Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia

Colorectal cancer is a major cause of cancer death and approximately 20% arises within serrated polyps, which are under-recognized and poorly understood. Human serrated colorectal polyps frequently exhibit both oncogenic BRAF mutation and widespread DNA methylation changes, which are important in silencing genes restraining neoplastic progression. Here, we investigated whether in vivo induction of mutant Braf is sufficient to result in coordinated promoter methylation changes for multiple cancer-related genes. The BrafV637E mutation was induced in murine intestine on an FVB;C57BL/6J background and assessed for morphological and DNA methylation changes at multiple time points from 10 days to 14 months. Extensive intestinal hyperplasia developed by 10 days post-induction of the mutation. By 8 months, most mice had murine serrated adenomas with dysplasia and invasive cancer developed in 40% of mice by 14 months. From 5 months onwards, Braf mutant mice showed extensive, gene-specific increases in DNA methylation even in hyperplastic mucosa without lesions. This demonstrates that persistent oncogenic Braf signaling is sufficient to induce widespread DNA methylation changes. This occurs over an extended period of time, mimicking the long latency followed by rapid progression of human serrated neoplasia. This study establishes for the first time that DNA methylation arises slowly in direct response to prolonged oncogenic Braf signaling in serrated polyps; this finding has implications both for chemoprevention and for understanding the origin of DNA hypermethylation in cancer generally.Catherine E. Bond, Cheng Liu, Futoshi Kawamata, Diane M. McKeone, Winnie Fernando, Saara Jamieson, Sally-Ann Pearson, Alexandra Kane, Susan L. Woods, Tamsin R.M. Lannagan, Roshini Somashekar, Young Lee, Troy Dumenil, Gunter Hartel, Kevin J. Spring, Jennifer Borowsky, Lochlan Fennell, Mark Bettington, Jason Lee, Daniel L. Worthley, Barbara A. Leggett and Vicki L.J. Whitehal

Experiences of Heart Related Symptoms Among Younger Women

Other Supporting Agencies: Strategic Clinical Networks, Alberta Health Services and South Health Campus, Calgary.Libin Cardiovascular Institut

Neuronal gene expression correlates of Parkinson\u27s disease with dementia

Dementia is a common disabling complication in patients with Parkinson\u27s disease (PD). The underlying molecular causes of Parkinson\u27s disease with dementia (PDD) are poorly understood. To identify candidate genes and molecular pathways involved in PDD, we have performed whole genome expression profiling of susceptible cortical neuronal populations. Results show significant differences in expression of 162 genes (P \u3c 0.01) between PD patients who are cognitively normal (PD-CogNL) and controls. In contrast, there were 556 genes (P \u3c 0.01) significantly altered in PDD compared to either healthy controls or to PD-CogNL cases. These results are consistent with increased cortical pathology in PDD relative to PD-CogNL and identify underlying molecular changes associated with the increased pathology of PDD. Lastly, we have identified expression differences in 69 genes in PD cortical neurons that occur before the onset of dementia and that are exacerbated upon the development of dementia, suggesting that they may be relevant presymptomatic contributors to the onset of dementia in PD. These results provide new insights into the cortical molecular changes associated with PDD and provide a highly useful reference database for researchers interested in PDD. © 2008 Movement Disorder Society

Preferences of Patients With Chronic Kidney Disease for Invasive Versus Conservative Treatment of Acute Coronary Syndrome: A Discrete Choice Experiment

Background Patients with chronic kidney disease (CKD) can experience acute coronary syndromes (ACS) with high morbidity and mortality. Early invasive management of ACS is recommended for most high‐risk patients; however, choosing between an early invasive versus conservative management approach may be influenced by the unique risk of kidney failure for patients with CKD. Methods and Results This discrete choice experiment measured the preferences of patients with CKD for future cardiovascular events versus acute kidney injury and kidney failure following invasive heart procedures for ACS. The discrete choice experiment, consisting of 8 choice tasks, was administered to adult patients attending 2 CKD clinics in Calgary, Alberta. The part‐worth utilities of each attribute were determined using multinomial logit models, and preference heterogeneity was explored using latent class analysis. A total of 140 patients completed the discrete choice experiment. The mean age of patients was 64 years, 52% were male, and mean estimated glomerular filtration rate was 37 mL/min per 1.73 m2. Across the range of levels, risk of mortality was the most important attribute, followed by risk of end‐stage kidney disease and risk of recurrent myocardial infarction. Latent class analysis identified 2 distinct preference groups. The largest group included 115 (83%) patients, who placed the greatest value on treatment benefits and expressed the strongest preference for reducing mortality. A second group of 25 (17%) patients was identified who were procedure averse and had a strong preference toward conservative management of ACS and avoiding acute kidney injury requiring dialysis. Conclusions The preferences of most patients with CKD for management of ACS were most influenced by lowering mortality. However, a distinct subgroup of patients was strongly averse to invasive management. This highlights the importance of clarifying patient preferences to ensure treatment decisions are aligned with patient values

Patient perspectives on engagement in decision-making in early management of non-ST elevation acute coronary syndrome: a qualitative study

Abstract Background Surveys of patients suggest many want to be actively involved in treatment decisions for acute coronary syndromes. However, patient experiences of their engagement and participation in early phase decision-making have not been well described. Methods We performed a patient led qualitative study to explore patient experiences with decision-making processes when admitted to hospital with non-ST elevation acute coronary syndrome. Trained patient-researchers conducted the study via a three-phase approach using focus groups and semi-structured interviews and employing grounded theory methodology. Results Twenty patients discharged within one year of a non-ST elevation acute coronary syndrome participated in the study. Several common themes emerged. First, patients characterized the admission and early treatment of ACS as a rapidly unfolding process where they had little control. Participants felt they played a passive role in early phase decision-making. Furthermore, participants described feeling reduced capacity for decision-making owing to fear and mental stress from acute illness, and therefore most but not all participants were relieved that expert clinicians made decisions for them. Finally, once past the emergent phase of care, participants wanted to retake a more active role in their treatment and follow-up plans. Conclusions Patients admitted with ACS often do not take an active role in initial clinical decisions, and are satisfied to allow the medical team to direct early phase care. These results provide important insight relevant to designing patient-centered interventions in ACS and other urgent care situations

APC mutation marks an aggressive subtype of BRAF mutant colorectal cancers

WNT activation is a hallmark of colorectal cancer. mutation is present in 15% of colorectal cancers, and the role of mutations in WNT signaling regulators in this context is unclear. Here, we evaluate the mutational landscape of WNT signaling regulators in mutant cancers.we performed exome-sequencing on 24 BRAF mutant colorectal cancers and analyzed these data in combination with 175 publicly available BRAF mutant colorectal cancer exomes. We assessed the somatic mutational landscape of WNT signaling regulators, and performed hotspot and driver mutation analyses to identify potential drivers of WNT signaling. The effects of Apc and Braf mutation were modelled, in vivo, using the Apc and Braf/Villin-Cre mouse, respectively.RNF43 was the most frequently mutated WNT signaling regulator (41%). Mutations in the beta-catenin destruction complex occurred in 48% of cancers. Hotspot analyses identified potential cancer driver genes in the WNT signaling cascade, including MEN1, GNG12 and WNT16. Truncating APC mutation was identified in 20.8% of cancers. Truncating APC mutation was associated with early age at diagnosis (p < 2 × 10), advanced stage (p < 0.01), and poor survival (p = 0.026). Apc/Braf animals had more numerous and larger SI and colonic lesions (p < 0.0001 and p < 0.05, respectively), and a markedly reduced survival (median survival: 3.2 months, p = 8.8 × 10), compared to animals with Apc or Braf mutation alone.the WNT signaling axis is frequently mutated in BRAF mutant colorectal cancers. WNT16 and MEN1 may be novel drivers of aberrant WNT signaling in colorectal cancer. Co-mutation of BRAF and APC generates an extremely aggressive neoplastic phenotype that is associated with poor patient outcome

Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK +

The anaplastic lymphoma kinase ALK is chromosomally rearranged in a subset of certain cancers, including 2–7% non-small cell lung cancers (NSCLC) and ~70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors crizotinib and ceritinib are approved for relapsed ALK+ NSCLC, but acquired resistance to these drugs limits median progression-free survival on average to ~10 months. Kinase domain mutations are detectable in 25–37% of resistant NSCLC samples, with activation of bypass signaling pathways detected frequently with or without concurrent ALK mutations. Here we report that, in contrast to NSCLC cells, drug resistant ALCL cells show no evidence of bypassing ALK by activating alternate signaling pathways. Instead, drug resistance selected in this setting reflects upregulation of ALK itself. Notably, in the absence of crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested or killed cells, allowing a prolonged control of drug-resistant tumors in vivo with the administration of discontinuous rather than continuous regimens of drug dosing. Furthermore, even when drug resistance mutations were detected in the kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We confirmed these findings derived from human ALCL cells in murine pro-B cells that were transformed to cytokine independence by ectopic expression of an activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK activation functions as a double-edged sword for tumor cell viability, with potential therapeutic implications