other cancers in Europe, representing about 0.01% of all incident cancers since the accident. Models predict that by 2065 about 16,000 (95% UI 3,400-72,000) cases of thyroid cancer and 25,000 (95% UI 11,000-59,000) cases of other cancers may be expected due to radiation from the accident, whereas several hundred million cancer cases are expected from other causes. Although these estimates are subject to considerable uncertainty, they provide an indication of the order of magnitude of the possible impact of the Chernobyl accident. It is unlikely that the cancer burden from the largest radiological accident to date could be detected by monitoring national cancer statistics. Indeed, results of analyses of time trends in cancer incidence and mortality in Europe do not, at present, indicate any increase in cancer rates -- other than of thyroid cancer in the most contaminated regions -- that can be clearly attributed to radiation from the Chernobyl accident.

Adolescent↗
PubMed2006

Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma among women in Connecticut.

Several hereditary syndromes characterized by defective DNA repair are associated with high risk of non-Hodgkin lymphoma (NHL). To explore whether common polymorphisms in DNA repair genes affect risk of NHL in the general population, we evaluated the association between single nucleotide polymorphisms (SNPs) in DNA repair genes and risk of NHL in a population-based case-control study among women in Connecticut. A total of 518 NHL cases and 597 controls recruited into the study provided a biologic sample. Thirty-two SNPs in 18 genes involved in several DNA repair pathways were genotyped. Genotype data were analyzed by unconditional logistic regression adjusting for age and race. SNPs in four genes (ERCC5, ERCC2, WRN, and BRCA1) were associated with altered risk of NHL and diffuse large B-cell lymphoma (DLBCL), the major B cell subtype. In particular, ERCC5 Asp1104His was associated with increased risk of NHL overall (OR: 1.46; 95% CI: 1.13-1.88; P=0.004), DLBCL (OR: 1.44; 95% CI: 0.99-2.09; P=0.058), and also T cell lymphoma. WRN Cys1367Arg was associated with decreased risk of NHL overall (OR: 0.71; 95% CI: 0.56-0.91; P=0.007) and DLBCL (OR: 0.66; 95% CI: 0.45-0.95; P=0.024), as well as follicular and marginal zone lymphomas. Genetic polymorphisms in DNA repair genes, particularly ERCC5 and WRN, may play a role in the pathogenesis of NHL, especially for DLBCL. Further work is needed to extend these findings by carrying out extended haplotype analyses of these and related genes and to replicate the observations in other studies.

Adult↗
PubMed2006

Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma.

Studies have demonstrated that common polymorphisms in Th1 and Th2 cytokine genes can alter gene expression, modulate the balance between Th1/Th2 responsiveness, and influence susceptibility for autoimmune disorders, infectious diseases, and cancer. We analyzed one or more single nucleotide polymorphisms (SNPs) in 20 candidate Th1/Th2 genes in a population-based case-control study of non-Hodgkin lymphoma (NHL; n = 518 cases, 597 controls) among women in Connecticut. SNPs in critical genes, IL4, IL5, IL6, and IL10, were associated with risk for NHL and in some instances with a specific histologic subtype. Analysis of 4 SNPs in the IL10 promoter (-3575T>A, -1082A>G, -819C>T, and -592C>A) revealed that both the AGCC haplotype (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.21-1.96, P < .001) and the TATA haplotype (OR = 1.37, 95% CI = 1.05-1.79, P = .02) were associated with increased risk for B-cell lymphomas. In contrast, the IL4-1098G allele was associated with increased risk of T-cell lymphomas (OR = 3.84; 95% CI = 1.79-8.22; P < .001). Further, the IL10 and IL4 SNP associations remained significant after adjusting for multiple comparisons. These results suggest that SNPs in Th2 cytokine genes may be associated with risk of NHL.

Adult↗
PubMed2006

Measures of familial aggregation depend on definition of family history: meta-analysis for colorectal cancer.

OBJECTIVE: Familial aggregation, a primary theme in genetic epidemiology, can be estimated from family studies based on an index person. The excess risk due to the presence of affected family members can be classified according to whether disease in the relatives is considered a risk factor for the index person (type I relative risk) or whether the disease status of the index person is considered a risk factor for the relatives (type II relative risk). STUDY DESIGN AND SETTING: A meta-analysis of published colorectal cancer studies reporting a measure of familial association was performed and application of multilevel linear regression to model age-specific relative risks presented. RESULTS: The pooled type I relative risk of colorectal cancer given any affected first-degree relative (based on 20 studies) was 2.26 (95% confidence interval CI = 1.86, 2.73) and decreased with the age of the consultand. The pooled type II estimate (based on seven studies) was 2.81 (95% CI = 2.05, 3.85). CONCLUSION: Type I relative risks are useful in clinical counseling settings when a consultand wants to know his/her disease risk given his or her family history. Type II relative risks can be used to quantify the risk of disease to relatives of an affected individual and then identify subjects eligible for screening.

Age of Onset↗
PubMed2006

Does "clock" matter in prostate cancer?

The ancient adaptation of a 24-hour circadian clock has profound effect on our daily biochemical, physiologic, and behavioral processes, including the monitoring of sex hormone levels. Although the disruption of the circadian cycle has been implicated in the etiology of hormone-related female breast cancer, few studies have been undertaken to determine if a link exists in the development of the most common cancer type among men whose etiology remains largely unknown: hormone-related prostate cancer. Here, we hypothesize that both altered-lighted environments and genetic variations in genes responsible for maintaining circadian rhythms may result in deregulation of clock-associated biological processes, such as androgen expression, and consequently influence an individual's risk of prostate cancer. There is also a potential for the interaction of genetic variants and exposures, such as evening shift work. Confirmation of this hypothesis will add to our understanding of the role of the circadian clock in prostate tumorigenesis and further facilitate the development of novel risk and prognostic biomarkers for prostate cancer.

Androgens↗
PubMed2006

Circulating steroid hormones and the risk of prostate cancer.

Epidemiologic studies have failed to support the hypothesis that circulating androgens are positively associated with prostate cancer risk and some recent studies have even suggested that high testosterone levels might be protective particularly against aggressive cancer. We tested this hypothesis by measuring total testosterone, androstanediol glucuronide, androstenedione, DHEA sulfate, estradiol, and sex hormone-binding globulin in plasma collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean 8.7 years follow-up and a randomly sampled sub-cohort of 1,859 men. The association between each hormone level and prostate cancer risk was tested using Cox models adjusted for country of birth. The risk of prostate cancer was approximately 30% lower for a doubling of the concentration of estradiol but the evidence was weak (P(trend)=0.07). None of the other hormones was associated with overall prostate cancer (P(trend) >or= 0.3). None of the hormones was associated with nonaggressive prostate cancer (all P(trend) >or= 0.2). The hazard ratio [HR; 95% confidence interval (95% CI)] for aggressive cancer almost halved for a doubling of the concentration of testosterone (HR, 0.55; 95% CI, 0.32-0.95) and androstenedione (HR, 0.51; 95% CI, 0.31-0.83), and was 37% lower for a doubling of the concentration of DHEA sulfate (HR, 0.63; 95% CI, 0.46-0.87). Similar negative but nonsignificant linear trends in risk for aggressive cancer were obtained for free testosterone, estradiol, and sex hormone-binding globulin (P(trend)=0.06, 0.2, and 0.1, respectively). High levels of testosterone and adrenal androgens are thus associated with reduced risk of aggressive prostate cancer but not with nonaggressive disease.

Adult↗
PubMed2006

Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer.

Some recent epidemiologic studies have failed to confirm positive associations between insulin-like growth factor-I (IGF-I) and the risk of prostate cancer observed in earlier studies but have reported suggestive evidence for a positive association between IGF-binding protein-3 (IGFBP-3) and prostate cancer risk, a result contradicting the earlier assumption that high levels of IGFBP-3 would be protective against prostate cancer. We tested the association between IGF-I and IGFBP-3 and prostate cancer risk by measuring the two peptides in plasma samples collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean of 8.7 years follow-up and a randomly sampled subcohort of 1,826 men. The association between each peptide level and prostate cancer risk was tested using Cox models adjusted for country of birth and alcohol consumption. The risk of prostate cancer was not associated with baseline levels of IGF-I or the molar ratio IGF-I/IGFBP-3 (all odds ratios are between 0.82 and 1.08; P(trend) > or = 0.2), whereas the risk increased with baseline levels of IGFBP-3 (P(trend) = 0.008), the hazard ratio (HR) associated with a doubling of the concentration of IGFBP-3 being 1.70 (95% confidence interval, 1.15-2.52). The HR for quartile 4 relative to quartile 1 of IGFBP-3 was 1.49 (95% confidence interval, 1.11-2.00). The HRs did not differ by tumor aggressiveness or age at onset (all Ps > or = 0.4). In our study, high levels of IGFBP-3 but not IGF-I were associated with an increased risk of prostate cancer.

Aged↗
PubMed2006

Variants in the prostate-specific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA.

An A to G substitution, rs925013, in the promoter of the prostate-specific antigen gene (PSA) was recently found to be associated with promoter activity and circulating PSA levels. The objective of this study was to test the associations between rs925013 and another A to G substitution, rs266882, in the PSA gene with prostate cancer risk using a population-based case-control study of 821 prostate cancer cases and 734 controls carried out in Perth and Melbourne, Australia. The study focused on young (i.e., < 70 years) and aggressive cases (i.e., well-differentiated tumors were excluded). Cases in the Melbourne arm of the study (N = 638) were followed up prospectively for an average period of 8.2 years and deaths from prostate cancer ascertained through record linkage to study the possible association between genetic variants and disease-specific survival. PSA-circulating levels were measured in controls to test the association with the genetic variants using a cross-sectional design. Linear regression of log PSA levels, unconditional logistic regression, Cox regression, and haplotype analyses were undertaken. For rs925013, the G allele was associated with an increased risk of prostate cancer [odds ratio, 1.4; 95% confidence interval (95% CI), 1.1-1.7; P = 0.001], and the hazard ratio for survival for cases homozygous for the G allele compared with cases homozygous for the A allele was increased but not statistically significant (hazard ratio, 2.3; 95% CI, 1-5.6; P = 0.06). For rs266882, there was no association with overall prostate cancer risk and survival (all P > 0.1). Men homozygous or heterozygous for the G/G (rs925013/rs266882) haplotype were at higher risk of prostate cancer than men homozygous for the A/A haplotype (odds ratio, 1.3; 95% CI, 1.1-1.7; P = 0.009). Adjusted geometric means of circulating PSA levels in controls were similar in men with zero, one, and two copies of the G allele in rs266882 (1.2, 1.1, and 1.3 ng/mL, respectively; all P > or = 0.2) and rs925013 (1.1, 1.2, and 1.5 ng/mL, respectively; all P > 0.1). For rs925013, our study provides good evidence of association with prostate cancer risk, marginal evidence of association with survival, and little evidence of detectable association with circulating PSA levels in controls. We found no evidence of an independent association between rs266882 and any of the outcomes. The genotypes and haplotypes studied might be associated with the PSA gene function or be in linkage disequilibrium with other unmeasured and functional variants in the PSA or other genes.

Aged↗
PubMed2005

A putative exonic splicing polymorphism in the BCL6 gene and the risk of non-Hodgkin lymphoma.

Recent studies have shown that the B-cell lymphoma 6 gene (BCL6) is an oncogene that contributes to lymphomagenesis. Exon 6 of BCL6 contains a common single nucleotide polymorphism (SNP) (-195 C>T; dbSNP ID: rs1056932) that alters a potential binding site for an exonic splicing enhancer. We used unconditional logistic regression models to examine the association between this SNP and the risk of non-Hodgkin lymphoma (NHL) in a population-based case-control study of women residing in Connecticut (461 case patients and 535 control subjects). The risk of NHL among women with the CC genotype was more than double that of women with the TT genotype (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.5 to 3.3). Higher risks were observed for two NHL subtypes, namely B-cell chronic lymphatic leukemia/prolymphocytic leukemia/small lymphocytic lymphoma (OR = 3.5, 95% CI = 1.6 to 7.8) and T-cell lymphoma (OR = 5.2, 95% CI = 2.0 to 13.3). Our results support the hypothesis that a genetic variant that could alter mRNA transcripts of BCL6 may contribute to the etiology of NHL and suggest that this variant warrants further investigation.

Case-Control Studies↗
PubMed2005

Effect of tamoxifen on venous thromboembolic events in a breast cancer prevention trial.

BACKGROUND: Tamoxifen, a selective estrogen-receptor modulator, increases venous thromboembolic events (VTE), but the factors explaining this risk are unclear. Atherosclerosis may induce VTE, or the 2 conditions may share common risk factors. We assessed the effect of tamoxifen on VTE in a breast cancer prevention trial and studied its association with risk factors for VTE. METHODS AND RESULTS: The incidence of VTE was studied in 5408 hysterectomized women randomly assigned to tamoxifen 20 mg/d or placebo for 5 years. There were 28 VTEs on placebo and 44 on tamoxifen therapy (hazard ratio [HR]=1.63; 95% confidence interval [CI], 1.02 to 2.63), 80% of which were superficial phlebitis, accounting for all of the excess due to tamoxifen within 18 months from randomization. Compared with placebo, the risk of VTE on tamoxifen was higher in women aged 55 years or older, women with a body mass index > or =25 kg/m2, elevated blood pressure, total cholesterol > or =250 mg/dL, current smoking, and a family history of coronary heart disease (CHD). Of the 685 women with a CHD risk score > or =5 who entered the trial, 1 in the placebo arm and 13 in the tamoxifen arm developed VTE (log-rank P=0.0013). In multivariate regression analysis, age > or =60 years, height > or =165 cm, and diastolic blood pressure > or =90 mm Hg had independent detrimental effects on VTE risk during tamoxifen therapy, whereas transdermal estrogen therapy concomitant with tamoxifen was not associated with any excess of VTE (HR=0.64; 95% CI, 0.23 to 1.82). CONCLUSIONS: Women with conventional risk factors for atherosclerosis have a higher risk of VTE during tamoxifen therapy. This information should be incorporated into counseling women on its risk-benefit ratio, particularly in the prevention setting.

Adult↗
PubMed2005

Breast cancer control: signs of progress, but more work required.

Breast cancer represents 10% of the global cancer burden and there is no population, or population sub-group, which has yet been identified to be at a truly low risk of developing the disease. Mortality rates have been steadily growing for nearly a century in many countries and it is only during the past decade that there have been signs of a sustainable decrease in mortality rates in a number of western-lifestyle countries. This represents considerable progress in breast cancer control and, although different factors contribute to different degrees in different countries, is mainly due to increased breast awareness, earlier detection and the delivery of the most appropriate therapy to women with the disease. The failure to prevent the incidence from continuing to rise represents to a great extent the failure to understand the precise mechanisms of breast carcinogenesis and the role of risk determinants whose alteration in society could lead to a reduced risk of developing the disease. The declines seen in mortality represent a considerable success, but there is no room for complacency until research can impact positively on reducing incidence.

Breast Neoplasms↗