Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape
ConclusionsThese results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment.Trial registrationThe study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015. (Source: Genome Medicine)
Source: Genome Medicine - December 19, 2022 Category: Genetics & Stem Cells Source Type: research
Multi-region sequencing with spatial information enables accurate heterogeneity estimation and risk stratification in liver cancer
ConclusionsThis study provides new insights into the complex phenotypes of HCC and may serve as a guide for future studies in this field. (Source: Genome Medicine)
Source: Genome Medicine - December 16, 2022 Category: Genetics & Stem Cells Source Type: research
Calculating variant penetrance from family history of disease and average family size in population-scale data
ConclusionsThe present approach broadens the spectrum of traits for which reliable penetrance estimates can be obtained. It has substantial utility for facilitating the characterisation of disease risks associated with rare variants with an autosomal dominant inheritance pattern. The yielded estimates avoid any kinship-specific effects and can circumvent ascertainment biases common when sampling rare variants among control populations. (Source: Genome Medicine)
Source: Genome Medicine - December 15, 2022 Category: Genetics & Stem Cells Source Type: research
Loss of Y in leukocytes as a risk factor for critical COVID-19 in men
ConclusionsWe present a link between LOY and an acute, life-threatening infectious disease. Furthermore, this study highlights LOY as the most prominent clonal mutation affecting the myeloid cell lineage during emergency myelopoiesis. The correlation between LOY level and COVID-19 severity might suggest that this mutation affects the functions of monocytes and neutrophils, which could have consequences for male innate immunity. (Source: Genome Medicine)
Source: Genome Medicine - December 14, 2022 Category: Genetics & Stem Cells Source Type: research
Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes
ConclusionsIntegrating multi-tissue pQTLs with MR and the druggable genome may open doors to pinpoint novel interventions for complex traits with no effective treatments, such as ovarian and lung cancers. (Source: Genome Medicine)
Source: Genome Medicine - December 12, 2022 Category: Genetics & Stem Cells Source Type: research
CRAG: de novo characterization of cell-free DNA fragmentation hotspots in plasma whole-genome sequencing
AbstractThe fine-scale cell-free DNA fragmentation patterns in early-stage cancers are poorly understood. We developed a de novo approach to characterize the cell-free DNA fragmentation hotspots from plasma whole-genome sequencing. Hotspots are enriched in open chromatin regions, and, interestingly, 3 ′end of transposons. Hotspots showed global hypo-fragmentation in early-stage liver cancers and are associated with genes involved in the initiation of hepatocellular carcinoma and associated with cancer stem cells. The hotspots varied across multiple early-stage cancers and demonstrated high perf ormance for the diagnosis ...
Source: Genome Medicine - December 8, 2022 Category: Genetics & Stem Cells Source Type: research
Therapy sculpts the complex interplay between cancer and the immune system during tumour evolution
AbstractCancer development is an evolutionary process. A key selection pressure is exerted by therapy, one of the few players in cancer evolution that can be controlled. As such, an understanding of how treatment acts to sculpt the tumour and its microenvironment and how this influences a tumour ’s subsequent evolutionary trajectory is critical. In this review, we examine cancer evolution and intra-tumour heterogeneity in the context of therapy. We focus on how radiotherapy, chemotherapy and immunotherapy shape both tumour development and the environment in which tumours evolve and how re sistance can develop or be selec...
Source: Genome Medicine - December 7, 2022 Category: Genetics & Stem Cells Source Type: research
Cell type-specific changes identified by single-cell transcriptomics in Alzheimer ’s disease
AbstractThe rapid advancement of single-cell transcriptomics in neurology has allowed for profiling of post-mortem human brain tissue across multiple diseases. Over the past 3 years, several studies have examined tissue from donors with and without diagnoses of Alzheimer ’s disease, highlighting key changes in cell type composition and molecular signatures associated with pathology and, in some cases, cognitive decline. Although all of these studies have generated single-cell/nucleus RNA-seq or ATAC-seq data from the full array of major cell classes in the brain, they have each focused on changes in specific cell types. ...
Source: Genome Medicine - November 30, 2022 Category: Genetics & Stem Cells Source Type: research
Epigenetic and transcriptomic reprogramming in monocytes of severe COVID-19 patients reflects alterations in myeloid differentiation and the influence of inflammatory cytokines
ConclusionOur findings show the occurrence of an epigenetic and transcriptional reprogramming of peripheral blood monocytes, which could be associated with the release of aberrant immature monocytes, increased systemic levels of pro-inflammatory cytokines, and changes in immune cell crosstalk in these patients. (Source: Genome Medicine)
Source: Genome Medicine - November 29, 2022 Category: Genetics & Stem Cells Source Type: research
Neutrophil extracellular traps have auto-catabolic activity and produce mononucleosome-associated circulating DNA
ConclusionsOur work describes the mechanisms by which NET and cirDNA are linked. In doing so, we demonstrate that NET are a major source of mono-N cirDNA independent of apoptosis and establish a new paradigm of the mechanisms of cirDNA release in normal and pathological conditions. We also demonstrate a link between immune response and cirDNA. (Source: Genome Medicine)
Source: Genome Medicine - November 28, 2022 Category: Genetics & Stem Cells Source Type: research
Illuminating links between cis-regulators and trans-acting variants in the human prefrontal cortex
ConclusionsWe demonstrate that the transcriptional architecture of the human brain is orchestrated by both cis- and trans-regulatory variants and found that trans-eQTLs provide insights into brain-disease biology. (Source: Genome Medicine)
Source: Genome Medicine - November 24, 2022 Category: Genetics & Stem Cells Source Type: research
Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations
ConclusionsWe identified lipid and apolipoprotein-associated variants in the previously knownLIPC andAPOB genes, as well as PAVs inGTF3C5 associated with LDLC, and inRBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in thePCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD. (Source: Genome Medicine)
Source: Genome Medicine - November 23, 2022 Category: Genetics & Stem Cells Source Type: research
Return of non-ACMG recommended incidental genetic findings to pediatric patients: considerations and opportunities from experiences in genomic sequencing
ConclusionsWhile there may be considerable benefit to return of incidental genetic findings, these findings can be burdensome to providers and present risk to patients. It is important that laboratories conducting genomic testing establish internal guidelines in anticipation of detection. Moreover, cross-laboratory guidelines may aid in reducing the potential for policy heterogeneity across laboratories as it relates to incidental finding detection and return. However, future discussion is required to determine whether cohesive guidelines or policy statements are warranted. (Source: Genome Medicine)
Source: Genome Medicine - November 21, 2022 Category: Genetics & Stem Cells Source Type: research
Extracellular matrix profiles determine risk and prognosis of the squamous cell carcinoma subtype of non-small cell lung carcinoma
ConclusionsCollectively, this analysis defines matrix-driven features of poor prognosis to inform precision medicine prevention and treatment strategies towards improving SqCC patient outcome. (Source: Genome Medicine)
Source: Genome Medicine - November 21, 2022 Category: Genetics & Stem Cells Source Type: research
Towards elucidating disease-relevant states of neurons and glia by CRISPR-based functional genomics
AbstractOur understanding of neurological diseases has been tremendously enhanced over the past decade by the application of new technologies. Genome-wide association studies have highlighted glial cells as important players in diseases. Single-cell profiling technologies are providing descriptions of disease states of neurons and glia at unprecedented molecular resolution. However, significant gaps remain in our understanding of the mechanisms driving disease-associated cell states, and how these states contribute to disease. These gaps in our understanding can be bridged by CRISPR-based functional genomics, a powerful ap...
Source: Genome Medicine - November 18, 2022 Category: Genetics & Stem Cells Source Type: research
