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Search Results: 1 - 10 of 236959 matches for " John L Hopper "
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More breast cancer genes?
John L Hopper
Breast Cancer Research , 2001, DOI: 10.1186/bcr290
Abstract: A study of Nordic families [1] has claimed 'preliminary evidence' that a region on chromosome 13q might contain a previously unrecognized tumour-suppressor gene, mutations in which may be associated with an unknown but probable high risk for breast cancer. This potentially exciting finding was achieved using new molecular techniques and 'a strategy that assumed that somatic genetic changes in cancer tissues may give insights to the nature of the germline predisposing loci'.Comparative genomic hybridization (CGH) was used to study tumours from multicase breast cancer families. Branching and phylogenetic tree models, and other evidence suggested that loss of 13q was an early genetic event in the development of breast cancers. All five tumours from one particular family showed distinct 13q deletions, which led to identification of a haplotype shared by all five affected members that coincided with the region of loss in the tumours identified by CGH. However, the 'significance' of the loss of homozygosity studies, in both the statistical and common language meanings, is difficult to assess, given that the role of chance was not evaluated.A linkage study, in an independent set of multicase breast cancer families in which BRAC1 and BRCA2 mutations had been excluded, was then targeted on the region of interest in their search for a novel breast cancer predisposition locus that they termed BRCAX [1]. They considered their lod score results promising, although there was no evidence of linkage in an interval that was only 0.5-2.1 cM from the position of their BRCAX. Those investigators were also confident that they could exclude the role of BRCA2, which is not far (recombination fraction 0.25) from where their putative locus lies, even though they did not study extensively markers on both sides of BRCA2. Is there really a BRCAX other than BRCA2 on this chromosome?Why would one think there are more genes associated with a high risk for breast cancer other than BRCA1 and BRCA2?
Disease-specific prospective family study cohorts enriched for familial risk
Hopper John L
Epidemiologic Perspectives and Innovations , 2011, DOI: 10.1186/1742-5573-8-2
Abstract: Most common diseases demonstrate familial aggregation; the ratio of the risk for relatives of affected people to the risk for relatives of unaffected people (the familial risk ratio)) > 1. This implies there are underlying genetic and/or environmental risk factors shared by relatives. The risk gradient across this underlying 'familial risk profile', which can be predicted from family history and measured familial risk factors, is typically strong. Under a multiplicative model, the ratio of the risk for people in the upper 25% of familial risk to the risk for those in the lower 25% (the inter-quartile risk gradient) is an order of magnitude greater than the familial risk ratio. If familial risk ratio = 2 for first-degree relatives, in terms of familial risk profile: (a) people in the upper quartile will be at more than 20 times the risk of those in the lower quartile; and (b) about 90% of disease will occur in people above the median. Historically, therefore, epidemiology has compared cases with controls dissimilar for underlying familial risk profile. Were gene-environment and gene-gene interactions to exist, environmental and genetic effects could be stronger for people with increased familial risk profile. Studies in which controls are better matched to cases for familial risk profile might be more informative, especially if both cases and controls are over-sampled for increased familial risk. Prospective family study cohort (ProF-SC) designs involving people across a range of familial risk profile provide such a resource for epidemiological, genetic, behavioural, psycho-social and health utilisation research. The prospective aspect gives credibility to risk estimates. The familial aspect allows family-based designs, matching for unmeasured factors, adjusting for underlying familial risk profile, and enhanced cohort maintenance.
Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?
Graham B Byrnes, Melissa C Southey, John L Hopper
Breast Cancer Research , 2008, DOI: 10.1186/bcr2099
Abstract: When an unaffected woman presents for breast-cancer related genetic counselling it is typically because her family history of the disease is unusually strong. Her primary interest is in knowing the probability that she will develop cancer in the future. That is, she is interested in her absolute risk of disease.Epidemiologists use the term 'relative risk', as a measure of 'increased' risk, when they are referring to either: a woman's risk divided by the risk to an average woman in the population (sense a); or the risk ratio or odds ratio associated with a particular genetic or environmental risk factor, which is how much having that factor multiplies a woman's risk compared to if they did not have that factor, with all other factors held constant (sense b).Not understanding that these are three distinct concepts and measures of risk (absolute risk, relative risk in the sense a, relative risk on the sense b) can result in a failure to correctly appreciate or communicate the consequences of studies on genetic testing in the clinical setting. We shall illustrate this by reference to recently published papers on mutations in ATM, BRIP1 and PALB2, and a similar paper on a founder mutation in CHEK2.At least five papers [1-5] have recently reported on studies of women with breast cancer who have a strong cancer family history not known to be due to germline mutations in BRCA1 or BRCA2 (familial cases; see group A in Figure 1), screening them variously for mutations in ATM, BRIP1 or PALB2, or for the 1100delC mutation in CHEK2. Comparison groups of unaffected women from the general population were similarly screened (controls; see group B+D in Figure 1).Each study found that the frequency of mutations for the familial cases was substantially higher than for the controls (Table 1). For ATM, BRIP1 and PALB2, this relative frequency (RF) was higher by about seven-fold or more (though with wide confidence intervals). For the three UK studies [1-3], in total, 31 mutations were f
Using mammographic density to predict breast cancer risk: dense area or percentage dense area
Jennifer Stone, Jane Ding, Ruth ML Warren, Stephen W Duffy, John L Hopper
Breast Cancer Research , 2010, DOI: 10.1186/bcr2778
Abstract: We measured MD, including nondense area (here a surrogate for weight), in the mediolateral oblique (MLO) mammogram using a computer-assisted thresholding technique for 634 cases and 1,880 age-matched controls from the Cambridge and Norwich Breast Screening programs. Conditional logistic regression was used to estimate the risk of breast cancer, and fits of the models were compared using likelihood ratio tests and the Bayesian information criteria (BIC). All P values were two-sided.Square-root dense area was the best single predictor (for example, χ12 = 53.2 versus 44.4 for PDA). Addition of PDA and/or square-root nondense area did not improve the fit (both P > 0.3). Addition of nondense area improved the fit of the model with PDA (χ12 = 11.6; P < 0.001). According to the BIC, the PDA and nondense area model did not provide a better fit than the dense area alone model. The fitted values of the two models were highly correlated (r = 0.97). When a measure of body size is included with PDA, the predicted risk is almost identical to that from fitting dense area alone.As a single parameter, dense area provides more information than PDA on breast cancer risk.A number of prospective, nested case control studies have shown that, for women of the same age, those with greater mammographic density are more likely to develop breast cancer [1]. Mammographic density refers to the white or opaque area on a mammogram representing the epithelial and stromal tissue in the breast. It can be measured many ways and usually is expressed as the percentage of dense area in the total area of the breast image. Denoted here as percentage dense area (PDA), it can be measured reliably within and between trained observers using a computerized thresholding technique [2], in part a consequence of PDA's having a large variance even after adjusting its mean for age.Body mass index (BMI) is negatively correlated with PDA and accounts for almost one third of the variation in age-adjusted PDA [3]. When
Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age
Lidija Turkovic, Lyle C Gurrin, Melanie Bahlo, Gillian S Dite, Melissa C Southey, John L Hopper
BMC Cancer , 2010, DOI: 10.1186/1471-2407-10-466
Abstract: DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test.A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level.We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data.Mutations in BRCA1 and BRCA2 are found in a proportion of mul
Australian clinicians and chemoprevention for women at high familial risk for breast cancer
Louise A Keogh, John L Hopper, Doreen Rosenthal, Kelly-Anne Phillips
Hereditary Cancer in Clinical Practice , 2009, DOI: 10.1186/1897-4287-7-9
Abstract: Focus groups were conducted with clinicians at five Family Cancer Centers in three Australian states. Discussions were recorded, transcribed and analyzed thematically.Twenty three clinicians, including genetic counselors, clinical geneticists, medical oncologists, breast surgeons and gynaecologic oncologists, participated in six focus groups in 2007. The identified barriers to the discussion of the use of tamoxifen and raloxifene for chemoprevention pertained to issues of evidence (evidence for efficacy not strong enough, side-effects outweigh benefits, oophorectomy superior for mutation carriers), practice (drugs not approved for chemoprevention by regulatory authorities and not government subsidized, chemoprevention not endorsed in national guidelines and not many women ask about it), and perception (clinicians not knowledgeable about chemoprevention and women thought to be opposed to hormonal treatments).The study demonstrated limited enthusiasm for discussing breast cancer chemoprevention as a management option for women at high familial risk. Several options for increasing the likelihood of clinicians discussing chemoprevention were identified; maintaining up to date national guidelines on management of these women and education of clinicians about the drugs themselves, the legality of "off-label" prescribing, and the actual costs of chemopreventive medications.Effective chemoprevention strategies are now available for women at increased risk for breast cancer [1]. This represents a major addition to the risk management options for such women, particularly those who choose to avoid or postpone risk-reducing surgery. However, uptake of breast cancer chemoprevention is low in women at high familial risk [2-5]. The reasons for this low uptake must be elucidated with priority if the promise of chemoprevention to reduce morbidity from breast cancer is to be fulfilled.Four randomized controlled trials involving over 25,000 women at increased risk have demonstrated th
How do women at increased, but unexplained, familial risk of breast cancer perceive and manage their risk? A qualitative interview study
Louise A Keogh, Belinda J McClaren, Carmel Apicella, John L Hopper, the Australian Breast Cancer Family Study
Hereditary Cancer in Clinical Practice , 2011, DOI: 10.1186/1897-4287-9-7
Abstract: Participants were recruited from a population-based sample (the Australian Breast Cancer Family Study - ABCFS). The ABCFS includes women diagnosed with breast cancer and their relatives. For this study, women without breast cancer with at least one first- or second-degree relative diagnosed with breast cancer before age 50 were eligible unless a BRCA1 or BRCA2 mutation had been identified in their family. Data collection consisted of an audio recorded, semi-structured interview on the topic of breast cancer risk and screening decision-making. Data was analysed thematically.A total of 24 interviews were conducted, and saturation of the main themes was achieved. Women were classified into one of five groups: don't worry about cancer risk, but do screening; concerned about cancer risk, so do something; concerned about cancer risk, so why don't I do anything?; cancer inevitable; cancer unlikely.The language and framework women use to describe their risk of breast cancer must be the starting point in attempts to enhance women's understanding of risk and their prevention behaviour.It has been argued that health and risk have replaced illness and disease as the domains of interest for medicine [1,2]. 'The focus is no longer on illness, disability, and disease as matters of fate, but on health as a matter of ongoing moral self-transformation' [1, p172]. Women who have not had breast cancer, but who have a high familial risk of the disease, are a pertinent example of this phenomenon. While they may be physically well, the risk of breast cancer is likely to be a focus of their health care and practice, and there are proven interventions that decrease breast cancer incidence for women at high risk [3-5]. Genetic testing for a disease-predisposing mutation can provide a risk estimate and appropriate risk reduction options can be recommended for women from families in which a mutation is found, but for women from families in which no mutation has been identified this clarity and
Is there a positive association between mammographic density and bone mineral density?
Gillian S Dite, John D Wark, Graham G Giles, Dallas R English, Margaret RE McCredie, John L Hopper
Breast Cancer Research , 2005, DOI: 10.1186/bcr1383
Abstract: We have now analysed our data on 268 pre- and postmenopausal female twins following the approach of Crandall and colleagues [1]. We fitted linear regression models with robust standard errors that took into account the clustering within twin pairs. Percent mammographic density was the outcome variable and bone mineral density measures (g/cm2) were the key exposure variables. As in Crandall and colleagues [1], we adjusted for age, body mass index (weight kg/height m2) and smoking (ever/never), even though there was no evidence in our data that smoking was associated with percent mammographic density.We found no evidence of a positive association with bone mineral density at the hip or lumbar spine either overall or for women who were not current or recent users of hormone replacement therapy (Table 1) and no tests of interaction between hormone replacement therapy use and bone mineral density were significant. After restricting analyses to postmenopausal women and stratification by use of hormone replacement therapy, to replicate the analyses of Crandall and colleagues [1], the lack of an association persisted both for women who were past or never users and for women who were current or recent users. Similar results were obtained for analyses of bone mineral density at the forearm and femoral neck and total body bone mineral content (data not shown). There was also no evidence that "recent hormone use has residual effects that may obscure the [putative positive] association between mammographic density and bone mineral density" [1].Consequently, Crandall and colleagues' [1] claims of a positive association between mammographic density and bone mineral density and for a "unifying biological mechanism behind bone mineral density, mammographic density and breast cancer risk" may be overstated. Their apparent finding may be an artefact of having conducted multiple analyses, having been misled by outliers or influential points, chance or by assuming effect modification wi
Tumour morphology of early-onset breast cancers predicts breast cancer risk for first-degree relatives: the Australian Breast Cancer Family Registry
Gillian S Dite, Enes Makalic, Daniel F Schmidt, Graham G Giles, John L Hopper, Melissa C Southey
Breast Cancer Research , 2012, DOI: 10.1186/bcr3248
Abstract: We studied female first-degree relatives of a population-based sample of 452 index cases with a first primary invasive breast cancer diagnosed before the age of 40 years. For the index cases, a standardised tumour morphology review had been conducted for all; estrogen (ER) and progesterone receptor (PR) status was available for 401 (89%), and 77 (17%) had a high-risk mutation in a breast cancer susceptibility gene or methylation of the BRCA1 promoter region in peripheral blood DNA. We calculated standardised incidence ratios (SIR) by comparing the number of mothers and sisters with breast cancer with the number expected based on Australian incidence rates specific for age and year of birth.Using Cox proportional hazards modelling, absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors with between a 1.8- and 3.1-fold increased risk for relatives (all P <0.02). Excluding index cases with known genetic predisposition or BRCA1 promoter methylation, absence of extensive sclerosis, circumscribed growth, extensive intraductal carcinoma and lobular growth pattern were independent predictors with between a 2.0- and 3.3-fold increased risk for relatives (all P <0.02). Relatives of the 128 (34%) index cases with none of these four features were at population risk (SIR = 1.03, 95% CI = 0.57 to 1.85) while relatives of the 37 (10%) index cases with two or more features were at high risk (SIR = 5.18, 95% CI = 3.22 to 8.33).This wide variation in risks for relatives based on tumour characteristics could be of clinical value, help discover new breast cancer susceptibility genes and be an advance on the current clinical practice of using ER and PR as pathology-based predictors of familial and possibly genetic risks.While information about breast tumour morphology is used to make important decisions about treatment, it can also be importan
Second to fourth digit ratio (2D:4D) and concentrations of circulating sex hormones in adulthood
David C Muller, Graham G Giles, Julie Bassett, Howard A Morris, John T Manning, John L Hopper, Dallas R English, Gianluca Severi
Reproductive Biology and Endocrinology , 2011, DOI: 10.1186/1477-7827-9-57
Abstract: This analysis was based on a random sample from the Melbourne Collaborative Cohort Study. The sample consisted of of 1036 men and 620 post-menopausal women aged between 39 and 70 at the time of blood draw. Concentrations of circulating sex hormones were measured from plasma collected at baseline (1990-1994), while digit length was measured from hand photocopies taken during a recent follow-up (2003-2009). The outcome measures were circulating concentrations of testosterone, oestradiol, dehydroepiandrosterone sulphate, androstenedione, Sex Hormone Binding Globulin, androstenediol glucoronide for men only and oestrone sulphate for women only. Free testosterone and oestradiol were estimated using standard formulae derived empirically. Predicted geometric mean hormone concentrations (for tertiles of 2D:4D) and conditional correlation coefficients (for continuous 2D:4D) were obtained using mixed effects linear regression models.No strong associations were observed between 2D:4D measures and circulating concentrations of hormones for men or women. For males, right 2D:4D was weakly inversely associated with circulating testosterone (predicted geometric mean testosterone was 15.9 and 15.0 nmol/L for the lowest and highest tertiles of male right 2D:4D respectively (P-trend = 0.04). There was a similar weak association between male right 2D:4D and the ratio of testosterone to oestradiol. These associations were not evident in analyses of continuous 2D:4D.There were no strong associations between any adult circulating concentration of sex hormone or SHGB and 2D:4D. These results contribute to the growing body of evidence indicating that 2D:4D is unrelated to adult sex hormone concentrations.The length of the index finger divided by the length of the ring finger (2D:4D) has been proposed as a marker of prenatal androgen action. The investigation of digit ratios as possible markers of androgen action in early life began with the long-recognised observation that, compared with wo
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