During August 2014, five high school students who had attended an outdoor education camp were hospitalized with a febrile illness, prompting further investigation. Ten total cases of tick-borne ...relapsing fever (TBRF) were identified-six cases confirmed by culture or visualization of spirochetes on blood smear and four probable cases with compatible symptoms (attack rate: 23%). All patients had slept in the campsite's only cabin. Before the camp, a professional pest control company had rodent proofed the cabin, but no acaricides had been applied. Cabin inspection after the camp found rodents and Ornithodoros ticks, the vector of TBRF. Blood samples from a chipmunk trapped near the cabin and from patients contained Borrelia hermsii with identical gene sequences (100% over 630 base pairs). Health departments in TBRF endemic areas should consider educating cabin owners and pest control companies to apply acaricides during or following rodent proofing, because ticks that lack rodents for a blood meal might feed on humans.
Adults experiencing homelessness experience a disproportionate burden of health disparities which has further exacerbated mental health, substance use, and coping during the COVID-19 pandemic. As ...limited data is available to understand the experience of adults experiencing homelessness and their health during this time, the purpose of this study was to explore how COVID-19 may have impacted their mental health, substance use, and ways of coping in this population. Using community-based participatory research, a community advisory board was established and remote individual interviews with 21 adults experiencing homelessness and 10 providers were conducted in Skid Row, Los Angeles. Using a qualitative, data analytic approach, the following major themes emerged: (1) Negative Impact of COVID-19 on Mental Health; (2) Negative Impact of COVID-19 on Limitation of Harm Reduction Services; and (3) Coping Strategies Utilized During the COVID-19 Pandemic. More research is needed to understand the impact of this pandemic on underserved communities.
Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy ...number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.
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•Analysis of hepatocellular carcinomas integrates data of multiple genomic platforms•Mutated genes reveal oncogenic processes altering hepatocyte energy balance•Multiplex analyses suggest a key role for Sonic hedgehog signaling in HCC•IDH mutations point to a HCC subgroup molecularly similar to cholangiocarcinoma
Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a ...framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.
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•Represents the largest integrative analysis of cutaneous melanoma (331 patients)•Establishes a framework for melanoma genomic classification: BRAF, RAS, NF1, and Triple-WT•Identifies additional subtypes that may benefit from MAPK- and RTK-targeted therapies•Multi-dimensional analyses identify immune signatures associated with improved survival
An integrative analysis of cutaneous melanomas establishes a framework for genomic classification into four subtypes that can guide clinical decision-making for targeted therapies. A subset of each of the genomic classes expresses considerable immune infiltration markers that are associated with improved survival, with potential implications for immunotherapy.
The discovery of drivers of cancer has traditionally focused on protein-coding genes
. 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) Consortium
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 drivers
, 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.
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations ...in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
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•Alteration map of 10 signaling pathways across 9,125 samples from 33 cancer types•Reusable, curated pathway templates that include a catalogue of driver genes•57% of tumors have at least one potentially actionable alteration in these pathways•Co-occurrence of actionable alterations suggests combination therapy opportunities
An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.
Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large ...datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.
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•PanSoftware applied to PanCancer data identified 299 cancer driver genes•Driver genes and mutations are shared across anatomical origins and cell types•In silico discovery of ∼3,400 driver mutations coupled with experimental validation•57% of tumors harbor potentially actionable oncogenic events
A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically ...significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.
•Integrated analysis finds molecular features characteristic of gynecologic tumors•Subtypes with high leukocyte infiltration, a marker for immune response, identified•Gene-lncRNA interaction network of ESR1, DKC1, and lncRNAs TERC, NEAT1, and TUG1 identified•Decision tree to group patients into clinically relevant prognostic subtypes proposed
By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes.
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. ...Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
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•Multi-platform study of 150 pancreatic cancers accounting for neoplastic cellularity•Identify KRAS mutational heterogeneity and alternate drivers in KRAS wild-type tumors•Identify proteomic subtypes with prognostic significance and therapeutic implications•Integrated analysis of mRNA and non-coding RNA suggests consensus subtypes
This TCGA study reveals the complex molecular landscape of PDAC, with a small number of tumors carrying multiple KRAS mutations, KRAS wild-type PDACs harboring alterations in other RAS pathway genes or alternate oncogenic drivers, and integrated RNA and protein subtypes indicating clinically significant subsets of disease.
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