Have the roles of two functional polymorphisms in breast cancer, R72P in P53 and MDM2-309 in MDM2, become clearer?

Genetic differences between individuals have been predicted to account for disparate outcomes in patients diagnosed with cancer. The search for genetic determinants has been ongoing for a considerable amount of time and it is only now that insights have been gained into which polymorphisms are most likely to be important in determining not only disease likelihood but also outcome. The quest to be able to accurately predict patient outcomes in breast cancer may now be a step closer as increased sample size is leading to more robust statistical analysis and a better understanding of molecular mechanisms of disease are forthcoming

Risk of Cardiovascular Events and Death—Does Insurance Matter?

BACKGROUND: Many Americans lack health insurance. Despite good evidence that lack of insurance compromises access to care, few prospective studies examine its relationship to health outcomes. OBJECTIVE: To determine the relationship between insurance and cardiovascular outcomes and the relationship between insurance and selected process measures. DESIGN AND PARTICIPANTS: We used data from 15,792 participants in the Atherosclerosis Risk in Communities Study, a prospective cohort study. Participants were enrolled in 1987–1989 and returned for follow-up visits every 3 years, for a total of 4 visits. MAIN OUTCOME MEASURES: We estimated the hazard of myocardial infarction, stroke, and death associated with insurance status using Cox proportional hazard modeling. We used generalized estimating equations to examine the association between insurance status and risk of (1) reporting no routine physical examinations, (2) being unaware of a personal cardiovascular risk condition, and (3) inadequate control of cardiovascular risk conditions. RESULTS: Persons without insurance had higher rates of stroke (adjusted hazard ratio, 95% CI 1.22–2.22) and death (adjusted hazard ratio 1.26, 95% CI 1.03–1.53), but not myocardial infarction, than those who were insured. The uninsured were less likely to report routine physical examinations (adjusted risk ratio 1.13, 95% CI 1.08–1.18); more likely to be unaware of hypertension (adjusted risk ratio 1.12, 95% CI 1.00–1.25) and hyperlipidemia (adjusted risk ratio 1.11, 95% CI 1.03–1.19); and more likely to have poor blood pressure control (adjusted risk ratio 1.23, 95% CI 1.08–1.39). CONCLUSIONS: Lack of health insurance is associated with increased rates of stroke and death and with less awareness and control of cardiovascular risk conditions. Health insurance may improve cardiovascular risk factor awareness, control and outcomes

Validation of the Edinburgh Claudication Questionnaire in 1st generation Black African-Caribbean and South Asian UK migrants: A sub-study to the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study

<p>Abstract</p> <p>Background</p> <p>We determined the diagnostic accuracy of the Edinburgh Claudication Questionnaire (ECQ) in 1^stgeneration Black African-Caribbean UK migrants as previous diagnostic questionnaires have been found to be less accurate in this population. We also determined the diagnostic accuracy of translated versions of the ECQ in 1^stgeneration South Asian UK migrants, as this has not been investigated before.</p> <p>Methods</p> <p>Subjects were recruited from the Ethnic-Echocardiographic Heart of England Screening (E-ECHOES) study, a community based screening survey for heart failure in minority ethnic groups. Translated versions of the ECQ were prepared following a recognised protocol. All participants attending screening between October 2007 and February 2009 were asked to complete the ECQ in the language of their choice (English, Punjabi, Bengali, Urdu, Hindi or Gujarati). Subjects answering positively to experiencing leg pain or discomfort on walking were asked to return to have Ankle Brachial Pressure Index (ABPI) measured.</p> <p>Results</p> <p>154 out of 2831 subjects participating in E-ECHOES (5.4%) were eligible to participate in this sub-study, for which 74.3% returned for ABPI assessment. Non-responders were younger than participants (59[9] vs. 65[11] years; p = 0.015). Punjabi, English and Bengali questionnaires identified participants with Intermittent Claudication, so these questionnaires were assessed. The sensitivities (SN), specificities (SP), positive (PPV) and negative (NPV) predictive values were calculated. English: SN: 50%; SP: 68%; PPV: 43%; NPV: 74%. Punjabi: SN: 50%; SP: 87%; PPV: 43%; NPV: 90%. Bengali: SN: 33%; SP: 50%; PPV: 13%; NPV: 73%. There were significant differences in diagnostic accuracy between the 3 versions (Punjabi: 83.8%; Bengali: 45%; English: 62.2%; p < 0.0001). No significant differences were found in sensitivity and specificity between illiterate and literate participants in any of the questionnaires and there was no significant different difference between those under and over 60 years of age.</p> <p>Conclusions</p> <p>Our findings suggest that the ECQ is not as sensitive or specific a diagnostic tool in 1^stgeneration Black African-Caribbean and South Asian UK migrants than in the Edinburgh Artery Study, reflecting the findings of other diagnostic questionnaires in these minority ethnic groups. However this study is limited by sample size so conclusions should be interpreted with caution.</p

Molecular subtypes of breast cancer and amplification of topoisomerase IIα: predictive role in dose intensive adjuvant chemotherapy

Benefit from chemotherapy treatment in breast cancer patients is determined by the molecular make-up of the tumour. In a retrospective analysis, we determined the molecular subtypes of breast cancer originally defined by expression microarrays by immunohistochemistry in tumours of patients who took part in a randomised study of adjuvant high-dose chemotherapy in breast cancer. In addition, the topoisomerase IIα (TOP2A) amplification status was determined by fluorescence in situ hybridisation and chromogenic in situ hybridisation. 411 of the 753 tumours (55%) were classified as luminal-like, 137 (18%) as basal-like and 205 (27%) as human epithelial receptor type 2 (HER2) amplified. The basal-like tumours were defined as having no expression of ER and HER2; 98 of them did express epidermal growth factor receptor and/or cytokeratin 5/6. The luminal-like tumours had a significantly better recurrence free and overall survival than the other two groups. From the 194 HER2-positive tumours, 47 (24%) were shown to harbour an amplification of TOP2A. Patients with an HER2-amplified tumour randomised to the high-dose therapy arm did worse than those in the conventional treatment arm, possibly caused by the lower cumulative anthracycline dose in the high-dose arm. The tumours with a TOP2A amplification contributed hardly to this difference, suggesting that TOP2A amplification is not the cause of the steep dose–response curve for anthracyclines in breast cancer. Possibly, the difference of the cumulative dose of only 25% between the treatment arms was insufficient to yield a survival difference

Re-evaluating early breast neoplasia

Historically, histomorphological and epidemiological data suggested that atypical ductal hyperplasia and ductal carcinoma in situ are the earliest recognizable neoplastic stages of breast cancer progression. Over the past several years, detailed high-throughput molecular genetic, gene expression and epigenetic analyses have enhanced our understanding of these early neoplastic lesions and have re-shaped our view of human breast cancer progression to include multiple distinct pathways of evolution

The removal of multiplicative, systematic bias allows integration of breast cancer gene expression datasets – improving meta-analysis and prediction of prognosis

BACKGROUND: The number of gene expression studies in the public domain is rapidly increasing, representing a highly valuable resource. However, dataset-specific bias precludes meta-analysis at the raw transcript level, even when the RNA is from comparable sources and has been processed on the same microarray platform using similar protocols. Here, we demonstrate, using Affymetrix data, that much of this bias can be removed, allowing multiple datasets to be legitimately combined for meaningful meta-analyses. RESULTS: A series of validation datasets comparing breast cancer and normal breast cell lines (MCF7 and MCF10A) were generated to examine the variability between datasets generated using different amounts of starting RNA, alternative protocols, different generations of Affymetrix GeneChip or scanning hardware. We demonstrate that systematic, multiplicative biases are introduced at the RNA, hybridization and image-capture stages of a microarray experiment. Simple batch mean-centering was found to significantly reduce the level of inter-experimental variation, allowing raw transcript levels to be compared across datasets with confidence. By accounting for dataset-specific bias, we were able to assemble the largest gene expression dataset of primary breast tumours to-date (1107), from six previously published studies. Using this meta-dataset, we demonstrate that combining greater numbers of datasets or tumours leads to a greater overlap in differentially expressed genes and more accurate prognostic predictions. However, this is highly dependent upon the composition of the datasets and patient characteristics. CONCLUSION: Multiplicative, systematic biases are introduced at many stages of microarray experiments. When these are reconciled, raw data can be directly integrated from different gene expression datasets leading to new biological findings with increased statistical power