5732 results for "canc*"

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• Cryopreservation of human cancers conserves tumour heterogeneity for single-cell multi-omics analysis

  Study EGAS00001005115

• Recapitulation of genetic predisposition to medulloblastoma in human neuroepithelial stem cells

  Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome, patients predisposed to medulloblastoma due to germline mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

  Study EGAS00001003620

• Mutations conferring differential treatment response in breast cancer

  Poor prognosis primary breast cancer patients usually receive cytotoxic chemotherapy as a component of treatment, but despite this aggressive therapy recurrences remain common. Improved understanding of chemoresistance pathways would allow better stratification of chemotherapy using predictive markers, and may allow therapeutic inhibition of resistance mechanisms in order to chemosensitise tumours. We aimed to identify molecular pathways that define chemoresponse using the novel approach of examining the selection exerted by neoadjuvant chemotherapy on sub-clonal somatic mutational profiles of cancer cells.

  Study EGAS00001003626

• Breast Cancer - immune clusters - RNA-seq

  In this study we use expression data from breast cancer tumors to define immune clusters in breast cancer. Immune clusters have gradual levels of immune infiltration. In the intermediate immune infiltration cluster, we found a worse prognosis which is independent of known clinicopathological features. We also found the immune clusters associated with treatment response. Further using gene expression data and deconvolution algorithms to dissect the immune contexture of the clusters.

  Study EGAS00001003631

• Latency and interval therapy affect the evolution in metastatic colorectal cancer

  While comparison of primary tumor and metastases has highlighted genomic heterogeneity in colorectal cancer (CRC), previous studies have focused on a single metastatic site or limited genomic testing. Combining data from whole exome and ultra-deep targeted sequencing, we explored possible evolutionary trajectories beyond the status of these mutations, particularly among patient-matched metastatic tumors. Our findings confirm the persistence of known clinically-relevant mutations (e.g. those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions. Specifically, our analysis of patient-matched primary and multiple metastatic lesions, developed over time, showed a similar genetic composition for liver metastatic tumors, which were 21-months apart. This genetic makeup was different from those identified in lung metastases developed before manifestation of the second liver metastasis. These results underscore the role of dormancy in the evolutionary path of metastatic CRC.

  Study EGAS00001003646

• Healthspan and lifespan extension by fecal microbiota transplantation in progeroid mice

  The gut microbiome is emerging as a key regulator of several metabolic, immune and neuroendocrine pathways. Gut microbiome deregulation has been implicated in major conditions such as obesity, type 2 diabetes, cardiovascular disease, non-alcoholic fatty acid liver disease or cancer, but its precise role in aging remains to be elucidated. Here, we characterize the gut microbiome profile of accelerated aging and show that its external modulation is sufficient to extend healthspan and lifespan. We found that two different mouse models of progeria present with intestinal dysbiosis, which is characterized, among other alterations, by an increment in proteobacteria, cyanobacteria and a loss in verrucomicrobia, whereas long-lived humans (i.e., centenarians) exhibit a remarkable increase in verrucomicrobia and a reduction in proteobacteria. Fecal microbiota transplantation proved to be effective to enhance healthspan and lifespan in both progeroid mouse models and, more importantly, the solely transplantation with the verrucomicrobia Akkermansia muciniphila was sufficient to exert beneficial effects. Our results demonstrate that intestinal dysbiosis is a phenotype associated with accelerated aging and its correction provides health benefits. Moreover, metabolomic analysis of ileal content points to the restoration of secondary bile acids as a possible mechanism for the beneficial outcome of reestablishing a healthy microbiome. Our results suggest the existence of a link between gut aging and the microbiota, and can help to gain insight into the rationale for microbiome-based interventions against age-related diseases. Mouse sequence data have been deposited in ENA (https://www.ebi.ac.uk/ena) under accession number PRJEB34214

  Study EGAS00001003656

• Genomic Signatures Reveal DNA Damage Response Deficiency in Brain Metastases of Colorectal Cancer

  Brain metastasis (BM) of colorectal cancer (CRC) is rare but lethal, and lacks effective therapies or a good understanding of its genomic landscapes. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue to (1) document genomic signatures during the evolution of CRC BM; (2) identify clinically actionable targets for the BM treatment; and (3) identify potential drivers in CRC BM.

  Study EGAS00001003659

• Bioinformatic Methods and Bridging of Assay Results for Reliable Tumor Mutational Burden Assessment in Non-Small Cell Lung Cancer

  Tumor mutational burden (TMB) has emerged as a predictive biomarker of response to immune checkpoint inhibitors. Standardization of TMB measurement is essential for implementing diagnostic tools to guide treatment. Here we evaluate bioinformatic TMB analysis by whole exome sequencing (WES) in formalin-fixed, paraffin-embedded samples. In CheckMate 026, TMB was retrospectively assessed in 312 patients with non-small cell lung cancer (58% of the intent-to-treat population) who received first-line nivolumab treatment or chemotherapy. We examined the sensitivity of TMB assessment to bioinformatic filtering methods and assessed concordance between TMB data derived by WES and the FoundationOne CDx™ assay. TMB scores comprising synonymous, indel, frameshift, and nonsense mutations (all mutations) were 3.1-fold higher than data including missense mutations only, but values were highly correlated (Spearman’s r = 0.99). Scores from CheckMate 026 samples including missense mutations only were similar to those generated from data in The Cancer Genome Atlas, but those including all mutations were generally higher. Using databases for germline subtraction (instead of matched controls) showed a trend for race-dependent increases in TMB scores. Parameter variation can therefore impact TMB calculations, highlighting the need for standardization. Encouragingly, WES and FoundationOne CDx outputs were highly correlated (Spearman’s r = 0.90) and differences could be accounted for by empirical calibration, suggesting that reliable TMB assessment across assays, platforms and centers is achievable.

  Study EGAS00001003661

• Mixed Histology Lung Cancers Driven by Transcriptomic Features rather than Genomic Characteristics

  Study EGAS00001005140

• Multi-layered molecular characterization defines prognostic subtypes of lung adenocarcinoma in Asian never-smokers

  Multi-layered genomic studies such as the TCGA project have greatly advanced our understanding on molecular pathogenesis of lung cancer. For Asian nonsmoker patients, however, majority of studies have been limited to mutational analyses, emphasizing ethnic differences in driver mutations (e.g. more frequent EGFR mutations and ALK fusions). In essence, a comprehensive multi-layered characterization that could lead to molecular etiology and patient stratification scheme to be translated into clinical applications for this patient group is still missing. Here we report molecular profiling of tumor and matched normal tissues from 114 non-small-cell lung adenocarcinoma patients using whole exome sequencing, transcriptome sequencing, and array comparative genomic hybridization (CGH).

  Study EGAS00001003705