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1.
Hum Mol Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600786

RESUMO

We previously identified five SNPs at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5,662 cases and 9,237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF]=0.40) was associated with DLBCL risk (OR=0.83, P=3.62x10-13). rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5,510 cases and 12,817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF=0.45) was also associated with DLBCL risk (OR=1.20, P=2.31x10-12). This SNP is 29,426 bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

2.
Genet Epidemiol ; 43(7): 844-863, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31407831

RESUMO

Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

3.
Int J Cancer ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340063

RESUMO

Cancer burden is increasing in kidney transplant recipients, but differences in mortality compared to the general population remain unclear. We sought to compare cancer mortality in paediatric and adult kidney transplant recipients with the general population and describe any differences, by site, age and sex, country and over time. We included kidney transplant recipients from the Australian and New Zealand Dialysis and Transplantation Registry, 1980-2013. Date of death and underlying cause of death were ascertained by data-linkage and classified using ICD10AM codes. Indirect standardisation was used to estimate standardised mortality ratios (SMR). There were 5,284 deaths in 17,628 kidney transplant recipients over 175,084 person-years of observation, including 1,061 (20%) cancer deaths. Relative cancer mortality was higher than the general population for all-site (SMR 2.9, 95% CI 2.7-3.1) cancer and highest for nonmelanoma skin cancer (SMR 50.9, 95% CI 43.5-59.6) and lymphoma (SMR 42.2, 95% CI 35.3-50.5). Relative cancer mortality decreased with increasing age in men (p < 0.001) and women (p = 0.001) but never reached parity with the general population. Relative mortality did not change with age for skin and lip, or colorectal cancers (p-value >0.1). Only relative colorectal cancer mortality increased over time (p = 0.002). Our study shows cancer mortality in kidney transplant recipients was higher than expected in the general population. The magnitude of excess mortality varied by cancer site, age and sex. Further evidence is needed to identify whether this variation is due to differences at diagnosis or access and effectiveness of cancer treatments in this population.

4.
Cancer Causes Control ; 30(8): 889-900, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165419

RESUMO

PURPOSE: To conduct a pooled analysis assessing the association of blood transfusion with risk of non-Hodgkin lymphoma (NHL). METHODS: We used harmonized data from 13 case-control studies (10,805 cases, 14,026 controls) in the InterLymph Consortium. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, adjusted for study design variables. RESULTS: Among non-Hispanic whites (NHW), history of any transfusion was inversely associated with NHL risk for men (OR 0.74; 95% CI 0.65-0.83) but not women (OR 0.92; 95% CI 0.83-1.03), pheterogeneity = 0.014. Transfusion history was not associated with risk in other racial/ethnic groups. There was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion, and further adjustment for socioeconomic status, body mass index, smoking, alcohol use, and HCV seropositivity did not alter the results. Associations for NHW men were stronger in hospital-based (OR 0.56; 95% CI 0.45-0.70) but still apparent in population-based (OR 0.84; 95% CI 0.72-0.98) studies. CONCLUSIONS: In the setting of a literature reporting mainly null and some positive associations, and the lack of a clear methodologic explanation for our inverse association restricted to NHW men, the current body of evidence suggests that there is no association of blood transfusion with risk of NHL.


Assuntos
Transfusão de Sangue , Linfoma não Hodgkin/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Adulto Jovem
5.
Int J Cancer ; 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31107541

RESUMO

Substantial changes in the prevalence of the principal kidney and bladder cancer risk factors, smoking (both cancers) and body fatness (kidney cancer), have occurred but the contemporary cancer burden attributable to these factors has not been evaluated. We quantified the kidney and bladder cancer burden attributable to individual and joint exposures and assessed whether these burdens differ between population subgroups. We linked pooled data from seven Australian cohorts (N = 367,058) to national cancer and death registries and estimated the strength of the associations between exposures and cancer using adjusted proportional hazards models. We estimated exposure prevalence from representative contemporaneous health surveys. We combined these estimates to calculate population attributable fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. During the first 10-year follow-up, 550 kidney and 530 bladder cancers were diagnosed and over 21,000 people died from any cause. Current levels of overweight and obesity explain 28.8% (CI = 17.3-38.7%), current or past smoking 15.5% (CI = 6.0-24.1%) and these exposures jointly 39.6% (CI = 27.5-49.7%) of the kidney cancer burden. Current or past smoking explains 44.4% (CI = 35.4-52.1%) of the bladder cancer burden, with 24.4% attributable to current smoking. Ever smoking explains more than half (53.4%) of the bladder cancer burden in men, and the burden potentially preventable by quitting smoking is highest in men (30.4%), those aged <65 years (28.0%) and those consuming >2 standard alcoholic drinks/day (41.2%). In conclusion, large fractions of kidney and bladder cancers in Australia are preventable by behavior change.

6.
Gynecol Oncol ; 153(3): 580-588, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30935715

RESUMO

OBJECTIVE: Evidence on the endometrial and ovarian cancer burden preventable through modifications to current causal behavioural and hormonal exposures is limited. Whether the burden differs by population subgroup is unknown. METHODS: We linked pooled data from six Australian cohort studies to national cancer and death registries, and quantified exposure-cancer associations using adjusted proportional hazards models. We estimated exposure prevalence from representative health surveys. We then calculated Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), accounting for competing risk of death, and compared PAFs for population subgroups. RESULTS: During a median 4.9 years follow-up, 510 incident endometrial and 303 ovarian cancers were diagnosed. Overweight and obesity explained 41.9% (95% CI 32.3-50.1) of the endometrial cancer burden and obesity alone 34.5% (95% CI 27.5-40.9). This translates to 12,800 and 10,500 endometrial cancers in Australia in the next 10 years, respectively. The body fatness-related endometrial cancer burden was highest (49-87%) among women with diabetes, living remotely, of older age, lower socio-economic status or educational attainment and born in Australia. Never use of oral contraceptives (OCs) explained 8.1% (95% CI 1.8-14.1) or 2500 endometrial cancers. A higher BMI and current long-term MHT use increased, and long-term OC use decreased, the risk of ovarian cancer, but the burden attributable to overweight, obesity or exogenous hormonal factors was not statistically significant. CONCLUSIONS: Excess body fatness, a trait that is of high and increasing prevalence globally, is responsible for a large proportion of the endometrial cancer burden, indicating the need for effective strategies to reduce adiposity.


Assuntos
Diabetes Mellitus/epidemiologia , Neoplasias do Endométrio/epidemiologia , Obesidade/epidemiologia , Neoplasias Ovarianas/epidemiologia , Adiposidade , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Índice de Massa Corporal , Estudos de Coortes , Anticoncepcionais Orais/uso terapêutico , Neoplasias do Endométrio/prevenção & controle , Feminino , Inquéritos Epidemiológicos , Terapia de Reposição Hormonal , Humanos , Incidência , Menopausa , Pessoa de Meia-Idade , Neoplasias Ovarianas/prevenção & controle , Fatores de Proteção , Sistema de Registros , Características de Residência , Fatores de Risco , População Rural , Fatores Socioeconômicos , Adulto Jovem
7.
AIDS ; 33(8): 1361-1368, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30950880

RESUMO

BACKGROUND: Anal cancer incidence increased markedly in people living with HIV (PLWHIV) after the introduction of HAART, but in a few setting settings, recent declines have been reported. We report the incidence and time trends of anal cancer in PLWHIV in Australia. STUDY DESIGN: A data linkage study between the National HIV Registries and the Australian Cancer Database. METHODS: Cases of anal squamous cell carcinoma (ASCC) in Australians aged 16 years and above diagnosed with HIV between 1982 and 2012 were identified. Standardized incidence ratios (SIRs) were calculated to compare incidence with that of the general population. Poisson regression models were developed to describe the time trends of ASCC over time and to compare ASCC risk within subgroups of PLWHIV. RESULTS: Among 28 696 individuals, a total of 129 cases of ASCC were identified. The crude incidence was 36.3 per 100 000 person-years and it increased sharply from 14.8 to 62.1 per 100 000 person-years between 1982-1995 and 2009-2012 (P trend <0.001). The SIR was 35.3 (95% confidence interval 29.5-42.0), and there was an inverse association between SIR and increasing age (P trend <0.001). In multivariate analyses, ASCC incidence was significantly higher in recent years (P trend <0.001), in those who acquired HIV through male homosexual contact (P = 0.002), and in those who had a history of AIDS (P < 0.001). CONCLUSION: PLWHIV in Australia are at markedly higher risk of anal cancer. Unlike in some industrialized countries with a mature HIV epidemic, the incidence of anal cancer is still increasing in this population in Australia.

8.
Int J Cancer ; 145(9): 2383-2394, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30802946

RESUMO

Estimates of the future breast cancer burden preventable through modifications to current behaviours are lacking. We assessed the effect of individual and joint behaviour modifications on breast cancer burden for premenopausal and postmenopausal Australian women, and whether effects differed between population subgroups. We linked pooled data from six Australian cohort studies (n = 214,536) to national cancer and death registries, and estimated the strength of the associations between behaviours causally related to cancer incidence and death using adjusted proportional hazards models. We estimated exposure prevalence from representative health surveys. We combined these estimates to calculate Population Attributable Fractions (PAFs) with 95% confidence intervals (CIs), and compared PAFs for population subgroups. During the first 10 years follow-up, there were 640 incident breast cancers for premenopausal women, 2,632 for postmenopausal women, and 8,761 deaths from any cause. Of future breast cancers for premenopausal women, any regular alcohol consumption explains 12.6% (CI = 4.3-20.2%), current use of oral contraceptives for ≥5 years 7.1% (CI = 0.3-13.5%), and these factors combined 18.8% (CI = 9.1-27.4%). Of future breast cancers for postmenopausal women, overweight or obesity (BMI ≥25 kg/m2 ) explains 12.8% (CI = 7.8-17.5%), current use of menopausal hormone therapy (MHT) 6.9% (CI = 4.8-8.9%), any regular alcohol consumption 6.6% (CI = 1.5-11.4%), and these factors combined 24.2% (CI = 17.6-30.3%). The MHT-related postmenopausal breast cancer burden varied by body fatness, alcohol consumption and socio-economic status, the body fatness-related postmenopausal breast cancer burden by alcohol consumption and educational attainment, and the alcohol-related postmenopausal breast cancer burden by breast feeding history. Our results provide evidence to support targeted and population-level cancer control activities.

9.
Med J Aust ; 210(5): 213-220, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30656698

RESUMO

OBJECTIVE: To estimate the burden of pancreatic cancer in Australia attributable to modifiable exposures, particularly smoking. DESIGN: Prospective pooled cohort study. SETTING, PARTICIPANTS: Seven prospective Australian study cohorts (total sample size, 365 084 adults); participant data linked to national registries to identify cases of pancreatic cancer and deaths. MAIN OUTCOME MEASURES: Associations between exposures and incidence of pancreatic cancer, estimated in a proportional hazards model, adjusted for age, sex, study, and other exposures; future burden of pancreatic cancer avoidable by changes in exposure estimated as population attributable fractions (PAFs) for whole population and for specific population subgroups with a method accounting for competing risk of death. RESULTS: There were 604 incident cases of pancreatic cancer during the first 10 years of follow-up. Current and recent smoking explained 21.7% (95% CI, 13.8-28.9%) and current smoking alone explained 15.3% (95% CI, 8.6-22.6%) of future pancreatic cancer burden. This proportion of the burden would be avoidable over 25 years were current smokers to quit and there were no new smokers. The burden attributable to current smoking is greater for men (23.9%; 95% CI, 13.3-33.3%) than for women (7.2%; 95% CI, -0.4% to 14.2%; P = 0.007) and for those under 65 (19.0%; 95% CI, 8.1-28.6%) than for older people (6.6%; 95% CI, 1.9-11.1%; P = 0.030). There were no independent relationships between body mass index or alcohol consumption and pancreatic cancer. CONCLUSIONS: Strategies that reduce the uptake of smoking and encourage current smokers to quit could substantially reduce the future incidence of pancreatic cancer in Australia, particularly among men.


Assuntos
Ex-Fumantes/estatística & dados numéricos , não Fumantes/estatística & dados numéricos , Neoplasias Pancreáticas/mortalidade , Fumantes/estatística & dados numéricos , Fumar/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/prevenção & controle , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Abandono do Hábito de Fumar
10.
Clin Transplant ; 33(2): e13470, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30586213

RESUMO

BACKGROUND: Most cohort studies investigating the effect of immunosuppression on transplant outcomes use drugs at first hospital discharge. We evaluated the extent of drug exposure misclassification and its impact on outcome prediction. METHODS: We retrospectively collected longitudinal immunosuppression data, at discharge and at 1, 5, 10, and 15 years after transplantation, and outcomes for solid organ transplant recipients 1984-2006 (n = 3133). We compared the risk of death from exposure to individual immunosuppressive drugs (cyclosporine, tacrolimus, azathioprine, and mycophenolate) and dual therapies, as defined by discharge only vs longitudinal immunosuppression data, using adjusted Cox proportional hazards models. RESULTS: During a median follow-up of 5.2 years, immunosuppressive drugs were altered for 947 (30%) recipients and 955 recipients died. Longitudinal receipt of cyclosporine and azathioprine were associated with an increased risk (HR 1.41, 95% CI 1.07-1.89, and HR 1.34, 95% CI 1.00-1.80), and mycophenolate with a reduced risk (HR 0.35, 0.16-0.78), of death. Recipients on mycophenolate and tacrolimus dual therapy had a lower risk of death compared to those on azathioprine and cyclosporine dual therapy (HR 0.30, 0.10-0.93). The increased risk of death associated with the receipt of cyclosporine or azathioprine was not shown in the analyses based on drugs allocated at discharge, and all of the associations between immunosuppressive regimens and death were strengthened in the analyses based on longitudinal immunosuppression data. CONCLUSIONS: Cohort findings based on immunosuppressive drugs allocated at discharge should be interpreted with caution due to potential exposure misclassification. The use of granular, longitudinal data on immunosuppressive regimens could improve prediction.

11.
Nat Commun ; 9(1): 4182, 2018 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305637

RESUMO

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40-31.03, P = 1.36 × 10-54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45-6.96, P = 8.75 × 10-19). Both risk alleles are observed at a low frequency among controls (~2-3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy.

12.
Int J Epidemiol ; 47(6): 1772-1783, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29982519

RESUMO

Background: Knowledge of preventable disease and differences in disease burden can inform public health action to improve health and health equity. We quantified the future lung cancer burden preventable by behavioural modifications across Australia. Methods: We pooled seven Australian cohort studies (n = 367 058) and linked them to national registries to identify lung cancers and deaths. We estimated population attributable fractions and their 95% confidence intervals (CIs) for modifiable risk factors, using risk estimates from the cohort data and risk factor exposure distribution from contemporary national health surveys. Results: During the first 10-year follow-up, there were 2025 incident lung cancers and 20 349 deaths. Stopping current smoking could prevent 53.7% (95% CI, 50.0-57.2%) of lung cancers over 40 years and 18.3% (11.0-25.1%) in 10 years. The smoking-attributable burden is highest in males, those who smoke <20 cigarettes per day, are <75 years of age, unmarried, of lower educational attainment, live in remote areas or are healthy weight. Increasing physical activity and fruit consumption, if causal, could prevent 15.6% (6.9-23.4%) and 7.5% (1.3-13.3%) of the lung cancer burden, respectively. Jointly, the three behaviour modifications could prevent up to 63.0% (58.0-67.5%) of lung cancers in 40 years, and 31.2% (20.9-40.1%) or 43 300 cancers in 10 years. The preventable burden is highest among those with multiple risk factors. Conclusions: Smoking remains responsible for the highest burden of lung cancer in Australia. The uneven burden distribution distinguishes subgroups that could benefit the most from activities to control the world's deadliest cancer.

13.
BMJ Open ; 8(6): e021064, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29950466

RESUMO

INTRODUCTION: The introduction of targeted therapies for cancer has contributed to dramatic improvements in patient survival. Nevertheless, several targeted therapies have been associated with 'off-target' adverse effects, based on varying levels of evidence. To date, this evidence has not been systematically synthesised. We will synthesise published systematic review evidence of cardiovascular toxicity associated with targeted cancer therapies. METHODS AND ANALYSIS: We will include systematic reviews of randomised controlled trials and observational studies that report on cardiovascular outcomes for individual agents. We will identify systematic reviews by applying predeveloped, standardised search strategies within Embase, Medline and Cochrane Central. Two independent reviewers will identify reviews published up to 31 December 2016 using predefined eligibility criteria. They will resolve ambiguous cases through consensus, arbitrated by a third reviewer if required. The reviewers will extract and report data according to methodological guidelines for overviews provided by the Cochrane Collaboration, Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. They will assess the quality of included reviews by applying the Assessment of Multiple Systematic Reviews tool. They will judge the quality of evidence in included reviews based on their assessment of bias and incorporation into the interpretation of findings. In synthesising the evidence, we will classify agents based on systematic review evidence of toxicity (sufficient, probable, possible or indeterminate) for specific cardiovascular outcomes (congestive heart failure, myocardial infarction, ischaemic heart disease, left ventricular ejection fraction decline, cerebrovascular disease, pulmonary embolism, thrombosis and hypertension). This will provide clinicians and patients with an accessible synthesis based on robust methodology. ETHICS AND DISSEMINATION: Ethics approval is not required for overviews. We will conduct the study in collaboration with consumer representatives. We will submit results for peer-review publication, and disseminate them through established clinical and consumer networks. PROSPERO REGISTRATION NUMBER: CRD42017080014.

14.
Cancer Res ; 78(14): 4086-4096, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29735552

RESUMO

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

15.
Blood ; 131(23): 2541-2551, 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29674426

RESUMO

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

16.
BMJ Open ; 8(4): e020858, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29643165

RESUMO

OBJECTIVES: To investigate between-hospital variation in the probability of reoperation within 90 days of initial breast-conserving surgery (BCS), and the contribution of health system-level and other factors. DESIGN: Population-based, retrospective cohort study. SETTING: New South Wales (NSW), Australia. PARTICIPANTS: Linked administrative hospitalisation data were used to define a cohort of adult women undergoing initial BCS for breast cancer in NSW between 1 July 2002 and 31 December 2013. PRIMARY OUTCOME MEASURES: Multilevel, cross-classified models with patients clustered within hospitals and residential areas were used to examine factors associated with any reoperation, and either re-excision or mastectomy, within 90 days. RESULTS: Of 34 458 women undergoing BCS, 29.1% underwent reoperation within 90 days, half of which were mastectomies. Overall, the probability of reoperation decreased slightly over time. However, there were divergent patterns by reoperation type; the probability of re-excision increased alongside a concomitant decrease in the probability of mastectomy. Significant between-hospital variation was observed. Non-metropolitan location and surgery at low-volume hospitals were associated with a higher overall probability of reoperation, and of mastectomy specifically, after accounting for patient-level factors, calendar year and area-level socioeconomic status. The magnitude of association with geographical location and surgical volume decreased over time. CONCLUSIONS: Reoperation rates within 90 days of BCS varied significantly between hospitals. For women undergoing mastectomy after BCS, this represents a dramatic change in clinical course. Multilevel modelling suggests unwarranted clinical variation may be an issue, likely due to disparities in access to multidisciplinary breast cancer care and preoperative diagnostic procedures. However, the observed reduction in disparities over time is encouraging and indicates that guidelines and policy initiatives have the potential to improve regional breast cancer care.

17.
Artigo em Inglês | MEDLINE | ID: mdl-29105289

RESUMO

AIM: Cancer of unknown primary site (CUP) is a medically challenging malignancy with a poor prognosis. We describe an incident tertiary CUP patient cohort and identify factors predictive of specific types of health care. METHODS: We reviewed the medical records of 217 patients diagnosed with CUP (2006-2011) in three public hospitals in New South Wales, Australia. We systematically abstracted data and performed multivariable logistic regression to identify factors predictive of tumor biopsy, surgery, chemotherapy, radiotherapy and palliative care. RESULTS: The median age at CUP diagnosis was 75 years (range 23-98) and 52% were male. The most common mode of presentation was emergency department admission (57%). Serum tumor markers were performed in 42%, fine needle aspiration alone in 15% and core biopsy in 52%. Younger age, health service referral, oncologist review and a family history of cancer predicted receipt of a biopsy (77%). Cancer-related surgery (17%) was more likely in younger patients, those presenting with pain, and those with single lymph node metastases. Younger age and good performance score predicted receipt of chemotherapy (22%). The location of metastases predicted receipt of radiotherapy (28%). Older age, emergency presentation, poor performance score and no oncology review predicted receipt of palliative care only (52%); 77% were referred for palliative care during hospitalization. CONCLUSION: The determinants of care were generally consistent with international CUP clinical guidelines. Areas of future research include potential underinvestigation and undertreatment of older patients, overuse of certain low-value diagnostic tests, suboptimal use of immunohistochemistry and mammography and underreferral to palliative care.

19.
BMJ Open ; 7(6): e016178, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28615275

RESUMO

PURPOSE: To estimate the Australian cancer burden attributable to lifestyle-related risk factors and their combinations using a novel population attributable fraction (PAF) method that accounts for competing risk of death, risk factor interdependence and statistical uncertainty. PARTICIPANTS: 365 173 adults from seven Australian cohort studies. We linked pooled harmonised individual participant cohort data with population-based cancer and death registries to estimate exposure-cancer and exposure-death associations. Current Australian exposure prevalence was estimated from representative external sources. To illustrate the utility of the new PAF method, we calculated fractions of cancers causally related to body fatness or both tobacco and alcohol consumption avoidable in the next 10 years by risk factor modifications, comparing them with fractions produced by traditional PAF methods. FINDINGS TO DATE: Over 10 years of follow-up, we observed 27 483 incident cancers and 22 078 deaths. Of cancers related to body fatness (n=9258), 13% (95% CI 11% to 16%) could be avoided if those currently overweight or obese had body mass index of 18.5-24.9 kg/m2. Of cancers causally related to both tobacco and alcohol (n=4283), current or former smoking explains 13% (11% to 16%) and consuming more than two alcoholic drinks per day explains 6% (5% to 8%). The two factors combined explain 16% (13% to 19%): 26% (21% to 30%) in men and 8% (4% to 11%) in women. Corresponding estimates using the traditional PAF method were 20%, 31% and 10%. Our PAF estimates translate to 74 000 avoidable body fatness-related cancers and 40 000 avoidable tobacco- and alcohol-related cancers in Australia over the next 10 years (2017-2026). Traditional PAF methods not accounting for competing risk of death and interdependence of risk factors may overestimate PAFs and avoidable cancers. FUTURE PLANS: We will rank the most important causal factors and their combinations for a spectrum of cancers and inform cancer control activities.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Neoplasias/mortalidade , Sobrepeso/epidemiologia , Fumar/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Consumo de Bebidas Alcoólicas/efeitos adversos , Austrália/epidemiologia , Índice de Massa Corporal , Efeitos Psicossociais da Doença , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Sobrepeso/complicações , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Fumar/efeitos adversos , Adulto Jovem
20.
Nat Commun ; 8: 14175, 2017 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-28165464

RESUMO

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10-10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.


Assuntos
Formação de Anticorpos/genética , Cromossomos Humanos/genética , Predisposição Genética para Doença , Leucemia Linfocítica Crônica de Células B/genética , Adulto , Linfócitos B/imunologia , Linfócitos B/fisiologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
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