77 research outputs found
microRNA Expression during Trophectoderm Specification
Segregation of the trophectoderm from the inner cell mass of the embryo represents the first cell-fate decision of mammalian development. Transcription factors essential for specifying trophectoderm have been identified, but the role of microRNAs (miRNAs) in modulating this fate-choice has been largely unexplored. We have compared miRNA expression in embryonic stem cell (ESC)-derived trophectoderm and in staged murine embryos to identify a set of candidate miRNAs likely to be involved in trophectoderm specification.We profiled embryonic stem cells (ESCs) as they were induced to differentiate into trophectodermal cells by ectopic expression of HRas/Q61L. We also profiled murine embryos at progressive stages of preimplantation development (zygote, 2-cell, 4-cell, 8-cell, morula, and blastocyst), which includes the time window in which the trophectoderm is specified in vivo Q61L/H.We describe miRNA expression changes that occur during trophectoderm specification and validate that our in vitro system faithfully recapitulates trophectoderm specification in vivo. By comparing our in vitro and in vivo datasets, we have identified a minimal set of candidate miRNAs likely to play a role in trophectoderm specification. These miRNAs are predicted to regulate a host of development-associated target genes, and many of these miRNAs have previously reported roles in development and differentiation. Additionally, we highlight a number of miRNAs whose tight developmental regulation may reflect a functional role in other stages of embryogenesis. Our embryo profiling data may be useful to investigators studying trophectoderm specification and other stages of preimplantation development
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Discovery and saturation analysis of cancer genes across 21 tumor types
Summary While a few cancer genes are mutated in a high proportion of tumors of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalog of cancer genes, we analyzed somatic point mutations in exome sequence from 4,742 tumor-normal pairs across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumor types. Our analysis also identified 33 genes not previously known to be significantly mutated, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes, mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5000 samples per tumor type, depending on background mutation rate. The results help guide the next stage of cancer genomics
Deep learning-based survival prediction for multiple cancer types using histopathology images
Prognostic information at diagnosis has important implications for cancer
treatment and monitoring. Although cancer staging, histopathological
assessment, molecular features, and clinical variables can provide useful
prognostic insights, improving risk stratification remains an active research
area. We developed a deep learning system (DLS) to predict disease specific
survival across 10 cancer types from The Cancer Genome Atlas (TCGA). We used a
weakly-supervised approach without pixel-level annotations, and tested three
different survival loss functions. The DLS was developed using 9,086 slides
from 3,664 cases and evaluated using 3,009 slides from 1,216 cases. In
multivariable Cox regression analysis of the combined cohort including all 10
cancers, the DLS was significantly associated with disease specific survival
(hazard ratio of 1.58, 95% CI 1.28-1.70, p<0.0001) after adjusting for cancer
type, stage, age, and sex. In a per-cancer adjusted subanalysis, the DLS
remained a significant predictor of survival in 5 of 10 cancer types. Compared
to a baseline model including stage, age, and sex, the c-index of the model
demonstrated an absolute 3.7% improvement (95% CI 1.0-6.5) in the combined
cohort. Additionally, our models stratified patients within individual cancer
stages, particularly stage II (p=0.025) and stage III (p<0.001). By developing
and evaluating prognostic models across multiple cancer types, this work
represents one of the most comprehensive studies exploring the direct
prediction of clinical outcomes using deep learning and histopathology images.
Our analysis demonstrates the potential for this approach to provide prognostic
information in multiple cancer types, and even within specific pathologic
stages. However, given the relatively small number of clinical events, we
observed wide confidence intervals, suggesting that future work will benefit
from larger datasets
Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer
SummaryChromatin factors have emerged as the most frequently dysregulated family of proteins in cancer. We have previously identified the histone deacetylase SIRT6 as a key tumor suppressor, yet whether point mutations are selected for in cancer remains unclear. In this manuscript, we characterized naturally occurring patient-derived SIRT6 mutations. Strikingly, all the mutations significantly affected either stability or catalytic activity of SIRT6, indicating that these mutations were selected for in these tumors. Further, the mutant proteins failed to rescue sirt6 knockout (SIRT6 KO) cells, as measured by the levels of histone acetylation at glycolytic genes and their inability to rescue the tumorigenic potential of these cells. Notably, the main activity affected in the mutants was histone deacetylation rather than demyristoylation, pointing to the former as the main tumor-suppressive function for SIRT6. Our results identified cancer-associated point mutations in SIRT6, cementing its function as a tumor suppressor in human cancer
Discovery and saturation analysis of cancer genes across 21 tumour types
Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics
GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers
We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets
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