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1.
Br J Cancer ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33597716

RESUMO

BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62-2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28-0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p = 0.56). CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33591610

RESUMO

INTRODUCTION: To evaluate the adoption of hypofractionated radiotherapy (HFRT) for breast cancer (BC) in Victoria, Australia. METHODS: This is a population-based cohort of women with BC who had breast RT as captured in the Victorian Radiotherapy Minimum Data Set between 2012 and 2017. We defined HFRT as < 25 fractions of RT. The pattern of HFRT use over time was evaluated with the Cochrane-Armitage test for trend. Factors associated with HFRT were identified using multivariable logistic regression. RESULTS: 12,717 women were included in the study. Overall, 6,653 (52%) patients had HFRT. HFRT use increased from 35% in 2012 to 66% in 2017 (P-trend < 0.001). Older women were more likely to have HFRT (74% for women aged ≥ 70 years vs. 27% for women aged < 50 years; P < 0.001). Women who had nodal irradiation were less likely to have HFRT compared with those who did not (13% vs. 57%; P < 0.001). HFRT use was more common in public than private institutions (57% vs. 46%, P < 0.001), and in metropolitan than regional centres (54% vs. 46%, P < 0.001). In multivariable analyses, the progressive increase in HFRT use over time was independent of other covariates - women treated in 2017 were 7.3 times (95% CI = 6.3-8.6, P < 0.001) more likely to be treated with HFRT than in 2012. Age at RT, nodal irradiation, area of residence and institutional type and locations were all independently associated with HFRT use. CONCLUSION: This large Australian contemporary population-based study demonstrates increasing use of HFRT for BC. However, large sociodemographic and institutional provider-related variations in practice still exist.

4.
Int J Cancer ; 2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33554339

RESUMO

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (Phomogeneity = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.

5.
Cancer Res ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33574088

RESUMO

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% CI 0.82-0.93; former smokers 1.00, 95 CI 0.91-1.07; current smokers 1.25, 95%CI 1.12-1.40, interaction P-value=3.08x10-9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high LD with rs1818613 (r2=0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.

6.
Clin Epigenetics ; 13(1): 11, 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33461604

RESUMO

BACKGROUND: Tumour DNA methylation profiling has shown potential to refine disease subtyping and improve the diagnosis and prognosis prediction of breast cancer. However, limited data exist regarding invasive lobular breast cancer (ILBC). Here, we investigated the genome-wide variability of DNA methylation levels across ILBC tumours and assessed the association between methylation levels at the variably methylated regions and overall survival in women with ILBC. METHODS: Tumour-enriched DNA was prepared by macrodissecting formalin-fixed paraffin embedded (FFPE) tumour tissue from 130 ILBCs diagnosed in the participants of the Melbourne Collaborative Cohort Study (MCCS). Genome-wide tumour DNA methylation was measured using the HumanMethylation 450K (HM450K) BeadChip array. Variably methylated regions (VMRs) were identified using the DMRcate package in R. Cox proportional hazards regression models were used to assess the association between methylation levels at the ten most significant VMRs and overall survival. Gene set enrichment analyses were undertaken using the web-based tool Metaspace. Replication of the VMR and survival analysis findings was examined using data retrieved from The Cancer Genome Atlas (TCGA) for 168 ILBC cases. We also examined the correlation between methylation and gene expression for the ten VMRs of interest using TCGA data. RESULTS: We identified 2771 VMRs (P < 10-8) in ILBC tumours. The ten most variably methylated clusters were predominantly located in the promoter region of the genes: ISM1, APC, TMEM101, ASCL2, NKX6, HIST3H2A/HIST3H2BB, HCG4P3, HES5, CELF2 and EFCAB4B. Higher methylation level at several of these VMRs showed an association with reduced overall survival in the MCCS. In TCGA, all associations were in the same direction, however stronger than in the MCCS. The pooled analysis of the MCCS and TCGA data showed that methylation at four of the ten genes was associated with reduced overall survival, independently of age and tumour stage; APC: Hazard Ratio (95% Confidence interval) per one-unit M-value increase: 1.18 (1.02-1.36), TMEM101: 1.23 (1.02-1.48), HCG4P3: 1.37 (1.05-1.79) and CELF2: 1.21 (1.02-1.43). A negative correlation was observed between methylation and gene expression for CELF2 (R = - 0.25, P = 0.001), but not for TMEM101 and APC. CONCLUSIONS: Our study identified regions showing greatest variability across the ILBC tumour genome and found methylation at several genes to potentially serve as a biomarker of survival for women with ILBC.

7.
Am J Obstet Gynecol ; 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33493488

RESUMO

BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive use. Although the effects of using oral contraceptives in the general population are well established (approximately 50% risk reduction in ovarian cancer), the estimated risk reduction in mutation carriers is much less precise because of potential bias and small sample sizes. In addition, only a few studies on oral contraceptive use have examined the associations of duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer. OBJECTIVE: This study aimed to investigate in more detail the associations of various characteristics of oral contraceptive use and risk of ovarian cancer, to provide healthcare providers and carriers with better risk estimates. STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using oral contraceptives data on 3989 BRCA1 and 2445 BRCA2 mutation carriers. Age-dependent-weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as a covariate. To minimize survival bias, analyses were left truncated at 5 years before baseline questionnaire. Separate analyses were conducted for each aspect of oral contraceptive use and in a multivariate analysis, including all these aspects. In addition, the analysis of duration of oral contraceptive use was stratified by recency of use. RESULTS: Oral contraceptives were less often used by mutation carriers who were diagnosed with ovarian cancer (ever use: 58.6% for BRCA1 and 53.5% BRCA2) than by unaffected carriers (ever use: 88.9% for BRCA1 and 80.7% for BRCA2). The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer and 9 and 8 years for unaffected BRCA1 and BRCA2 carriers with ovarian cancer, respectively. For BRCA1 mutation carriers, univariate analyses have shown that both a longer duration of oral contraceptive use and more recent oral contraceptive use were associated with a reduction in the risk of ovarian cancer. However, in multivariate analyses, including duration of use, age at first use, and time since last use, duration of oral contraceptive use proved to be the prominent protective factor (compared with <5 years: 5-9 years [hazard ratio, 0.67; 95% confidence interval, 0.40-1.12]; >10 years [hazard ratio, 0.37; 95% confidence interval, 0.19-0.73]; Ptrend=.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (duration of ≥10 years; BRCA1 <15 years since last use [hazard ratio, 0.24; 95% confidence interval, 0.14-0.43]; BRCA1 >15 years since last use [hazard ratio, 0.56; 95% confidence interval, 0.18-0.59]). Univariate results for BRCA2 mutation carriers were similar but were inconclusive because of limited sample size. CONCLUSION: For BRCA1 mutation carriers, longer duration of oral contraceptive use is associated with a greater reduction in ovarian cancer risk, and the protection is long term.

8.
Public Health Nutr ; : 1-13, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33472714

RESUMO

OBJECTIVE: To examine associations between diet and risk of developing gastro-oesophageal reflux disease (GERD). DESIGN: Prospective cohort with a median follow-up of 15·8 years. Baseline diet was measured using a FFQ. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least 2 years after baseline. Sex-specific logistic regressions were performed to estimate OR for GERD associated with diet quality scores and intakes of nutrients, food groups and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined. SETTING: Melbourne, Australia. PARTICIPANTS: A cohort of 20 926 participants (62 % women) aged 40-59 years at recruitment between 1990 and 1994. RESULTS: For men, total fat intake was associated with increased risk of GERD (OR 1·05 per 5 g/d; 95 % CI 1·01, 1·09; P = 0·016), whereas total carbohydrate (OR 0·89 per 30 g/d; 95 % CI 0·82, 0·98; P = 0·010) and starch intakes (OR 0·84 per 30 g/d; 95 % CI 0·75, 0·94; P = 0·005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores. CONCLUSIONS: Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.

9.
Addict Biol ; 26(1): e12855, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789449

RESUMO

DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10-7 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1414 cross-sectional associations. Our study indicates that alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with alcohol consumption changes in adulthood.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33268487

RESUMO

BACKGROUND: Obesity increases the risk of 13 cancer types. Given the long process of carcinogenesis, it is important to determine the impact of patterns of body mass over time. METHODS: Using data from 30,377 participants in the Melbourne Collaborative Cohort Study, we identified body mass index (BMI) trajectories across adulthood and examined their association with the risk of obesity-related cancer. Participants completed interviews and questionnaires at baseline (1990-1994, age 40-69 years), follow-up 1 (1995-1998) and follow-up 2 (2003-2005). Body mass was recalled for age 18-21 years, measured at baseline, self-reported at follow-up 1 and measured at follow-up 2. Height was measured at baseline. Cancer diagnoses were ascertained from the Victorian Cancer Registry and the Australian Cancer Database. A latent class trajectory model was used to identify BMI trajectories which were not defined a priori. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of obesity-related cancer risks by BMI trajectory. RESULTS: Six distinct BMI trajectories were identified. Compared with people who maintained lower-normal BMI, higher risks of developing obesity-related cancer were observed for participants who transitioned from normal to overweight (HR=1.29, 95% CI: 1.13, 1.47), normal to class I obesity (HR=1.50, 95% CI: 1.28, 1.75) or from overweight to class II obesity (HR=1.66, 95% CI: 1.32, 2.08). CONCLUSION: Our findings suggest that maintaining a healthy BMI across the adult lifespan is important for cancer prevention. IMPACT: Categorisation of BMI by trajectory allowed us to identify specific risk groups to target with public health interventions.

11.
J Natl Cancer Inst ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33301022

RESUMO

BACKGROUND: Clinical guidelines often use predicted lifetime risk from birth to define criteria for making decisions regarding breast cancer screening rather than thresholds based on absolute 5-year risk from current age. METHODS: We used the Prospective Family Cohort Study of 14,657 women without breast cancer at baseline in which, during a median follow-up of 10 years, 482 women were diagnosed with invasive breast cancer. We examined the performances of the IBIS and BOADICEA risk models when using alternative thresholds by comparing predictions based on 5-year risk with those based on lifetime risk from birth and remaining lifetime risk. All statistical tests were two-sided. RESULTS: Using IBIS, the areas under the receiver-operating characteristic curves were 0.66 (95% confidence interval = 0.63 to 0.68) and 0.56 (95% confidence interval = 0.54 to 0.59) for 5-year and lifetime risks, respectively (Pdiff<0.001). For equivalent sensitivities, the 5-year incidence almost always had higher specificities than lifetime risk from birth. For women aged 20-39 years, 5-year risk performed better than lifetime risk from birth. For women aged 40 years or more, receiver-operating characteristic curves were similar for 5-year and lifetime IBIS risk from birth. Classifications based on remaining lifetime risk were inferior to 5-year risk estimates. Results were similar using BOADICEA. CONCLUSIONS: Our analysis shows that risk stratification using clinical models will likely be more accurate when based on predicted 5-year risk compared with risks based on predicted lifetime and remaining lifetime, particularly for women aged 20-39 years.

12.
BMC Med ; 18(1): 396, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33327948

RESUMO

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

13.
Int J Epidemiol ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33169152

RESUMO

BACKGROUND: Prenatal exposure to maternal smoking is detrimental to child health but its association with risk of cancer has seldom been investigated. Maternal smoking induces widespread and long-lasting DNA methylation changes, which we study here for association with risk of cancer in adulthood. METHODS: Eight prospective case-control studies nested within the Melbourne Collaborative Cohort Study were used to assess associations between maternal-smoking-associated methylation marks in blood and risk of several cancers: breast (n = 406 cases), colorectal (n = 814), gastric (n = 166), kidney (n = 139), lung (n = 327), prostate (n = 847) and urothelial (n = 404) cancer and B-cell lymphoma (n = 426). We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between cancer and five methylation scores calculated as weighted averages for 568, 19, 15, 28 and 17 CpG sites. Models were adjusted for confounders, including personal smoking history (smoking status, pack-years, age at starting and quitting) and methylation scores for personal smoking. RESULTS: All methylation scores for maternal smoking were strongly positively associated with risk of urothelial cancer. Risk estimates were only slightly attenuated after adjustment for smoking history, other potential confounders and methylation scores for personal smoking. Potential negative associations were observed with risk of lung cancer and B-cell lymphoma. No associations were observed for other cancers. CONCLUSIONS: We found that methylation marks of prenatal exposure to maternal smoking are associated with increased risk of urothelial cancer. Our study demonstrates the potential for using DNA methylation to investigate the impact of early-life, unmeasured exposures on later-life cancer risk.

14.
Int J Cancer ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197272

RESUMO

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10-12 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.

15.
Eur J Epidemiol ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33128203

RESUMO

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m2, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33115784

RESUMO

Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. 725 women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. 378 (52%) kConFab women, two (3%) breast surgeons and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side-effects (31%) and inadequate information (23%) which operate in the Theoretical Domains Framework domains of "beliefs about consequences" and "knowledge", respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, "knowledge", "beliefs about consequences" and "goals" domains), staying healthy for family (13%, "social role" and "goals" domains) and abnormal breast biopsy (13%, "environmental context" domain). The strongest barrier for family physicians was insufficient knowledge (45%, "knowledge" domain) and for breast surgeons was medication side-effects (40%, "beliefs about consequences" domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history and better tools to select patients ("environmental context and resources" domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention are key domains that could be targeted to potentially enhance uptake.

17.
Cancer Epidemiol Biomarkers Prev ; 29(12): 2719-2728, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33008876

RESUMO

BACKGROUND: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and therefore variants in genes related to Treg differentiation and function could be associated with colorectal cancer prognosis. METHODS: In a prospective German cohort of 3,593 colorectal cancer patients, we assessed the association of 771 single-nucleotide polymorphisms (SNP) in 58 Treg-related genes with overall and colorectal cancer-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated because tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2,047 colorectal cancer patients of the International Survival Analysis in Colorectal Cancer Consortium (ISACC). RESULTS: A significant association of the TGFBR3 SNP rs7524066 with more favorable colorectal cancer-specific survival [hazard ratio (HR) per minor allele: 0.83; 95% confidence interval (CI), 0.74-0.94; P value: 0.0033] was replicated in ISACC (HR: 0.82; 95% CI, 0.68-0.98; P value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed. CONCLUSIONS: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of colorectal cancer patients. IMPACT: The implicated genes warrant further investigation.

18.
Clin Epigenetics ; 12(1): 158, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092643

RESUMO

BACKGROUND: DNA methylation-based biological age (DNAm age) is an important biomarker for adult health. Studies in specific age ranges have found widely varying results about its genetic and environmental causes of variation. However, these studies are not able to provide a comprehensive view of the causes of variation over the lifespan. RESULTS: In order to investigate the genetic and environmental causes of DNAm age variation across the lifespan, we pooled genome-wide DNA methylation data for 4217 people aged 0-92 years from 1871 families. DNAm age was calculated using the Horvath epigenetic clock. We estimated familial correlations in DNAm age for monozygotic (MZ) twin, dizygotic (DZ) twin, sibling, parent-offspring, and spouse pairs by cohabitation status. Genetic and environmental variance components models were fitted and compared. We found that twin pair correlations were - 0.12 to 0.18 around birth, not different from zero (all P > 0.29). For all pairs of relatives, their correlations increased with time spent living together (all P < 0.02) at different rates (MZ > DZ and siblings > parent-offspring; P < 0.001) and decreased with time spent living apart (P = 0.02) at similar rates. These correlation patterns were best explained by cohabitation-dependent shared environmental factors, the effects of which were 1.41 (95% confidence interval [CI] 1.16 to 1.66) times greater for MZ pairs than for DZ and sibling pairs, and the latter were 2.03 (95% CI 1.13 to 9.47) times greater than for parent-offspring pairs. Genetic factors explained 13% (95% CI - 10 to 35%) of variation (P = 0.27). Similar results were found for another two epigenetic clocks, suggesting that our observations are robust to how DNAm age is measured. In addition, results for the other clocks were consistent with there also being a role for prenatal environmental factors in determining their variation. CONCLUSIONS: Variation in DNAm age is mostly caused by environmental factors, including those shared to different extents by relatives while living together and whose effects persist into old age. The equal environment assumption of the classic twin study might not hold for epigenetic aging.

19.
Med J Aust ; 213(9): 411-417, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32996611

RESUMO

OBJECTIVE: To compare treatments for localised prostate cancer for men diagnosed in private and public health services in Victoria. DESIGN: Retrospective analysis of Victorian Cancer Registry data linked to population-based administrative health datasets. SETTING, PARTICIPANTS: 29 325 Victorian men diagnosed with prostate cancer during 2011-2017. MAIN OUTCOME MEASURES: Proportions of men in private and public health services receiving radical prostatectomy (with or without curative radiation therapy) or curative external beam radiation therapy alone within 12 months of diagnosis. RESULTS: After adjusting for age, tumour classification and comorbidity, men diagnosed in private health services received radical treatment more frequently than men diagnosed in public health services (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.31-1.49). The proportion of private patients who underwent radical prostatectomy was larger than that for public patients (44% v 28%; OR, 2.28; 95% CI, 2.13-2.44) and the proportion of private patients who received curative external beam radiation therapy alone (excluding brachytherapy) was smaller (9% v 19%; OR, 0.45; 95% CI, 0.42-0.49). These differences were apparent for all International Society of Urological Pathology (ISUP) tumour grades. The magnitude of the difference for prostatectomy was greater for men aged 70 years or more; for radiation therapy alone, it was larger for those diagnosed before age 70. The differences between private and public services narrowed during 2011-2017 for men with ISUP grade 1 disease, but not ISUP grade 2-5 tumours. CONCLUSION: Prostate cancer treatment choices differ substantially between men diagnosed in private and public health services in Victoria. These differences are not explained by disease severity or comorbidity.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32958588

RESUMO

DNA methylation in peripheral blood is a potential biomarker of gastric cancer risk which could be used for early detection. We conducted a prospective case-control study nested within the Melbourne Collaborative Cohort Study. Genomic DNA was prepared from blood samples collected a median of 12 years before diagnosis for cases (N=168). Controls (N=163) were matched to cases on sex, year of birth, country of birth and blood sample type using incidence density sampling. Genome-wide DNA methylation was measured using the Infinium HumanMethylation450K Beadchip. Global measures of DNA methylation were defined as the median methylation M-value, calculated for each of 13 CpG subsets representing genomic function, mean methylation and location, and reliability of measurement. Conditional logistic regression was conducted to assess associations between these global measures of methylation and gastric cancer risk, adjusting for Helicobacter pylori and other potential confounders. We tested non-linear associations using quintiles of the global measure distribution. A genome-wide association study of DNA methylation and gastric cancer risk was also conducted (N=484,989 CpGs) using conditional logistic regression, adjusting for potential confounders. Differentially methylated regions (DMRs) were investigated using the R package DMRcate. We found no evidence of associations with gastric cancer risk for individual CpGs or DMRs (p> 7.6×10-6). No evidence of association was observed with global measures of methylation (Odds ratio (OR) 1.07 per SD of overall median methylation, 95% CI 0.80-1.44, p=0.65). We found no evidence that blood DNA methylation is prospectively associated with gastric cancer risk.

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