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Severe trauma induces a widespread response of the immune system. This \"genomic storm\" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways. We postulated that the hyperacute window after trauma may hold the key to understanding how the genomic storm is initiated and may lead to a new understanding of the pathogenesis of MODS. We performed whole blood transcriptome and flow cytometry analyses on a total of 70 critically injured patients (Injury Severity Score [ISS] ≥ 25) at The Royal London Hospital in the hyperacute time period within 2 hours of injury. We compared transcriptome findings in 36 critically injured patients with those of 6 patients with minor injuries (ISS ≤ 4). We then performed flow cytometry analyses in 34 critically injured patients and compared findings with those of 9 healthy volunteers. Immediately after injury, only 1,239 gene transcripts (4%) were differentially expressed in critically injured patients. By 24 hours after injury, 6,294 transcripts (21%) were differentially expressed compared to the hyperacute window. Only 202 (16%) genes differentially expressed in the hyperacute window were still expressed in the same direction at 24 hours postinjury. Pathway analysis showed principally up-regulation of pattern recognition and innate inflammatory pathways, with down-regulation of adaptive responses. Immune deconvolution, flow cytometry, and modular analysis suggested a central role for neutrophils and Natural Killer (NK) cells, with underexpression of T- and B cell responses. In the transcriptome cohort, 20 critically injured patients later developed MODS. Compared with the 16 patients who did not develop MODS (NoMODS), maximal differential expression was seen within the hyperacute window. In MODS versus NoMODS, 363 genes were differentially expressed on admission, compared to only 33 at 24 hours postinjury. MODS transcripts differentially expressed in the hyperacute window showed enrichment among diseases and biological functions associated with cell survival and organismal death rather than inflammatory pathways. There was differential up-regulation of NK cell signalling pathways and markers in patients who would later develop MODS, with down-regulation of neutrophil deconvolution markers. This study is limited by its sample size, precluding more detailed analyses of drivers of the hyperacute response and different MODS phenotypes, and requires validation in other critically injured cohorts. In this study, we showed how the hyperacute postinjury time window contained a focused, specific signature of the response to critical injury that led to widespread genomic activation. A transcriptomic signature for later development of MODS was present in this hyperacute window; it showed a strong signal for cell death and survival pathways and implicated NK cells and neutrophil populations in this differential response.

[This corrects the article DOI: 10.1371/journal.pmed.1002352.].

BackgroundThe identification and characterisation of somatic cancer driver mutations in the non-coding genome remains challenging.ObjectiveTo broadly characterise non-coding driver mutations for pancreatic ductal adenocarcinoma (PDAC).DesignUsing mutation calls from whole-genome sequence data in PDACs and genome-scale maps of accessible gene regulatory regions in normal-derived and tumour-derived pancreatic samples, we analysed enrichment of non-coding mutations in gene regulatory regions relevant to normal-derived and tumour-derived pancreatic contexts. Functional follow-up of potential driver mutations was performed using chromatin interaction analyses, massively parallel reporter assays (MPRA) and targeted analysis of selected non-coding somatic mutations (NCSMs).ResultsWe first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3614 NCSMs. Chromatin interaction analysis identified 416 potential target genes and MPRA revealed 178 NCSMs impacting reporter activity (19.45% of those tested). Targeted luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near ZFP36L2 and CDKN2A. For the former, CRISPR interference identified ZFP36L2 as a target gene (16.0–24.0% reduced expression, p=0.023–0.0047), and growth inhibition after overexpression of ZFP36L2 (4.1–14.1-fold reduction, p=6.0×10–4 − 3.2×10–3) implicates a possible tumour suppressor function.ConclusionOur integrative approach provides a catalogue of potential non-coding driver mutations and nominates ZFP36L2 as a novel PDAC driver gene with a likely tumour suppressor function.

In the need to characterise the genomic landscape of cancers and to establish novel biomarkers and therapeutic targets, studies have largely focused on the identification of driver mutations within the protein-coding gene regions, where the most pathogenic alterations are known to occur. However, the noncoding genome is significantly larger than its protein-coding counterpart, and evidence reveals that regulatory sequences also harbour functional mutations that significantly affect the regulation of genes and pathways implicated in cancer. Due to the sheer number of noncoding mutations (NCMs) and the limited knowledge of regulatory element functionality in cancer genomes, differentiating pathogenic mutations from background passenger noise is particularly challenging technically and computationally. Here we review various up-to-date high-throughput sequencing data/studies and in silico methods that can be employed to interrogate the noncoding genome. We aim to provide an overview of available data resources as well as computational and molecular techniques that can help and guide the search for functional NCMs in cancer genomes.

Non-coding mutations (NCMs) that perturb the function of cis-regulatory elements (CRE, enhancers) contribute to cancer. Due to the vast search space, mutation abundance and indirect activity of non-coding sequences, it is challenging to identify which somatic NCMs are contributing to tumour development and progression. Here, we focus our investigation on the somatic NCMs that are enriched at enhancers from 659 pancreatic ductal adenocarcinoma (PDAC) tumours. We identify cis-regulatory NCMs within PDAC-specific enhancers derived from high and low-grade PDAC cell lines and patient derived organoids using two independent computational approaches. Five such CREs enriched for PDAC associated NCMs are also frequently mutated in other common solid tumours. Functional validation using STARR-seq reporter assays enables the prioritisation of 43 NCMs (7.3%) from a pool of 587 NCMs with 6,082 oligos, that significantly alter reporter enhancer activity compared to wild-type sequences. CRISPRi perturbation of an enhancer cluster harbouring NCMs over long non-coding RNA gene MIR100HG, which hosts a microRNA cluster (mir100-let7a-2-125b-1), leads to the downregulation of MIR100HG accompanied by a significant reduction in the TGF-β pathway (known to induce MIR100HG) and other PDAC critical pathways, including KRAS, p53, MTOR and TNF α signalling. Collectively, we have reported here cis-regulatory NCMs in PDAC proximal to many cancer-relevant genes, and our integrated approach paves way to explore CRE-associated NCMs in other human cancer genomes.

Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations ( n  = 14,789) and mCAs ( n  = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P  < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms. Patients with solid cancers have high rates of clonal haematopoiesis associated with increased risk of secondary leukemias. Here, by using peripheral blood sequencing data from patients with solid non-hematologic cancer, the authors profile the landscape of mosaic chromosomal alterations and gene mutations, defining patients at high risk of leukemia progression.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes ( TP53 , PPM1D , CHEK2 ). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.

Abstract Billions of doses of coronavirus disease 2019 (COVID-19) vaccines have been administered globally, dramatically reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidence and severity in some settings. Many studies suggest vaccines provide a high degree of protection against infection and disease, but precise estimates vary and studies differ in design, outcomes measured, dosing regime, location, and circulating virus strains. In this study, we conduct a systematic review of COVID-19 vaccines through February 2022. We included efficacy data from Phase 3 clinical trials for 15 vaccines undergoing World Health Organization Emergency Use Listing evaluation and real-world effectiveness for 8 vaccines with observational studies meeting inclusion criteria. Vaccine metrics collected include protection against asymptomatic infection, any infection, symptomatic COVID-19, and severe outcomes including hospitalization and death, for partial or complete vaccination, and against variants of concern Alpha, Beta, Gamma, Delta, and Omicron. We additionally review the epidemiological principles behind the design and interpretation of vaccine efficacy and effectiveness studies, including important sources of heterogeneity. We conduct a systematic review of COVID-19 vaccine efficacy and effectiveness through February 2022. This synthesis includes 15 vaccine products and covers protection against infection and disease for multiple SARS-CoV-2 variants, for partial and complete primary vaccination series.

Somatic mutations in the isocitrate dehydrogenase 2 gene ( IDH2 ) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG) 1 – 8 . Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants 9 , 10 . In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2 -mutant AML 11 . Here we describe two patients with IDH2 -mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans , such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis , which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH -mutant malignancies. A new mechanism of acquired clinical resistance in two patients with acute myeloid leukaemia driven by mutant IDH2 is described, in which a second-site mutation on the wild-type allele induces therapeutic resistance to IDH2 inhibitors.

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10 −3 ) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10 −3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation. Clonal haematopoiesis (CH) has been associated with altered inflammatory profiles and increased risk of cardiovascular and malignant diseases. Here, the authors analyze patient data from two different cohorts and show that CH is associated with severe infections and severe Covid19.