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

Intercostal Cryo Nerve Block in Minimally Invasive Cardiac Surgery: The Prospective Randomized FROST Trial

Abstract Introduction Intercostal cryo nerve block has been shown to enhance pulmonary function recovery and pain management in post-thoracotomy procedures. However, its benefit have never been demonstrated in minimal invasive thoracotomy heart valve surgery (Mini-HVS). The purpose of the study was to determine whether intraoperative intercostal cryo nerve block in conjunction with standard of care (collectively referred to hereafter as CryoNB) provided superior analgesic efficacy in patients undergoing Mini-HVS compared to standard-of-care (SOC). Methods FROST was a prospective, 3:1 randomized (CryoNB vs. SOC), multicenter trial in patients undergoing Mini-HVS. The primary endpoint was the 48-h postoperative forced expiratory volume in 1 s (FEV1) result. Secondary endpoints were visual analog scale (VAS) scores for pain at the surgical site and general pain, intensive care unit and hospital length-of-stay, total opioid consumption, and allodynia at 6 months postoperatively. Results A total of 84 patients were randomized to the two arms of the trial CryoNB (n = 65) and SOC (n = 19). Baseline Society of Thoracic Surgeons Predictive Risk of Mortality (STS PROM) score, ejection fraction, and FEV1 were similar between cohorts. A higher 48-h postoperative FEV1 result was demonstrated in the CryoNB cohort versus the SOC cohort (1.20 ± 0.46 vs. 0.93 ± 0.43 L; P = 0.02, one-sided two-sample t test). Surgical site VAS scores were similar between the CryoNB and SOC cohorts at all postoperative timepoints evaluated, but VAS scores not related to the surgical site were lower in the SOC group at 72, 94, and 120 h postoperatively. The SOC cohort had a 13% higher opioid consumption than the CryoNB cohort. One of 64 CryoNB patients reported allodynia that did not require pain medication at 10 months. Conclusions The results of FROST demonstrated that intercostal CryoNB provided enhanced FEV1 score at 48 h postoperatively with optimized analgesic effectiveness versus SOC. Future larger prospective randomized trials are warranted to determine whether intercostal CryoNB has an opioid-sparing effect in patients undergoing Mini-HVS. Trial Registration Clinicaltrials.gov identifier: NCT02922153.http://deepblue.lib.umich.edu/bitstream/2027.42/173960/1/40122_2021_Article_318.pd

A juvenile sheep model for the long-term evaluation of stentless bioprostheses implanted as aortic root replacements

Background and aim of the study: Orthotopic valve replacement in large animals is an important component of the preclinical assessment of bioprosthetic valves. To provide the most useful preclinical information, the development of models that parallel clinical practice patterns is essential. Therefore, we sought to develop a technically feasible and reproducible model for chronic evaluation of stentless bioprosthetic aortic valves implanted as aortic root replacements in juvenile sheep.Methods: Juvenile domestic sheep (mean age 21 2.28 weeks; range: 17-26 weeks) underwent aortic root replacement using standard cardiopulmonary bypass (CPB) and surgical techniques. Animals were implanted with 19 mm (n = 21), 21 mm (n = 18) or 23 mm (n = 4) bioprostheses from two different manufacturers, and followed for 150 days. Animals surviving at least 150 days were considered long-term survivors; those which died prior to postoperative day (POD) 31 were considered operative deaths.Results: Forty-three animals underwent aortic root replacement. The mean CPB time was 91 +/- 20 min (range: 62-149 min); mean cross-clamp time was 63 +/- 13 min (range: 39-95 min). Thirty-five animals (81%) survived the first 30 days of the study period. Five deaths occurred at POD 0 due to anastomotic complications. One death occurred each on POD 3, 6, and 26 as a result of prosthesis size mismatching, thromboembolic complications, and endocarditis, respectively. There were five late deaths. Twenty animals survived the minimum 150-day study period, and 12 were sacrificed at 183 +/- 17 days. Six animals remain alive at 151 +/- 0.98 days, and one animal died each on POD 184 and 190. The remaining 10 animals are not yet 150 days from their operation. Currently, all are well at 102 +/- 34 days (range: 33-140) days.Conclusion: These data suggest that long-term evaluation of stentless aortic bioprostheses implanted as aortic root replacements can be accomplished using juvenile sheep.Univ Minnesota, Dept Surg, Div Expt Surg, Minneapolis, MN 55455 USAUniv Minnesota, Div Thorac & Cardiovasc Surg, Minneapolis, MN 55455 USAEscola Paulista Med, Dept Cardiovasc & Thorac Surg, BR-04023 Sao Paulo, BrazilLabcor Labs Ltda, Belo Horizonte, MG, BrazilEscola Paulista Med, Dept Cardiovasc & Thorac Surg, BR-04023 Sao Paulo, BrazilWeb of Scienc

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

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

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

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.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.Peer reviewe