Tissue specificity of in vitro drug sensitivity Yao, Fupan; Madani Tonekaboni, Seyed Ali; Safikhani, Zhaleh ...
Journal of the American Medical Informatics Association,
02/2018, Letnik:
25, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
Objectives
We sought to investigate the tissue specificity of drug sensitivities in large-scale pharmacological studies and compare these associations to those found in drug clinical ...indications.
Materials and Methods
We leveraged the curated cell line response data from PharmacoGx and applied an enrichment algorithm on drug sensitivity values’ area under the drug dose-response curves (AUCs) with and without adjustment for general level of drug sensitivity.
Results
We observed tissue specificity in 63% of tested drugs, with 8% of total interactions deemed significant (false discovery rate <0.05). By restricting the drug-tissue interactions to those with AUC > 0.2, we found that in 52% of interactions, the tissue was predictive of drug sensitivity (concordance index > 0.65). When compared with clinical indications, the observed overlap was weak (Matthew correlation coefficient, MCC = 0.0003, P > .10).
Discussion
While drugs exhibit significant tissue specificity in vitro, there is little overlap with clinical indications. This can be attributed to factors such as underlying biological differences between in vitro models and patient tumors, or the inability of tissue-specific drugs to bring additional benefits beyond gold standard treatments during clinical trials.
Conclusion
Our meta-analysis of pan-cancer drug screening datasets indicates that most tested drugs exhibit tissue-specific sensitivities in a large panel of cancer cell lines. However, the observed preclinical results do not translate to the clinical setting. Our results suggest that additional research into showing parallels between preclinical and clinical data is required to increase the translational potential of in vitro drug screening.
Abstract
Background
Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event present in ...nearly all cases. Indeed, recent studies demonstrated 3 molecular subgroups of ATRTs that are genetically, epigenetically, and clinically distinct. As these studies included different numbers of tumors, various subgrouping techniques, and naming, an international working group sought to align previous findings and to reach a consensus on nomenclature and clinicopathological significance of ATRT subgroups.
Methods
We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data.
Results
In concordance with previous studies, the analyses identified 3 main molecular subgroups of ATRTs, for which a consensus was reached to name them ATRT-TYR, ATRT-SHH, and ATRT-MYC. The ATRT-SHH subgroup exhibited further heterogeneity, segregating further into 2 subtypes associated with a predominant supratentorial (ATRT-SHH-1) or infratentorial (ATRT-SHH-2) location. For each ATRT subgroup we provide an overview of its main molecular and clinical characteristics, including SMARCB1 alterations and pathway activation.
Conclusions
The introduction of a common classification, characterization, and nomenclature of ATRT subgroups will facilitate future research and serve as a common ground for subgrouping patient samples and ATRT models, which will aid in refining subgroup-based therapies for ATRT patients.
Abstract
Embryonal tumors with multilayered rosettes (ETMRs) are rare pediatric brain tumors defined primarily by overexpression of the C19MC microRNA cluster. These tumors affect mostly children ...under the age of 3. However, little is known about the origin and developmental contexts of ETMRs. We hypothesized that the early onset of these tumors suggests an embryonic tumorigenic event. To elucidate the embryonic contexts of which ETMRs arise, we curated three mouse embryogenesis datasets representing the full spectrum of murine embryonic development. We generated timepoint structure signatures of this atlas and projected them onto a single nuclei RNA sequencing dataset of 8 primary ETMRs. Consistent with existing literature, we discovered that ETMRs resemble a spectrum of radial glial, neuronal, and oligodendrocytic cell types. We also recapitulated potential ETMR driver mechanisms such as overexpression of WNT and SHH signaling by gene set enrichment analysis. We validated the enrichment of lineage and driver markers through GSEA and marker gene enrichment in a separate cohort of ETMRs characterized by bulk RNA sequencing. Taken together, the embryonic context of ETMR development may play crucial roles in the early identification and treatments of this lethal disease.
Abstract
Embryonal tumors with multilayered rosettes (ETMRs) are highly fatal diseases characterized by recurrent amplification of C19MC, an oncogenic miRNA cluster. While C19MC was discovered as a ...major driver of ETMRs, its direct role in ETMRs remains unknown. As ETMRs exhibit significant heterogeneity in C19MC expression, we employed single cell transcriptomics to investigate features of C19MC+ population. We conducted single-nuclei RNAseq of 23,269 cells from 6 primary and 2 matched recurrent ETMRs. We also conducted single-cell RNAseq of human neural stem cells (hNSC-5miR) and ETMR cell line (A664-5miR) with stable expression of 5 C19MC miRNAs. Bulk RNAseq (n=27), H3K27Ac ChiP-seq (n=5) and ATAC-seq (n=5) corroborated scRNAseq data and identified core transcription factors (TFs) of C19MC+ population. C19MC+ population (24%) mapped to neuro-epithelial cells and exhibited signatures of cell cycle and stem cell maintenance, consistent with bulk-RNAseq data. The C19MC+ population overlaps with MKI67+ cycling (57%) and PROM1+ stem cell population (56%). Interestingly, interrogation of hNSC-5mir and A664-5miR showed a larger MKI67+/PROM1+ population compared to controls. Likewise, hNSC-5miR/A664-5miR in vitro and in vivo experiments showed increased proliferation/stemness. C19MC+ population is characterized by SHH, WNT, mTOR, Hippo and IGF-signalling and driven by MEIS1, SOX11, ZNF521, RFX4 and NR2F2 TFs. Recurrent ETMRs exhibit a persistent but smaller C19MC+ population. Intriguingly, recurrent tumors were more quiescent with a smaller proliferative population. C19MC is directly involved in driving cell cycle and stemness in ETMRs. Cellular and molecular features of primary and recurrent ETMRs were remarkably different, suggesting that C19MC plays a different role upon recurrence.
Abstract
In recent years, using gene expression and methylation array platform, multiple research groups have reported the presence of at least three major Atypical Teratoid Rhabdoid Tumor (ATRT) ...subtypes that exhibit distinct epigenetic, transcriptomic and clinical features. Yet, utilizing ATRT subtypes in a clinical setting remains challenging due to a lack of suitable biological markers, limited sample quantities and relatively high cost of current assays. To address this gap between research and clinical practice, we have designed an assay that utilizes a custom 35 signature genes panel for the NanoString nCounter System and have created a flexible machine learning classifier package for ATRT tumour subtyping. We have analyzed 71 ATRT primary tumours with matching gene expression data using the 35 genes panel. 60% of the data was used for models training (10 repeats of 10-fold cross validation with subgroup balanced sample splitting) resulting in overall 94.6% training accuracy. The remaining 40% of the samples were used for model validation and the assay was able to achieve 92–100% accuracy with no subgroup bias. To demonstrate the flexibility of the workflow, we have tested it against other transcriptome-based methods such as gene expression array and RNASeq. We have also demonstrated its use in samples that were not classifiable by methylation-based method. We are presenting here a rapid and accurate ATRT subtyping assay for clinical usage that is compatible with archived ATRT tissues.
Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of ...PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (
DICER1
,
DROSHA
, and
DGCR8
) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic
MYC-miR-17/92-RB1
pathway were observed in the RB and MYC sub-group, respectively, characterized by
RB1
loss with gain of
miR-17/92
, and recurrent gain or amplification of
MYC
. PB sub-groups exhibited distinct clinical features: group 1–3 arose in older children (median ages 5.2–14.0 years) and had intermediate to excellent survival (5-year OS of 68.0–100%), while Group RB and MYC PB patients were much younger (median age 1.3–1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.
Summary
Limber pine (Pinus flexilis) is a keystone species of high‐elevation forest ecosystems of western North America, but some parts of the geographic range have high infection and mortality from ...the non‐native white pine blister rust caused byCronartium ribicola. Genetic maps can provide essential knowledge for understanding genetic disease resistance as well as local adaptation to changing climates. Exome‐seq was performed to construct high‐density genetic maps in two seed families. Composite maps positioned 9612 unigenes across 12 linkage groups (LGs). Syntenic analysis of genome structure revealed that the majority of orthologs were positional orthologous genes (POGs) with localization on homologousLGs among conifer species. Gene ontology (GO) enrichment analysis showed relatively fewer constraints forPOGs with putative roles in adaptation to environments and relatively more conservation forPOGs with roles in basic cell function and maintenance. The mapped genes included 639 nucleotide‐binding site leucine‐rich repeat genes (NBS‐LRRs), 290 receptor‐like protein kinase genes (RLKs), and 1014 genes with potential roles in the defense response and induced systemic resistance to attack by pathogens. Orthologous loci for resistance to rust pathogens were identified and were co‐positioned with multiple members of theR gene family, revealing the evolutionary pressure acting upon them. This high‐density genetic map provides a genomic resource and practical tool for breeding and genetic conservation programs, with applications in genome‐wide association studies (GWASs), the characterization of functional genes underlying complex traits, and the sequencing and assembly of the full‐length genomes of limber pine and relatedPinus species.
Significance Statement
Using exome‐seq, we constructed a high‐density genetic map for limber pine and revealed that evolutionary pressure acts upon orthologous loci for resistance to rust pathogens. The availability and application of this genetic map can enable GWAS studies and the fine dissection of genetic architecture of complex traits with adaptive significance in limber pine and related five‐needle pines.
Abstract
Embryonal brain tumors (EBTs) remain the most common malignant pediatric brain tumors. Despite recent advances and improved understanding of the molecular biology of EBTs, clinical outcomes ...remain poor for rare EBTs. Previous large-scale genomic studies of rare EBTs have shed light on distinct genomic, transcriptomic and epigenomic profiles. Interestingly, these studies have revealed prominent tumor heterogeneity that provides opportunity to develop novel treatment strategies to improve patient outcomes. To examine the tumor microenvironment and identify tumor- specific biological dependencies, we performed deconvolution analysis of bulk gene expression (171 RNA-seq, 236 microarrays) and 586 methylation arrays, which revealed significant intra and inter-tumoral heterogeneity and implicated interferon (IFN)-mediated signalling as a determinant of a distinct immunological profile in rare EBTs. To further elucidate the importance of IFN signalling, we performed scRNA-seq on 20 primary samples, which provided evidence of a spectrum of IFN-immunological responses that vary from immunosuppressive to immunologically exhaustive that occur in a host dependent manner. To further validate our findings, we utilised a genetically engineered murine model of Atypical Teratoid Rhabdoid Tumor and primary xenografts in humanised mice to corroborate our in-silico profiles in vivo. Through amalgamation of our in-silico data with our in vivo data, we have identified evidence that dysregulated IFN responses represent a core element of the immunological heterogeneity present within subsets of rare EBTs. An improved understanding of the immune milieu in rare EBTs will provide avenues to develop specific onco-immune targets to address this clinical need.
Abstract
Background
Despite genomic simplicity, recent studies have reported at least 3 major atypical teratoid rhabdoid tumor (ATRT) subgroups with distinct molecular and clinical features. Reliable ...ATRT subgrouping in clinical settings remains challenging due to a lack of suitable biological markers, sample rarity, and the relatively high cost of conventional subgrouping methods. This study aimed to develop a reliable ATRT molecular stratification method to implement in clinical settings.
Methods
We have developed an ATRT subgroup predictor assay using a custom genes panel for the NanoString nCounter System and a flexible machine learning classifier package. Seventy-one ATRT primary tumors with matching gene expression array and NanoString data were used to construct a multi-algorithms ensemble classifier. Additional validation was performed using an independent gene expression array against the independently generated dataset. We also analyzed 11 extra-cranial rhabdoid tumors with our classifier and compared our approach against DNA methylation classification to evaluate the result consistency with existing methods.
Results
We have demonstrated that our novel ensemble classifier has an overall average of 93.6% accuracy in the validation dataset, and a striking 98.9% accuracy was achieved with the high-prediction score samples. Using our classifier, all analyzed extra-cranial rhabdoid tumors are classified as MYC subgroups. Compared with the DNA methylation classification, the results show high agreement, with 84.5% concordance and up to 95.8% concordance for high-confidence predictions.
Conclusions
Here we present a rapid, cost-effective, and accurate ATRT subgrouping assay applicable for clinical use.
Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor arising in young children. Inactivation of chromatin remodeling complex members SMARCB1 (INI1/hSNF5) or (rarely) ...SMARCA4 (Brg1) are the sole recurrent genetic alterations. Despite this apparent genetic homogeneity, several studies have independently shown that ATRT represents an epigenetically heterogeneous disease and can be divided into molecular subgroups based on gene expression and DNA methylation profiles. In an international cooperative effort, published and unpublished methylation and transcriptome data of 304 and 133 ATRTs, respectively, were compiled in order to develop a consensus on the number of molecular subgroups and their characteristics. Clustering analyses independently performed in Toronto, Heidelberg, Newcastle and Paris identified three major molecular subgroups, previously annotated as Group1/SHH/hIC2, Group2A/TYR/hIC1 and Group2B/MYC/hIC3. Concordance was high and the vast majority of ATRT was allocated to the same main molecular subgroup across different clustering approaches. Additional heterogeneity was noted within the neurogenic Group1/SHH/hIC2 subgroup, characterized by NOTCH/SHH signaling. The other two subgroups, Group2A/TYR/hIC1 and Group2B/MYC/hIC3 share activation of BMP and PDGFRB pathways, but also show subgroup-specific differences (e.g. MYC/HOX more highly expressed in Group2B/MYC/hIC3 tumors) and different anatomical associations. The majority of Group1/SHH/hIC2 and Group2B/MYC/hIC3 tumors were supratentorial, while 77% of Group2A/TYR/hIC1 tumors were located infratentorially. Of note, 7/8 spinal tumors of the dataset were allocated to Group2B/MYC/hIC3. These results represent an important step towards reaching a consensus on molecular subgrouping in ATRT, which will be pivotal for the development of subgroup-specific therapies and stratification in future clinical trials.
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