Yield of Downstream Tests After Exercise Treadmill Testing A Prospective Cohort Study

ObjectivesThe purpose of this study was to estimate the frequency and results of downstream testing after exercise treadmill tests (ETTs).BackgroundThe utility of additional diagnostic testing after ETT is not well characterized.MethodsWe followed consecutive individuals without known coronary artery disease referred for clinical ETT at a large medical center. We measured the frequency and results of downstream imaging tests and invasive angiography within 6 months of ETT and the combined endpoint of survival free from cardiovascular death, myocardial infarction, and coronary revascularization.ResultsAmong 3,656 consecutive subjects who were followed for a mean of 2.5 ± 1.1 years, 332 (9.0%) underwent noninvasive imaging and 84 (2.3%) were referred directly to invasive angiography after ETT. The combined endpoint occurred in 76 (2.2%) patients. The annual incidence of the combined endpoint after negative, inconclusive, and positive ETT was 0.2%, 1.3%, and 12.4%, respectively (p < 0.001). Rapid recovery of electrocardiography (ECG) changes during ETT was associated with negative downstream test results and excellent prognosis, whereas typical angina despite negative ECG was associated with positive downstream tests and adverse prognosis (p < 0.001). Younger age, female sex, higher metabolic equivalents of task achieved, and rapid recovery of ECG changes were predictors of negative downstream tests.ConclusionsAmong patients referred for additional testing after ETT, the lowest yield was observed among individuals with rapid recovery of ECG changes or negative ETT, whereas the highest yield was observed among those with typical angina despite negative ECG or a positive ETT. These findings may be used to identify patients who are most and least likely to benefit from additional testing

Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

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

The yield of downstream tests after exercise treadmill testing: a prospective cohort study

Background: The utility of additional cardiac diagnostic testing following exercise treadmill tests (ETT) is not well characterized. Our aim was to estimate the frequency and yield of downstream testing following exercise treadmill testing (ETT) and identify/predictors of patients who are most and least likely to benefit from additional testing. Methods and Results We followed a cohort of 3,345 consecutive individuals without known coronary artery disease referred for a clinical ETT at large medical center. Downstream tests included all tests (invasive and noninvasive) within six months of ETT. Overall, 332 (9.0%) underwent noninvasive imaging while 84 (2.3%) were referred directly to invasive angiography. The rates of positive downstream testing following negative, inconclusive and positive ETT were 6.4%, 14.2% and 32.9% respectively. Over a mean follow-up of 2.5± 1.1 years, there were 76 (2.2%) adverse events (cardiovascular death, myocardial infarctions, and coronary revascularizations) with annual incidence of 0.2%, 1.3% and 12.4% following negative, inconclusive and positive ETT respectively (P<0.001). Among 1,043 (28.5%) inconclusive ETT studies, rapid recovery of ECG changes (n=134, 13%) was associated with negative downstream test results and excellent prognosis while typical angina despite negative ECG (n= 103, 10%) was associated with a higher frequency of positive downstream tests and adverse prognosis (P<0.001). ConcIusions: Among patients referred for additional testing after ETT, the lowest yield was observed among individuals with rapid recovery of ECG changes or negative ETT while the highest yield was observed among those who developed , typical angina despite negative ECG or had a positive ETT. These findings may be used to identify patients who are most and least likely to benefit from additional testing.Apresentado no Scientific Sessions and Resuscitation Science Symposium of the American Heart Association, realizado em 16-17 de novembro de 2013 em Dallas, TX

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

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

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.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 (VAFPeer reviewe

Sex differences in oncogenic mutational processes

Funder: Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (NSERC Canadian Network for Research and Innovation in Machining Technology); doi: https://doi.org/10.13039/501100002790Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762Funder: Canada Foundation for Innovation (Fondation canadienne pour l'innovation); doi: https://doi.org/10.13039/501100000196Funder: Terry Fox Research Institute (Institut de Recherche Terry Fox); doi: https://doi.org/10.13039/501100004376Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research