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

Etude descriptive des paramètres inflammatoires échographiques chez 83 patients atteints de Polyarthrite Rhumatoïde et Proposition de scores échographiques binaire et semi quantitatif d'évaluation de l'activité

Un des enjeux majeurs de prise en charge de la polyarthrite rhumatoïde (PR) est le contrôle de l'activité inflammatoire, évalué en pratique courante par le score composite Disease Activity Score (DAS) 28 sur lequel repose les recommandations actuelles. L'examen échographique se révèle plus sensible que l'examen clinique pour le diagnostic de synovites et ténosynovites et apparaît comme un outil performant, dont la place en pratique clinique est réservée au diagnostic de synovite et d'érosion dans les PR débutantes. L'objectif de notre étude est d'apprécier l'intérêt de deux scores échographiques binaire (score DP+) et semi quantitatif (ScUSI : Scoring by US inflammation) d'évaluation de l'activité inflammatoire portant sur 14 articulations ciblées des mains et des avant-pieds dans une population de PR divisée en deux groupes selon l activité DAS28 (seuil=3,2). Dans le groupe de patients DAS28 3,2 (n=57), l'activité inflammatoire moyenne observée est : Score DP+=5,42 +- 4,75; ScUSI=20, 70 +- 20,63. Dans ce dernier groupe, 42,1 à 43,8% des patients présentent une activité échographique faible (DP + = 6 et/ou ScUSI >= 21). Ces deux scores présentent une excellente concordance. L'étude d'un sous-groupe de patients en rémission (DAS28 = 5 et ScUSI >= 19) chez 4/15 paticnts (26,7%). En conclusion, l'utilisation d'un score échographique des sites articulaires les plus informatifs au cours de la PR permet d'objectiver un niveau d'activité inflammatoire élevé chez près de 15% des patients en faible niveau d'activité et 26% des patients en rémission, chez qui une adaptation thérapeutique serait justifiée. L'échographie apparaît ainsi être un outil de choix applicable en pratique courante en complément de l'évaluation clinique afin de guider le suivi thérapeutique.NANCY1-SCD Medecine (545472101) / SudocSudocFranceF

Improving agreement in assessment of synovitis in rheumatoid arthritis.

International audienceSynovitis assessment through evaluation of swollen joints is integral in steering treatment decisions in rheumatoid arthritis (RA). However, there is high inter-observer variation. The objective was to assess if a short collegiate consensus would improve swollen joint agreement between rheumatologists and whether this was affected by experience.Eighteen rheumatologists from French university rheumatology units participated in three 30 minutes rounds over a half day meeting evaluating joint counts of RA patients in small groups, followed by short consensus discussions. Agreement was evaluated at the end of each round as follows: (i) global agreement of swollen joints (ii) swollen joint agreement according to level of experience of the rheumatologist (iii) swollen joint count and (iv) agreement of disease activity state according to the Disease Activity Score (DAS28). Agreement was calculated using percentage agreement and kappa.Global agreement of swollen joints failed to improve (kappa 0.50 to 0.52) at the joint level. Agreement between seniors did not improve but agreement between newly qualified rheumatologists and their senior peer, which was initially poor (kappa 0.28), improved significantly (to 0.54) at the end of the consensus exercises. Concordance of DAS28 activity states improved from 71% to 87%.Consensus exercises for swollen joint assessment is worthwhile and may potentially improve agreement between clinicians in clinical synovitis and disease activity state, benefit was mostly observed in newly qualified rheumatologists

The learning curve of nurses for the assessment of swollen and tender joints in rheumatoid arthritis

International audienceObjective: In rheumatoid arthritis (RA), nurses are now increasingly involved in joint count assessment but training is not standardized. The aim was to evaluate and describe the learning curve of nurses for the assessment of swollen and tender joints in RA. Method: Twenty nurses from university rheumatology centres inexperienced with joint counts were allocated to a rheumatologist from their centre (teacher). Acquisition of skills consisted of Phase 1: (training), a centralized 4 hour training session, with (a) lecture and demonstration, and (b) practical sessions on patients with their teachers, followed by Phase 2: (practice) involving further practice on 20 patients in their own hospitals. Primary outcome was achievement of adequate swollen joint agreement between nurse and their teacher (''gold standard'') at the ``joint'' level defined by prevalence adjusted biased adjusted kappa (PABAK) > 0.60. Agreement at the ``patient'' level of swollen joint count (SJC), tender joint count (TJC) as well as DAS28 between nurse and their teacher were assessed with intra-class correlation coefficients (ICC). Results: During the training phase, 75% of nurses achieved a swollen joint PABAK > 0.60 when compared with their teachers, which further improved to 89% after the 20 practice patients (Phase 2). Median swollen joint PABAK improved from 0.64 (Q1 :Q3 0.55,0.86) to 0.83 (Q1 :Q3 0.77,1) by the end of Phase 2. At the ``patient'' level, SJC agreement remained globally stable (ICC, 0.52 to 0.66), while TJC and DAS28 agreement remained excellent throughout. Conclusion: Nurses inexperienced in joint counts were able to achieve excellent agreement with their teachers in assessment of tender and swollen joints through a short training session; practice further enhanced this agreement. Larger longitudinal studies are required to assess skills retention. (C) 2013 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved

Megabase level sequencing reveals contrasted organization and evolution patterns of the wheat gene and transposable element spaces

To improve our understanding of the organization and evolution of the wheat (Triticum aestivum) genome, we sequenced and annotated 13-Mb contigs (18.2 Mb) originating from different regions of its largest chromosome, 3B (1 Gb), and produced a 2x chromosome survey by shotgun Illumina/Solexa sequencing. All regions carried genes irrespective of their chromosomal location. However, gene distribution was not random, with 75% of them clustered into small islands containing three genes on average. A twofold increase of gene density was observed toward the telomeres likely due to high tandem and interchromosomal duplication events. A total of 3222 transposable elements were identified, including 800 new families. Most of them are complete but showed a highly nested structure spread over distances as large as 200 kb. A succession of amplification waves involving different transposable element families led to contrasted sequence compositions between the proximal and distal regions. Finally, with an estimate of 50,000 genes per diploid genome, our data suggest that wheat may have a higher gene number than other cereals. Indeed, comparisons with rice (Oryza sativa) and Brachypodium revealed that a high number of additional noncollinear genes are interspersed within a highly conserved ancestral grass gene backbone, supporting the idea of an accelerated evolution in the Triticeae lineages

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

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