Communicating science: epigenetics in the spotlight.

Given the public interest in epigenetic science, this study aimed to better understand media representations of epigenetics in national newspaper coverage in various regions in North America, Europe, and Asia. Content analysis was used to study media messages about epigenetics, their policy focus, and the balance of the reporting. We identified several recurring themes in the news reports, including policy messages relating to individual and societal responsibilities. We also found shortcomings in the media's portrayal of epigenetic science, and sought to identify potential causes by considering the underlying scientific evidence that the media reported on. A case study analysis showed that the results of epigenetic studies were often overstated in academic research publications due to common experimental limitations. We suggest that defining standardized criteria with which to evaluate epigenetic studies could help to overcome some of the challenges inherent in translating complex epigenetic research findings for non-technical audiences, and present a Press Kit template that researchers can adapt and use to aid in the development of accurate and balanced press releases.

Recurrent tumor-specific regulation of alternative polyadenylation of cancer-related genes.

BACKGROUND: Alternative polyadenylation (APA) results in messenger RNA molecules with different 3' untranslated regions (3' UTRs), affecting the molecules' stability, localization, and translation. APA is pervasive and implicated in cancer. Earlier reports on APA focused on 3' UTR length modifications and commonly characterized APA events as 3' UTR shortening or lengthening. However, such characterization oversimplifies the processing of 3' ends of transcripts and fails to adequately describe the various scenarios we observe. RESULTS: We built a cloud-based targeted de novo transcript assembly and analysis pipeline that incorporates our previously developed cleavage site prediction tool, KLEAT. We applied this pipeline to elucidate the APA profiles of 114 genes in 9939 tumor and 729 tissue normal samples from The Cancer Genome Atlas (TCGA). The full set of 10,668 RNA-Seq samples from 33 cancer types has not been utilized by previous APA studies. By comparing the frequencies of predicted cleavage sites between normal and tumor sample groups, we identified 77 events (i.e. gene-cancer type pairs) of tumor-specific APA regulation in 13 cancer types; for 15 genes, such regulation is recurrent across multiple cancers. Our results also support a previous report showing the 3' UTR shortening of FGF2 in multiple cancers. However, over half of the events we identified display complex changes to 3' UTR length that resist simple classification like shortening or lengthening. CONCLUSIONS: Recurrent tumor-specific regulation of APA is widespread in cancer. However, the regulation pattern that we observed in TCGA RNA-seq data cannot be described as straightforward 3' UTR shortening or lengthening. Continued investigation into this complex, nuanced regulatory landscape will provide further insight into its role in tumor formation and development.

Kleat: cleavage site analysis of transcriptomes.

In eukaryotic cells, alternative cleavage of 3' untranslated regions (UTRs) can affect transcript stability, transport and translation. For polyadenylated (poly(A)) transcripts, cleavage sites can be characterized with short-read sequencing using specialized library construction methods. However, for large-scale cohort studies as well as for clinical sequencing applications, it is desirable to characterize such events using RNA-seq data, as the latter are already widely applied to identify other relevant information, such as mutations, alternative splicing and chimeric transcripts. Here we describe KLEAT, an analysis tool that uses de novo assembly of RNA-seq data to characterize cleavage sites on 3' UTRs. We demonstrate the performance of KLEAT on three cell line RNA-seq libraries constructed and sequenced by the ENCODE project, and assembled using Trans-ABySS. Validating the KLEAT predictions with matched ENCODE RNA-seq and RNA-PET libraries, we show that the tool has over 90% positive predictive value when there are at least three RNA-seq reads supporting a poly(A) tail and requiring at least three RNA-PET reads mapping within 100 nucleotides as validation. We also compare the performance of KLEAT with other popular RNA-seq analysis pipelines that reconstruct 3' UTR ends, and show that it performs favourably, based on an ROC-like curve.

Impact of routine pathology review on treatment for node-negative breast cancer.

PURPOSE: Routine secondary pathology review influences diagnosis and treatment among patients diagnosed with breast cancer. The impact of review on patients with node-negative breast cancer and the nature of the pathology elements leading to management changes are not well described. METHODS: Patients with node-negative, invasive, or in situ breast cancer and evaluable nodes referred to the British Columbia Cancer Agency during two time periods between 2004 and 2007 were included. Pathologists with expertise in breast cancer reviewed the original reports and slides. Biomarker testing was not routinely repeated. Medical record review was conducted to determine whether original pathology was changed and whether recommended therapy was affected. RESULTS: Among 906 eligible patients, 405 (45%) received a pathology review. Univariate comparisons revealed that reviewed patients were younger (P < .001) and more likely to have close margins (P < .001), whereas other characteristics were similar. A total of 102 pathology changes were documented among 81 patients (20%). The most frequently changed elements were grade (40%) and lymphovascular (26%), nodal (15%), and margin (12%) status. These changes resulted in 27 treatment modifications among 25 patients (6%). Treatment changes were primarily related to nodal and margin status, and only two of 27 were related to measurement of tumor biology in women with estrogen receptor-positive, node-negative breast cancer. CONCLUSION: Reported rates of change are significant and warrant routine secondary pathology review among patients with node-negative breast cancer or ductal carcinoma in situ before final treatment is recommended. Review remains relevant in the era of gene expression signatures to determine margin and nodal status.

Opening Pandora's Box--the new biology of driver mutations and clonal evolution in cancer as revealed by next generation sequencing.

Recent advances in next generation sequencing have greatly enhanced the scope and speed of genomic cancer research. Apart from merely listing identified mutations from cancer genomes sequencing, this review will summarize some insights specifically focusing on the biology of allele generating cancer driver mutations and clonal patterns during tumor evolution. Studies using massively parallel sequencing of primary tumor samples and cancer cell lines have identified neomorphic alleles and other recurrent mutations in proteins involved in chromatin modification and in the regulation of transcription and translation. Further studies with deep sequencing of matched primary and metastatic tumors have also started to characterize distinct patterns of tumor clonal evolution. The development of single cell sequencing is expected to help further elucidate tumor clonality and aid the translation of these discoveries into diagnostic and therapeutic applications.