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1.
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.

2.
JNCI Cancer Spectr ; 4(5): pkaa062, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33134836

RESUMO

Background: In many countries, population colorectal cancer (CRC) screening is based on age and family history, though more precise risk prediction could better target screening. We examined the impact of a CRC risk prediction model (incorporating age, sex, lifestyle, genomic, and family history factors) to target screening under several feasible screening scenarios. Methods: We estimated the model's predicted CRC risk distribution in the Australian population. Predicted CRC risks were categorized into screening recommendations under 3 proposed scenarios to compare with current recommendations: 1) highly tailored, 2) 3 risk categories, and 3) 4 sex-specific risk categories. Under each scenario, for 35- to 74-year-olds, we calculated the number of CRC screens by immunochemical fecal occult blood testing (iFOBT) and colonoscopy and the proportion of predicted CRCs over 10 years in each screening group. Results: Currently, 1.1% of 35- to 74-year-olds are recommended screening colonoscopy and 56.2% iFOBT, and 5.7% and 83.2% of CRCs over 10 years were predicted to occur in these groups, respectively. For the scenarios, 1) colonoscopy was recommended to 8.1% and iFOBT to 37.5%, with 36.1% and 50.1% of CRCs in each group; 2) colonoscopy was recommended to 2.4% and iFOBT to 56.0%, with 13.2% and 76.9% of cancers in each group; and 3) colonoscopy was recommended to 5.0% and iFOBT to 54.2%, with 24.5% and 66.5% of cancers in each group. Conclusions: A highly tailored CRC screening scenario results in many fewer screens but more cancers in those unscreened. Category-based scenarios may provide a good balance between number of screens and cancers detected and are simpler to implement.

3.
Public Health Genomics ; 23(3-4): 110-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32688362

RESUMO

INTRODUCTION: Genomic tests can predict risk and tailor screening recommendations for colorectal cancer (CRC). Primary care could be suitable for their widespread implementation. OBJECTIVE: We aimed to assess the feasibility and acceptability of administering a CRC genomic test in primary care. METHODS: Participants aged 45-74 years recruited from 4 Australian general practices were offered a genomic CRC risk test. Participants received brief verbal information about the test comprising 45 CRC-associated single-nucleotide polymorphisms, before choosing whether to undertake the test. Personalized risks were given to testers. Uptake and knowledge of the genomic test, cancer-specific anxiety (Cancer Worry Scale), psychosocial impact (Multidimensional Impact of Cancer Risk Assessment [MICRA] score), and impact on CRC screening behaviour within 6 months were measured. RESULTS: In 150 participants, test uptake was high (126, 84%), with 125 (83%) having good knowledge of the genomic test. Moderate risk participants were impacted more by the test (MICRA mean: 15.9) than average risk participants (mean: 9.5, difference in means: 6.4, 95% confidence interval (CI): 1.5, 11.2, p = 0.01), but all scores were low. Average risk participants' cancer-specific anxiety decreased (mean differences from baseline: 1 month -0.5, 95% CI: -1.0, -0.1, p = 0.03; 6 months -0.6, 95% CI: -1.0, -0.2, p = 0.01). We found limited evidence for genomic testers being more likely to complete the risk-appropriate CRC screening than non-testers (41 vs. 17%, odds ratio = 3.4, 95% CI: 0.6, 34.8, p = 0.19), but some mediators of screening behaviour were altered in genomic testers. CONCLUSIONS: Genomic testing for CRC risk in primary care is acceptable and likely feasible. Further development of the risk assessment intervention could strengthen the impact on screening behaviour.

4.
J Clin Med ; 9(3)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32110975

RESUMO

This commentary is about predicting a woman's breast cancer risk from her mammogram, building on the work of Wolfe, Boyd and Yaffe on mammographic density. We summarise our efforts at finding new mammogram-based risk predictors, and how they combine with the conventional mammographic density, in predicting risk for interval cancers and screen-detected breast cancers across different ages at diagnosis and for both Caucasian and Asian women. Using the OPERA (odds ratio per adjusted standard deviation) concept, in which the risk gradient is measured on an appropriate scale that takes into account other factors adjusted for by design or analysis, we show that our new mammogram-based measures are the strongest of all currently known breast cancer risk factors in terms of risk discrimination on a population-basis. We summarise our findings graphically using a path diagram in which conventional mammographic density predicts interval cancer due to its role in masking, while the new mammogram-based risk measures could have a causal effect on both interval and screen-detected breast cancer. We discuss attempts by others to pursue this line of investigation, the measurement challenge that allows different measures to be compared in an open and transparent manner on the same datasets, as well as the biological and public health consequences.

5.
Fam Cancer ; 19(3): 215-222, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32107660

RESUMO

Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75-1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81-1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52-1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Therefore, despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we do not recommend that POEs be incorporated into the clinical guidelines or advice for such carriers.

6.
Cancer Epidemiol Biomarkers Prev ; 29(3): 549-557, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932410

RESUMO

PURPOSE: Reducing colorectal cancer incidence and mortality through early detection would improve efficacy if targeted. We developed a colorectal cancer risk prediction model incorporating personal, family, genetic, and environmental risk factors to enhance prevention. METHODS: A familial risk profile (FRP) was calculated to summarize individuals' risk based on detailed cancer family history (FH), family structure, probabilities of mutation in major colorectal cancer susceptibility genes, and a polygenic component. We developed risk models, including individuals' FRP or binary colorectal cancer FH, and colorectal cancer risk factors collected at enrollment using population-based colorectal cancer cases (N = 4,445) and controls (N = 3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). Model validation used CCFRC follow-up data for population-based (N = 12,052) and clinic-based (N = 5,584) relatives with no cancer history at recruitment to assess model calibration [expected/observed rate ratio (E/O)] and discrimination [area under the receiver-operating-characteristic curve (AUC)]. RESULTS: The E/O [95% confidence interval (CI)] for FRP models for population-based relatives were 1.04 (0.74-1.45) for men and 0.86 (0.64-1.20) for women, and for clinic-based relatives were 1.15 (0.87-1.58) for men and 1.04 (0.76-1.45) for women. The age-adjusted AUCs (95% CI) for FRP models for population-based relatives were 0.69 (0.60-0.78) for men and 0.70 (0.62-0.77) for women, and for clinic-based relatives were 0.77 (0.69-0.84) for men and 0.68 (0.60-0.76) for women. The incremental values of AUC for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) for men and 0.10 (0.04-0.16) for women, and for clinic-based relatives were 0.11 (0.05-0.17) for men and 0.11 (0.06-0.17) for women. CONCLUSIONS: Both models calibrated well. The FRP-based model provided better risk stratification and risk discrimination than the FH-based model. IMPACT: Our findings suggest detailed FH may be useful for targeted risk-based screening and clinical management.

7.
Fam Cancer ; 18(4): 389-397, 2019 10.
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.


Assuntos
Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/prevenção & controle , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Programas de Rastreamento , Anamnese , Pessoa de Meia-Idade , Razão de Chances
8.
Int J Cancer ; 145(12): 3207-3217, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771221

RESUMO

Our aim was to estimate how long-term mortality following breast cancer diagnosis depends on age at diagnosis, tumor estrogen receptor (ER) status, and the time already survived. We used the population-based Australian Breast Cancer Family Study which followed-up 1,196 women enrolled during 1992-1999 when aged <60 years at diagnosis with a first primary invasive breast cancer, over-sampled for younger ages at diagnosis, for whom tumor pathology features and ER status were measured. There were 375 deaths (median follow-up = 15.7; range = 0.8-21.4, years). We estimated the mortality hazard as a function of time since diagnosis using a flexible parametric survival analysis with ER status a time-dependent covariate. For women with ER-negative tumors compared with those with ER-positive tumors, 5-year mortality was initially higher (p < 0.001), similar if they survived to 5 years (p = 0.4), and lower if they survived to 10 years (p = 0.02). The estimated mortality hazard for ER-negative disease peaked at ~3 years post-diagnosis, thereafter declined with time, and at 7 years post-diagnosis became lower than that for ER-positive disease. This pattern was more pronounced for women diagnosed at younger ages. Mortality was also associated with lymph node count (hazard ratio (HR) per 10 nodes = 2.52 [95% CI:2.11-3.01]) and tumor grade (HR per grade = 1.62 [95% CI:1.34-1.96]). The risk of death following a breast cancer diagnosis differs substantially and qualitatively with diagnosis age, ER status and time survived. For women who survive >7 years, those with ER-negative disease will on average live longer, and more so if younger at diagnosis.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Receptores Estrogênicos/metabolismo , Adulto , Austrália , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida
9.
Prostate ; 78(13): 962-969, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30133758

RESUMO

BACKGROUND: DNA methylation can mimic the effects of germline mutations in cancer predisposition genes. Recently, we identified twenty-four heritable methylation marks associated with breast cancer risk. As breast and prostate cancer share genetic risk factors, including rare, high-risk mutations (eg, in BRCA2), we hypothesized that some of these heritable methylation marks might also be associated with the risk of prostate cancer. METHODS: We studied 869 incident prostate cancers (430 aggressive and 439 non-aggressive) and 869 matched controls nested within a prospective cohort study. DNA methylation was measured in pre-diagnostic blood samples using the Illumina Infinium HM450K BeadChip. Conditional logistic regression models, adjusted for prostate cancer risk factors and blood cell composition, were used to estimate odds ratios and 95% confidence intervals for the association between the 24 methylation marks and the risk of prostate cancer. RESULTS: Five methylation marks within the VTRNA2-1 promoter region (cg06536614, cg00124993, cg26328633, cg25340688, and cg26896946), and one in the body of CLGN (cg22901919) were associated with the risk of prostate cancer. In stratified analyses, the five VTRNA2-1 marks were associated with the risk of aggressive prostate cancer. CONCLUSIONS: This work highlights a potentially important new area of investigation for prostate cancer susceptibility and adds to our knowledge about shared risk factors for breast and prostate cancer.


Assuntos
Adenocarcinoma/genética , Neoplasias da Mama/genética , Metilação de DNA , Predisposição Genética para Doença , Neoplasias da Próstata/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia
10.
Trials ; 19(1): 397, 2018 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30045764

RESUMO

BACKGROUND: Australia and New Zealand have the highest incidence rates of colorectal cancer worldwide. In Australia there is significant unwarranted variation in colorectal cancer screening due to low uptake of the immunochemical faecal occult blood test, poor identification of individuals at increased risk of colorectal cancer, and over-referral of individuals at average risk for colonoscopy. Our pre-trial research has developed a novel Colorectal cancer RISk Prediction (CRISP) tool, which could be used to implement precision screening in primary care. This paper describes the protocol for a phase II multi-site individually randomised controlled trial of the CRISP tool in primary care. METHODS: This trial aims to test whether a standardised consultation using the CRISP tool in general practice (the CRISP intervention) increases risk-appropriate colorectal cancer screening compared to control participants who receive standardised information on cancer prevention. Patients between 50 and 74 years old, attending an appointment with their general practitioner for any reason, will be invited into the trial. A total of 732 participants will be randomised to intervention or control arms using a computer-generated allocation sequence stratified by general practice. The primary outcome (risk-appropriate screening at 12 months) will be measured using baseline data for colorectal cancer risk and objective health service data to measure screening behaviour. Secondary outcomes will include participant cancer risk perception, anxiety, cancer worry, screening intentions and health service utilisation measured at 1, 6 and 12 months post randomisation. DISCUSSION: This trial tests a systematic approach to implementing risk-stratified colorectal cancer screening in primary care, based on an individual's absolute risk, using a state-of-the-art risk assessment tool. Trial results will be reported in 2020. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry, ACTRN12616001573448p . Registered on 14 November 2016.


Assuntos
Neoplasias Colorretais/diagnóstico , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Medicina Geral , Atenção Primária à Saúde , Idoso , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Vitória
11.
Nat Commun ; 9(1): 867, 2018 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-29491469

RESUMO

Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.


Assuntos
Neoplasias da Mama/genética , Metilação de DNA , Austrália , Neoplasias da Mama/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Ilhas de CpG , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos
12.
JNCI Cancer Spectr ; 2(4): pky057, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31360877

RESUMO

Background: We applied machine learning to find a novel breast cancer predictor based on information in a mammogram. Methods: Using image-processing techniques, we automatically processed 46 158 analog mammograms for 1345 cases and 4235 controls from a cohort and case-control study of Australian women, and a cohort study of Japanese American women, extracting 20 textural features not based on pixel brightness threshold. We used Bayesian lasso regression to create individual- and mammogram-specific measures of breast cancer risk, Cirrus. We trained and tested measures across studies. We fitted Cirrus with conventional mammographic density measures using logistic regression, and computed odds ratios (OR) per standard deviation adjusted for age and body mass index. Results: Combining studies, almost all textural features were associated with case-control status. The ORs for Cirrus measures trained on one study and tested on another study ranged from 1.56 to 1.78 (all P < 10-6). For the Cirrus measure derived from combining studies, the OR was 1.90 (95% confidence interval [CI] = 1.73 to 2.09), equivalent to a fourfold interquartile risk ratio, and was little attenuated after adjusting for conventional measures. In contrast, the OR for the conventional measure was 1.34 (95% CI = 1.25 to 1.43), and after adjusting for Cirrus it became 1.16 (95% CI = 1.08 to 1.24; P = 4 × 10-5). Conclusions: A fully automated personal risk measure created from combining textural image features performs better at predicting breast cancer risk than conventional mammographic density risk measures, capturing half the risk-predicting ability of the latter measures. In terms of differentiating affected and unaffected women on a population basis, Cirrus could be one of the strongest known risk factors for breast cancer.

13.
Oncotarget ; 8(60): 102110-102118, 2017 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-29254229

RESUMO

This study was conducted to identify the role of reproductive factors as environmental modifiers for breast cancer (BC) risk in clinic-based, East-Asian BRCA1 and BRCA2 mutation carriers and non-carriers with high-risk criteria of BRCA mutations (family history (FH) of BC, early-onset BC (aged ≤40 years)). A total of 581 women who were BRCA carriers (222 BRCA1 and 359 BRCA2), 1,083 non-carriers with FH, and 886 non-carriers with early-onset BC were enrolled and interviewed to examine the reproductive factors, from 2007 to 2014. The hazard ratio (HR) and its 95% confidence interval (CI) in the weighted Cox regression model were used to calculate the BC risk based on the reproductive factors. Earlier menarche increased BC risk by 3.49-fold in BRCA2 mutation carriers (95%CI=2.03-6.00) and 3.30-fold in non-carriers with FH (95%CI=1.73-6.34), but was insignificantly associated with BRCA1 carriers and non-carriers for early-onset BC (P-heterogeneity=0.047). Higher parity decreased BC risk in BRCA carriers and non-carriers with FH, especially in BRCA1 carriers (HR=0.27, 95% CI=0.09-0.83 for two parity; and HR=0.23, 95%CI=0.05-1.00 for ≥3 parity), but increased the early-onset BC risk (HR=4.63, 95%CI=2.56-8.51 for >3 parity, p-heterogeneity=0.045). Oral contraceptive (OC) use and longer estrogen exposure periods (≥30 years) were associated with an increased risk of early-onset BC (HR=3.99, 95%CI=1.65-9.67; HR=7.69, 95%CI=1.96-25.01), while OC use was not associated with BC risk in other groups and longer estrogen exposure had rather decreased risk for BC risk (both p-heterogeneity<0.001). Several reproductive factors as risk modifiers could heterogeneously be associated with BC among BRCA1/2 mutation carriers, non-carriers with FH, and early-onset BC non-carriers.

14.
Am J Epidemiol ; 185(6): 487-500, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28399571

RESUMO

The ability to classify people according to their underlying genetic susceptibility to a disease is increasing with new knowledge, better family data, and more sophisticated risk prediction models, allowing for more effective prevention and screening. To do so, however, we need to know whether risk associations are the same for people with different genetic susceptibilities. To illustrate one way to estimate such gene-environment interactions, we used prospective data from 3 Australian family cancer cohort studies, 2 enriched for familial risk of breast cancer. There were 288 incident breast cancers in 9,126 participants from 3,222 families. We used Cox proportional hazards models to investigate whether associations of breast cancer with body mass index (BMI; weight (kg)/height (m)2) at age 18-21 years, BMI at baseline, and change in BMI differed according to genetic risk based on lifetime breast cancer risk from birth, as estimated by BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) software, adjusted for age at baseline data collection. Although no interactions were statistically significant, we have demonstrated the power with which gene-environment interactions can be investigated using a cohort enriched for persons with increased genetic risk and a continuous measure of genetic risk based on family history.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/genética , Saúde da Família/estatística & dados numéricos , Interação Gene-Ambiente , Predisposição Genética para Doença , História Reprodutiva , Adolescente , Adulto , Austrália/epidemiologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco/métodos , Adulto Jovem
15.
Int J Epidemiol ; 46(2): 652-661, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28338721

RESUMO

Background: Mammographic density defined by the conventional pixel brightness threshold, and adjusted for age and body mass index (BMI), is a well-established risk factor for breast cancer. We asked if higher thresholds better separate women with and without breast cancer. Methods: We studied Australian women, 354 with breast cancer over-sampled for early-onset and family history, and 944 unaffected controls frequency-matched for age at mammogram. We measured mammographic dense area and percent density using the CUMULUS software at the conventional threshold, which we call Cumulus , and at two increasingly higher thresholds, which we call Altocumulus and Cirrocumulus , respectively. All measures were Box-Cox transformed and adjusted for age and BMI. We estimated the odds per adjusted standard deviation (OPERA) using logistic regression and the area under the receiver operating characteristic curve (AUC). Results: Altocumulus and Cirrocumulus were correlated with Cumulus (r ∼ 0.8 and 0.6 , respectively) . For dense area, the OPERA was 1.62, 1.74 and 1.73 for Cumulus, Altocumulus and Cirrocumulus , respectively (all P < 0.001). After adjusting for Altocumulus and Cirrocumulus , Cumulus was not significant ( P > 0.6). The OPERAs for percent density were less but gave similar findings. The mean of the standardized adjusted Altocumulus and Cirrocumulus dense area measures was the best predictor; OPERA = 1.87 [95% confidence interval (CI): 1.64-2.14] and AUC = 0.68 (0.65-0.71). Conclusions: The areas of higher mammographically dense regions are associated with almost 30% stronger breast cancer risk gradient, explain the risk association of the conventional measure and might be more aetiologically important. This has substantial implications for clinical translation and molecular, genetic and epidemiological research.


Assuntos
Densidade da Mama , Neoplasias da Mama/diagnóstico por imagem , Mama/diagnóstico por imagem , Mamografia , Adulto , Austrália , Índice de Massa Corporal , Estudos de Casos e Controles , Detecção Precoce de Câncer , Reações Falso-Positivas , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Curva ROC , Sistema de Registros , Fatores de Risco , Software
16.
BMC Med Inform Decis Mak ; 17(1): 13, 2017 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-28103848

RESUMO

BACKGROUND: In Australia, screening for colorectal cancer (CRC) with colonoscopy is meant to be reserved for people at increased risk, however, currently there is a mismatch between individuals' risk of CRC and the type of CRC screening they receive. This paper describes the development and optimisation of a Colorectal cancer RISk Prediction tool ('CRISP') for use in primary care. The aim of the CRISP tool is to increase risk-appropriate CRC screening. METHODS: CRISP development was informed by previous experience with developing risk tools for use in primary care and a systematic review of the evidence. A CRISP prototype was used in simulated consultations by general practitioners (GPs) with actors as patients. GPs were interviewed to explore their experience of using CRISP, and practice nurses (PNs) and practice managers (PMs) were interviewed after a demonstration of CRISP. Transcribed interviews and video footage of the 'consultations' were qualitatively analyzed. Themes arising from the data were mapped onto Normalization Process Theory (NPT). RESULTS: Fourteen GPs, nine PNs and six PMs were recruited from 12 clinics. Results were described using the four constructs of NPT: 1) Coherence: Clinicians understood the rationale behind CRISP, particularly since they were familiar with using risk tools for other conditions; 2) Cognitive participation: GPs welcomed the opportunity CRISP provided to discuss healthy and unhealthy behaviors with their patients, but many GPs challenged the screening recommendation generated by CRISP; 3) Collective Action: CRISP disrupted clinician-patient flow if the GP was less comfortable with computers. GP consultation time was a major implementation barrier and overall consensus was that PNs have more capacity and time to use CRISP effectively; 4) Reflexive monitoring: Limited systematic monitoring of new interventions is a potential barrier to the sustainable embedding of CRISP. CONCLUSIONS: CRISP has the potential to improve risk-appropriate CRC screening in primary care but was considered more likely to be successfully implemented as a nurse-led intervention.


Assuntos
Neoplasias Colorretais/diagnóstico , Diagnóstico por Computador/métodos , Aplicações da Informática Médica , Atenção Primária à Saúde/métodos , Medição de Risco/métodos , Adulto , Idoso , Austrália , Neoplasias Colorretais/diagnóstico por imagem , Simulação por Computador , Feminino , Clínicos Gerais , Humanos , Masculino , Pessoa de Meia-Idade , Enfermeiras e Enfermeiros
17.
Prostate ; 77(5): 471-478, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28116812

RESUMO

BACKGROUND: Global measures of peripheral blood DNA methylation have been associated with risk of some malignancies, including breast, bladder, and gastric cancer. Here, we examined genome-wide measures of peripheral blood DNA methylation in prostate cancer and its non-aggressive and aggressive disease forms. METHODS: We used a matched, case-control study of 687 incident prostate cancer samples, nested within a larger prospective cohort study. DNA methylation was measured in pre-diagnostic, peripheral blood samples using the Illumina Infinium HM450K BeadChip. Genome-wide measures of DNA methylation were computed as the median M-value of all CpG sites and according to CpG site location and regulatory function. We used conditional logistic regression to test for associations between genome-wide measures of DNA methylation and risk of prostate cancer and its subtypes, and by time between blood draw and diagnosis. RESULTS: We observed no associations between the genome-wide measure of DNA methylation based on all CpG sites and risk of prostate cancer or aggressive disease. Risk of non-aggressive disease was associated with higher methylation of CpG islands (OR = 0.80; 95%CI = 0.68-0.94), promoter regions (OR = 0.79; 95%CI = 0.66-0.93), and high density CpG regions (OR = 0.80; 95%CI = 0.68-0.94). Additionally, higher methylation of all CpGs (OR = 0.66; 95%CI = 0.48-0.89), CpG shores (OR = 0.62; 95%CI = 0.45-0.84), and regulatory regions (OR = 0.68; 95% CI = 0.51-0.91) was associated with a reduced risk of overall prostate cancer within 5 years of blood draw but not thereafter. CONCLUSIONS: A reduced risk of overall prostate cancer within 5 years of blood draw and non-aggressive prostate cancer was associated with higher genome-wide methylation of peripheral blood DNA. While these data have no immediate clinical utility, with further work they may provide insight into the early events of prostate carcinogenesis. Prostate 77:471-478, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Ilhas de CpG/fisiologia , Metilação de DNA/fisiologia , Estudo de Associação Genômica Ampla/métodos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Fatores de Risco
19.
Cancer Epidemiol Biomarkers Prev ; 26(3): 404-412, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27799157

RESUMO

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known.Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component.Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age <40 years to 0.5 for age ≥70 years (equivalent to sibling relative risks of 5.1 to 1.3, respectively).Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer.Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404-12. ©2016 AACR.


Assuntos
Neoplasias Colorretais/epidemiologia , DNA Glicosilases/genética , Reparo de Erro de Pareamento de DNA , Predisposição Genética para Doença , Herança Multifatorial , Penetrância , Adulto , Idoso , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Mutação , Vigilância da População , Prevalência , Fatores de Risco
20.
J Med Genet ; 53(12): 800-811, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27595995

RESUMO

BACKGROUND: The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. METHODS: We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. RESULTS: For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. CONCLUSIONS: This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/metabolismo , Quinase do Ponto de Checagem 2/genética , Predisposição Genética para Doença , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/metabolismo , Proteínas Supressoras de Tumor/genética , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Proteína do Grupo de Complementação N da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Masculino , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Risco
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