Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

A proposal to standardize dyspnoea measurement in clinical trials of acute heart failure syndromes: the need for a uniform approach

Dyspnoea is the most common presenting symptom amongst patients with acute heart failure syndromes (AHFS). It is distressing to patients and therefore an important target for treatment in clinical practice, clinical trials, and for regulatory approval of novel agents. Despite its importance as a treatment target, no consensus exists on how to assess dyspnoea in this setting. There is a considerable uncertainty about the reproducibility of the various instruments used to measure dyspnoea, their ability to reflect changes in symptoms and whether they accurately reflect the patient’s experience. Little attempt has been made to ensure consistent implementation with respect to patients’ posture during assessment or timing in relationship to therapy. There is also limited understanding of how rapidly and completely dyspnoea responds to standard therapy. A standardized method with which to assess dyspnoea is required for clinical trials of AHFS in order to ensure uniform collection of data on a key endpoint. We propose the Provocative Dyspnoea Assessment, a method of measurement that combines sequential dyspnoea provocation by positioning and walking with a dyspnoea self assessment using a five-point Likert scale, to yield a final Dyspnoea Severity Score. This proposed tool requires detailed validation but has face validity for the uniform assessment of dyspnoea