An analysis of the sensitivity of proteogenomic mapping of somatic mutations and novel splicing events in cancer

Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations, and splice variants identified in cancer cells are translated. Herein, we apply a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast-cancer-patient-derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS sample process replicates defined here as an independent tandem MS experiment using identical sample material. Despite analysis of over 30 sample process replicates, only about 10% of SNVs (somatic and germline) detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNVs without a detectable mRNA transcript were also observed, suggesting that transcriptome coverage was incomplete (~80%). In contrast to germline variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than in the luminal tumor, raising the possibility of differential translation or protein degradation effects. In conclusion, this large-scale proteogenomic integration allowed us to determine the degree to which mutations are translated and identify gaps in sequence coverage, thereby benchmarking current technology and progress toward whole cancer proteome and transcriptome analysis

Report from Working Group 2: Higgs Physics at the HL-LHC and HE-LHC

The discovery of the Higgs boson in 2012, by the ATLAS and CMS experiments, was a success achieved with only a percent of the entire dataset foreseen for the LHC. It opened a landscape of possibilities in the study of Higgs boson properties, Electroweak Symmetry breaking and the Standard Model in general, as well as new avenues in probing new physics beyond the Standard Model. Six years after the discovery, with a conspicuously larger dataset collected during LHC Run 2 at a 13 TeV centre-of-mass energy, the theory and experimental particle physics communities have started a meticulous exploration of the potential for precision measurements of its properties. This includes studies of Higgs boson production and decays processes, the search for rare decays and production modes, high energy observables, and searches for an extended electroweak symmetry breaking sector. This report summarises the potential reach and opportunities in Higgs physics during the High Luminosity phase of the LHC, with an expected dataset of pp collisions at 14 TeV, corresponding to an integrated luminosity of 3~ab$^{-1}$. These studies are performed in light of the most recent analyses from LHC collaborations and the latest theoretical developments. The potential of an LHC upgrade, colliding protons at a centre-of-mass energy of 27 TeV and producing a dataset corresponding to an integrated luminosity of 15~ab$^{-1}$, is also discussed