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1.
Cancer Causes Control ; 30(9): 955-966, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31230151

RESUMO

PURPOSE: Pancreatic cancer has the highest fatality rate of all cancers. Adulthood obesity is an established risk factor for pancreatic cancer; however, life-course obesity is not well understood. The aim of this study was to evaluate the association between body mass index (BMI) trajectories throughout the life-course and pancreatic cancer risk. METHODS: A population-based case-control study was conducted (2011-2013) in Ontario, Canada. Cases were recruited from the Ontario pancreas cancer study (n = 310) and controls from the Ontario cancer risk factor study (n = 1258). Questionnaires captured self-reported height and weight at four timepoints (adolescence, 20 s, 30-40 s, 50-60 s). BMI trajectories were identified using latent class growth mixture modeling. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression. RESULTS: Five BMI trajectories were identified: stable-normal weight (38.9%), progressively overweight (42.2%), persistent overweight (12.6%), progressive obesity (4.2%), and persistent obesity (2.1%). The persistent overweight (OR = 1.55; 95% CI 1.02, 2.39) and progressive obesity trajectories (OR = 1.49; 95% CI 0.77, 2.87) compared to stable-normal weight were associated with increased odds of pancreatic cancer. When BMI was evaluated separately the strongest associations with pancreatic cancer emerged in young and mid-adulthood. CONCLUSION: BMI trajectories characterized by overweight in early adulthood were associated with increased pancreatic cancer risk suggesting a life-course approach to disease risk.

2.
BMC Cancer ; 19(1): 543, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170936

RESUMO

BACKGROUND: Iron has been shown to promote breast carcinogenesis in animal models through generation of oxidative stress and interaction with estrogen. Heme iron, which is found exclusively in animal-sourced foods, is suggested to have a more detrimental effect. Epidemiological evidence of the association between iron and breast cancer risk remains inconclusive and has not been comprehensively summarized. This systematic review and meta-analysis evaluated associations between both iron intake and body iron status and breast cancer risk. METHODS: Four electronic databases (MEDLINE, EMBASE, CINAHL, and Scopus) were searched up to December 2018 for studies assessing iron intake and/or biomarkers of iron status in relation to breast cancer risk. Using random-effects meta-analyses, pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated comparing the highest vs. lowest category of each iron measure. Dose-response meta-analyses were also performed to investigate linear and nonlinear associations. RESULTS: A total of 27 studies were included in the review, of which 23 were eligible for meta-analysis of one or more iron intake/status measures. Comparing the highest vs. lowest category, heme iron intake was significantly associated with increased breast cancer risk, with a pooled RR of 1.12 (95% CI: 1.04-1.22), whereas no associations were found for dietary (1.01, 95% CI: 0.89-1.15), supplemental (1.02, 95% CI: 0.91-1.13), or total (0.97, 95% CI: 0.82-1.14) iron intake. Associations of iron status indicators with breast cancer risk were generally in the positive direction; however, a significant pooled RR was found only for serum/plasma levels (highest vs. lowest) of iron (1.22, 95% CI: 1.01-1.47), but not for ferritin (1.13, 95% CI: 0.78-1.62), transferrin saturation (1.16, 95% CI: 0.91-1.47), or total iron-binding capacity (1.10, 95% CI: 0.97-1.25). In addition, a nonlinear dose-response was observed for heme iron intake and serum iron (both Pnonlinearity < 0.05). CONCLUSIONS: Heme iron intake and serum iron levels may be positively associated with breast cancer risk. Although associations were modest, these findings may have public health implications given the widespread consumption of (heme) iron-rich foods. In light of methodological and research gaps identified, further research is warranted to better elucidate the relationship between iron and breast cancer risk.

3.
Fam Cancer ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209717

RESUMO

Before SNP-based risk can be incorporated in colorectal cancer (CRC) screening, the ability of these SNPs to estimate CRC risk for persons with and without a family history of CRC, and the screening implications need to be determined. We estimated the association with CRC of a 45 SNP-based risk using 1181 cases and 999 controls, and its correlation with CRC risk predicted from detailed family history. We estimated the predicted change in the distribution across predefined risk categories, and implications for recommended screening commencement age, from adding SNP-based risk to family history. The inter-quintile risk ratio for colorectal cancer risk of the SNP-based risk was 3.28 (95% CI 2.54-4.22). SNP-based and family history-based risks were not correlated (r = 0.02). For persons with no first-degree relatives with CRC, screening could commence 4 years earlier for women (5 years for men) in the highest quintile of SNP-based risk. For persons with two first-degree relatives with CRC, screening could commence 16 years earlier for men and women in the highest quintile, and 7 years earlier for the lowest quintile. This 45 SNP panel in conjunction with family history, can identify people who could benefit from earlier screening. Risk reclassification by 45 SNPs could inform targeted screening for CRC prevention, particularly in clinical genetics settings when mutations in high-risk genes cannot be identified. Yet to be determined is cost-effectiveness, resources requirements, community, patient and clinician acceptance, and feasibility with potentially ethical, legal and insurance implications.

4.
Int J Cancer ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209889

RESUMO

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.

5.
J Natl Cancer Inst ; 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541042

RESUMO

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

6.
Curr Dev Nutr ; 2(3): nzx009, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30377679

RESUMO

Background: Isoflavones and lignans (phytoestrogens) are dietary components with potential anticarcinogenic effects. Although the intake of isoflavones and lignans may affect breast cancer treatment and prognosis-and associations may differ by menopausal status-postdiagnosis intake data are limited. Objective: We aimed to describe postdiagnosis isoflavone and lignan intake in newly diagnosed breast cancer patients, examine differences by menopausal status and phytoestrogen type, and inform the assessment of diet and survival in future prognostic studies. Methods: Our cross-sectional study included 278 women aged 25-74 y, diagnosed with pathologically confirmed breast cancer in April-May 2010 and identified using the Ontario Cancer Registry. Intake in the previous 2 mo was assessed using questionnaires listing 17 soy and 3 high-lignan foods (flaxseed, flaxseed bread, sesame seeds), completed 71 d after breast cancer diagnosis, on average. Food consumption by menopausal status was examined. Geometric mean and median phytoestrogen intakes were estimated among all patients and in consumers only; differences by menopausal status and phytoestrogen type were assessed. Results: Among all patients, foods were similarly consumed by menopausal status and isoflavone intakes were low (median: 56 µg/d). Consumers (n = 219) had higher intakes (median isoflavones: 1808 µg/d); 7% of isoflavone and 21% of lignan consumers had intakes ≥10 mg/d. Intakes were higher in premenopausal than in postmenopausal consumers, particularly for lignans, but were not significantly different (median lignans: 4375 compared with 1863 µg/d; P = 0.07). Lignans were significantly higher than isoflavones among most consumers (postmenopausal means: 746 compared with 100 µg/d; P < 0.0001). Conclusions: Postdiagnosis lignan intakes from 3 high-content foods may be considerable among newly diagnosed breast cancer patients, yet they have been unassessed in previous prognostic studies. The inclusion of these foods in dietary assessment methods may improve future intake estimates and the distributions on which breast cancer survival analyses are based.

7.
Int J Epidemiol ; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30476131

RESUMO

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development.

8.
Nutr Cancer ; : 1-14, 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30375890

RESUMO

Lignan intake, and its richest food source, flaxseed, have been associated with reduced breast cancer risk. Endogenous sex hormones, such as estrogens, play a role in breast cancer development, and lignans may alter these sex hormone levels. To assess the effect of flaxseed on circulating sex hormones, a randomized controlled trial was conducted among 99 postmenopausal women in Toronto, Canada. The intervention arm consumed 2 tablespoons (15 g) of ground flaxseed daily for 7 weeks; the control arm maintained usual diet. Baseline and week 7 concentrations of 14 serum sex hormones were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and immunoassay, and serum enterolignans (lignan biomarker) using LC-MS/MS. Intervention effects on sex hormone levels were assessed using analysis of covariance. Serum enterolignans increased among the flaxseed arm (+516%). Women consuming flaxseed (vs. controls) had increased serum 2-hydroxyestrone [treatment effect ratio (TER) = 1.54; 95% CI: 1.18-2.00] and 2:16α-hydroxyestrone ratio (TER =1.54; 95% CI: 1.15-2.06); effects on other hormones were not statistically significant. Within the flaxseed arm, change in enterolignan level was positively correlated with changes in 2-hydroxyestrone and 2:16α-hydroxyestrone ratio, and negatively with prolactin. Findings suggest flaxseed affects certain circulating sex hormone levels with possible implications for future breast cancer prevention research.

9.
J Natl Cancer Inst ; 2018 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-29917119

RESUMO

Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

11.
Nat Commun ; 9(1): 556, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422604

RESUMO

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

12.
Dis Colon Rectum ; 61(3): 355-363, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29377871

RESUMO

BACKGROUND: Data are lacking regarding physical functioning, psychological well-being, and quality of life among colorectal cancer survivors >10 years postdiagnosis. OBJECTIVE: The purpose of this study was to examine self-reported physical functioning, quality of life, and psychological well-being in long-term colorectal cancer survivors compared with age- and sex-matched unaffected control subjects. DESIGN: Participants completed a cross-sectional survey. SETTINGS: The colorectal cancer survivors and unaffected control subjects were recruited from the Ontario Familial Colorectal Cancer Registry. PATIENTS: A population-based sample of colorectal cancer survivors (N = 296) and their age- and sex-matched unaffected control subjects (N = 255) were included. Survivors were, on average, 15 years postdiagnosis. MAIN OUTCOME MEASURES: Quality of life was measured with the Functional Assessment of Cancer Therapy-General scale, bowel dysfunction with the Memorial Sloan-Kettering Cancer Center scale, urinary dysfunction with the International Consultation on Incontinence Questionnaire-Short Form, fatigue with the Functional Assessment of Chronic Illness Therapy-Fatigue scale, and depression with the Center for Epidemiologic Studies-Depression scale. RESULTS: In linear mixed-model analyses adjusting for income, education, race, and comorbid medical conditions, survivors reported good emotional, functional, physical, and overall quality of life, comparable to control subjects. Fatigue and urinary functioning did not differ significantly between survivors and control subjects. Survivors reported significantly higher social quality of life and lower depression compared with unaffected control subjects. The only area where survivors reported significantly worse deficits was in bowel dysfunction, but the magnitude of differences was relatively small. LIMITATIONS: Generalizability is limited by moderately low participation rates. Findings are likely biased toward healthy participants. No baseline assessment was available to examine change in outcomes over time. CONCLUSIONS: Long-term colorectal cancer survivors appear to have comparable quality of life and, in some areas, better well-being than their unaffected peers. Bowel dysfunction may continue to be an ongoing issue even 15 years after colorectal cancer diagnosis. Overall quality of life can be expected to be good in this group of older survivors. See Video Abstract at http://links.lww.com/DCR/A476.


Assuntos
Sobreviventes de Câncer/psicologia , Neoplasias Colorretais/psicologia , Qualidade de Vida/psicologia , Adulto , Idoso , Canadá , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Inquéritos e Questionários
13.
Prev Med ; 107: 14-20, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29197533

RESUMO

Cervical cancer caused by oncogenic types of the human papillomavirus (HPV) is of concern among HIV-positive women due to impairment of immune responses required to control HPV infection. Our objectives were to describe patterns of cervical cancer screening using Pap cytology testing among HIV-positive women in Ontario, Canada from 2008 to 2013 and to identify factors associated with adequate screening. We conducted a retrospective, population-based cohort study among screen-eligible HIV-positive women using provincial administrative health data. We estimated annual proportions tested and reported these with 95% confidence intervals (CI). Next, using person-years as the unit of analysis, we identified factors associated with annual Pap testing using log-binomial regression. A total of 2271 women were followed over 10,697 person-years. In 2008, 34.0% (95%CI 31.1-37.0%) had a Pap test. By 2013, the proportion of HIV-positive women tested was 25.9% (95%CI 23.6-28.2%). Women who were most likely to undergo testing were younger, were immigrants from countries with generalized HIV epidemics, lived in the highest income neighbourhoods, had a female primary care physician, had two or more encounters per year with an infectious disease or internal medicine specialist, and had greater comorbidity. Nearly three in four HIV-positive women were under-screened despite all having universal insurance for medically-necessary services. Annual Pap testing decreased following the 2011-2013 release of new guidelines for a lengthened screen interval for average risk women and a billing disincentive. Clinic-based intervention such as physician alerts or reminders may be needed to improve screening coverage among HIV-positive women.

14.
Cancer ; 123(23): 4701-4708, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28841225

RESUMO

BACKGROUND: Body weight is associated with colorectal cancer (CRC) risk and survival, but to the authors' knowledge, the impact of long-term postdiagnostic weight change is unclear. Herein, the authors investigated whether weight change over the 5 years after a diagnosis of CRC is associated with survival. METHODS: CRC cases diagnosed from 1997 to 2008 were identified through 4 population-based cancer registry sites. Participants enrolled within 2 years of diagnosis and reported their height and weight 2 years prior. Follow-up questionnaires were administered approximately 5 years after diagnosis. Associations between change in weight (in kg) or body mass index (BMI) with overall and CRC-specific survival were estimated using Cox regression analysis adjusted for age, sex, American Joint Committee on Cancer stage of disease, baseline BMI, nonsteroidal anti-inflammatory drug use, smoking, time between diagnosis and enrollment, and study site. RESULTS: At the 5-year postdiagnostic survey, 2049 participants reported higher (53%; median plus 5 kg), unchanged (12%), or lower (35%; median -4 kg) weight. Over a median of 5.1 years of subsequent follow-up (range, 0.3-9.9 years), 344 participants died (91 of CRC). Long-term weight loss (per 5 kg) was found to be associated with poorer overall survival (hazard ratio, 1.13; 95% confidence interval, 1.07-1.21) and CRC-specific survival (hazard ratio, 1.25; 95% confidence interval, 1.13-1.39). Significantly lower survival was similarly observed for relative weight loss (>5% vs ≤5% change), BMI reduction (per 1 unit), or BMI category change (overweight to normal vs remaining overweight). CONCLUSIONS: Weight loss 5 years after a diagnosis of CRC was found to be significantly associated with decreased long-term survival, suggesting the importance of avoiding weight loss in survivors of CRC. Future research should attempt to further evaluate this association, accounting for whether this weight change was intentional or represents a marker of declining health. Cancer 2017;123:4701-4708. © 2017 American Cancer Society.


Assuntos
Sobreviventes de Câncer , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Perda de Peso , Índice de Massa Corporal , Neoplasias Colorretais/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida
15.
Health Promot Chronic Dis Prev Can ; 37(8): 238-247, 2017 Aug.
Artigo em Inglês, Francês | MEDLINE | ID: mdl-28800293

RESUMO

INTRODUCTION: While some studies have suggested associations between shift work and obesity, few have been population-based or considered multiple shift schedules. Since obesity is linked with several chronic health conditions, understanding which types of shift work influence obesity is important and additional work with more detailed exposure assessment of shift work is warranted. METHODS: Using multivariate polytomous logistic regression, we investigated the associations between shift work (evening/night, rotating and other shift schedules) and overweight and obesity as measured by body mass index cross-sectionally among 1561 men. These men had previously participated as population controls in a prostate cancer case-control study conducted in northeastern Ontario from 1995 to 1999. We obtained information on work history (including shift work), height and weight from the existing self-reported questionnaire data. RESULTS: We observed an association for ever (vs. never) having been employed in rotating shift work for both the overweight (OR [odds ratio] = 1.34; 95% CI [confidence interval]: 1.05-1.73) and obese (OR = 1.57; 95% CI: 1.12-2.21) groups. We also observed nonsignificant associations for ever (vs. never) having been employed in permanent evening/night shifts. In addition, we found a significant trend of increased risk for both overweight and obesity with increasing duration of rotating shift work. CONCLUSION: Both the positive association between rotating shift work and obesity and the suggested positive association for permanent evening/night shift work in this study are consistent with previous findings. Future population-based research that is able to build on our results while examining additional shift work characteristics will further clarify whether some shift patterns have a greater impact on obesity than others.


Assuntos
Obesidade/epidemiologia , Obesidade/etiologia , Jornada de Trabalho em Turnos/efeitos adversos , Jornada de Trabalho em Turnos/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Sobrepeso/epidemiologia , Sobrepeso/etiologia , Fatores de Risco
16.
Oncotarget ; 7(41): 66328-66343, 2016 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-27579533

RESUMO

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.


Assuntos
Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 5/genética , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Neoplasias Pancreáticas/genética , Conjuntos de Dados como Assunto , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética
17.
Int J Cancer ; 139(11): 2474-81, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27487558

RESUMO

Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.


Assuntos
Neoplasias Pancreáticas/genética , Fatores de Transcrição/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Fatores Etários , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Neoplasias Pancreáticas/mortalidade , Polimorfismo Genético , Prognóstico , Regiões Promotoras Genéticas , Fatores Sexuais , Análise de Sobrevida
18.
Cancer Epidemiol Biomarkers Prev ; 25(11): 1524-1533, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27528600

RESUMO

BACKGROUND: This study investigated whether receiving the results of predictive genetic testing for Lynch syndrome, indicating the presence or absence of an inherited predisposition to various cancers, including colorectal cancer, was associated with change in individual colonoscopy and smoking behaviors, which could prevent colorectal cancer. METHODS: The study population included individuals with no previous diagnosis of colorectal cancer, whose families had already identified deleterious mutations in the mismatch repair or EPCAM genes. Hypotheses were generated from a simple health economics model and tested against individual-level panel data from the Australasian Colorectal Cancer Family Registry. RESULTS: The empirical analysis revealed evidence consistent with some of the hypotheses, with a higher likelihood of undergoing colonoscopy in those who discovered their genetic predisposition to colorectal cancer and a lower likelihood of quitting smoking in those who discovered their lack thereof. CONCLUSIONS: Predictive genetic information about Lynch syndrome was associated with change in individual colonoscopy and smoking behaviors but not necessarily in ways to improve population health. IMPACT: The study findings suggest that the impact of personalized medicine on disease prevention is intricate, warranting further analyses to determine the net benefits and costs. Cancer Epidemiol Biomarkers Prev; 25(11); 1524-33. ©2016 AACR.


Assuntos
Colonoscopia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Predisposição Genética para Doença , Fumar , Adulto , Idoso , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/psicologia , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Medicina de Precisão
19.
Int J Cancer ; 139(7): 1557-63, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27194394

RESUMO

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.


Assuntos
Neoplasias do Colo/genética , DNA Glicosilases/genética , Mutação em Linhagem Germinativa , Neoplasias/genética , Idoso , Alelos , Neoplasias do Colo/enzimologia , Neoplasias do Colo/epidemiologia , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Neoplasias/enzimologia , Neoplasias/epidemiologia , Sistema de Registros , Estados Unidos/epidemiologia
20.
Cancer Causes Control ; 27(4): 459-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26970739

RESUMO

Almost 7% of breast cancers are diagnosed among women age 40 years and younger in Western populations. Clinical outcomes among young women are worse. Early age-of-onset increases the risk of contralateral breast cancer, local and distant recurrence, and subsequent mortality. Breast cancers in young women (BCYW) are more likely to present with triple-negative (TNBC), TP53-positive, and HER-2 over-expressing tumors than among older women. However, despite these known differences in breast cancer outcomes and tumor subtypes, there is limited understanding of the basic biology, epidemiology, and optimal therapeutic strategies for BCYW. Several modifiable lifestyle factors associated with reduced risk of developing breast cancer have also been implicated in improved prognosis among breast cancer survivors of all ages. Given the treatment-related toxicities and the extended window for late effects, long-term lifestyle modifications potentially offer significant benefits to BCYW. In this review, we propose a model identifying three main areas of lifestyle factors (energy imbalance, inflammation, and dietary nutrient adequacy) that may influence survival in BCYW. In addition, we provide a summary of mechanisms of action and a synthesis of previous research on each of these topics.


Assuntos
Neoplasias da Mama/patologia , Estilo de Vida , Receptor ErbB-2 , Dieta , Feminino , Humanos , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Sobreviventes
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