In BCR-ABL1 lymphoblastic leukemia, treatment heterogeneity to tyrosine kinase inhibitors (TKIs), especially in the absence of kinase domain mutations in BCR-ABL1, is poorly understood. Through deep ...molecular profiling, we uncovered three transcriptomic subtypes of BCR-ABL1 lymphoblastic leukemia, each representing a maturation arrest at a stage of B-cell progenitor differentiation. An earlier arrest was associated with lineage promiscuity, treatment refractoriness and poor patient outcomes. A later arrest was associated with lineage fidelity, durable leukemia remissions and improved patient outcomes. Each maturation arrest was marked by specific genomic events that control different transition points in B-cell development. Interestingly, these events were absent in BCR-ABL1
preleukemic stem cells isolated from patients regardless of subtype, which supports that transcriptomic phenotypes are determined downstream of the leukemia-initialing event. Overall, our data indicate that treatment response and TKI efficacy are unexpected outcomes of the differentiation stage at which this leukemia transforms.
Abstract The statistics are alarming; pancreatic ductal adenocarcinoma (PDA) will be the second leading cause of death amongst all cancers by 2020. More worrisome is that incidence is on the rise, ...and without more effective cancer control of this disease, the trajectory of the virtually indistinguishable rates of incidence and mortality will remain the reality for years to come. Advances in genomics are beginning to clarify the key issues about the pathogenesis of this aggressive tumour type. New insights into classic pathogenic driver genes, such as KRAS , CDKN2A , TP53 and SMAD4 , are portraying alternative roles for these genes beyond their function at the preneoplastic level including metastatic dissemination and chemoresistance. Clinically relevant molecular subtypes have recently emerged, which will aid oncologists in making more informed treatment decisions to improve outcomes in the future. A wealth of data surrounding these issues has been generated over the last 5 years. Below, we attempt to bring readers up to speed on recent research findings in PDA.
Systemic inflammatory scores may aid prognostication and patient selection for trials. We compared five scores in advanced pancreatic adenocarcinoma (PDAC).
Unresectable/metastatic PDAC patients ...enrolled in the Comprehensive Molecular Characterisation of Advanced Pancreatic Ductal Adenocarcinoma for Better Treatment Selection trial (NCT02750657) were included. Patients had pre-treatment biopsies for whole genome and RNA sequencing. CD8 immunohistochemistry was available in a subset. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, Prognostic Nutritional Index, Gustave Roussy Immune Score (GRIm-S), and Memorial Sloan Kettering Prognostic Score (MPS) were calculated. Overall survival (OS) was estimated using Kaplan-Meier methods. Associations between inflammatory scores, clinical/genomic characteristics, and OS were analysed.
We analysed 263 patients. High-risk NLR, GRIm-S and MPS were poorly prognostic. The GRIm-S had the highest predictive ability: median OS 6.4 vs. 10 months for high risk vs. low-risk (P < 0.001); HR 2.26 (P < 0.001). ECOG ≥ 1, the basal-like subtype, and low-HRDetect were additional poor prognostic factors (P < 0.01). Inflammatory scores did not associate with RNA-based classifiers or homologous recombination repair deficiency genotypes. High-risk MPS (P = 0.04) and GRIm-S (P = 0.02) patients had lower median CD8 + tumour-infiltrating lymphocytes.
Inflammatory scores incorporating NLR have prognostic value in advanced PDAC. Understanding immunophenotypes of poor-risk patients and using these scores in trials will advance the field.
•Genomic profiling is recommended in patients with advanced pancreatic cancer.•Our analysis of 19 studies shows that 46% of patients had a targetable alteration and 12% of patients received matched ...therapy.•The meta-analysis exhibited inter-study statistical heterogeneity in the proportion of patients with targeted alterations and who received targeted treatments, likely partially explained by variation in methodological approaches.•Our review uncovered reporting deficiencies and could provide guidance towards the standardization of the classification of alterations and treatment recommendations, which could improve future research into pancreatic cancer precision oncology.
Current guidelines recommend somatic genomic sequencing for patients with advanced pancreatic cancer to identify targetable alterations amenable to targeted therapy. The benefit of somatic genomic sequencing in pancreatic cancer remains unclear. This study aims to assess the evidence supporting genomic sequencing to inform treatment selection for patients with advanced pancreatic cancer.
A systematic review identified prospective studies of exocrine pancreatic cancer patients published before August 2020 which conducted genomic sequencing to inform treatment selection. Outcomes of interest included the proportion of patients with targetable alterations, the proportion that received targeted treatments, and the impact of targeted treatments on overall survival. Meta-analysis for proportions and hazard ratios was performed using Dersimonian and Laird random effect models.
19 studies (representing 2048 pancreatic cancer patients) were included. Sequencing methodologies, definitions of targetable alterations, and approaches treatment selection varied across studies and were incompletely reported. 590 of 1382 sequenced patients harboured a targetable alteration (random effects meta-analysis estimate of the proportion 0.46, 95% confidence interval 0.32–0.61). The proportion of patients with targetable alterations was highly heterogenous between studies (I2 93%, P < 0.001). 91 of 1390 patients received a matched therapy based on their targetable alterations (random effects meta-analysis estimate of the proportion 0.12, 95% CI 0.06–0.23). One observational study reported an overall survival benefit of matched therapy.
Genomic sequencing frequently identifies targetable alterations in pancreatic cancers. Further research is required to standardize the definitions of targetable alterations, the approach to treatment matching, and quantify the benefit of targeted therapy.
Somatic mutations have been found in the mitochondria in different types of cancer cells, but it is not clear whether these affect tumorigenesis or tumor progression. We analyzed mitochondrial ...genomes of 268 early-stage, resected pancreatic ductal adenocarcinoma tissues and paired non-tumor tissues. We defined a mitochondrial somatic mutation (mtSNV) as a position where the difference in heteroplasmy fraction between tumor and normal sample was ≥0.2. Our analysis identified 304 mtSNVs, with at least 1 mtSNV in 61% (164 of 268) of tumor samples. The noncoding control region had the greatest proportion of mtSNVs (60 of 304 mutations); this region contains sites that regulate mitochondrial DNA transcription and replication. Frequently mutated genes included ND5, RNR2, and CO1, plus 29 mutations in transfer RNA genes. mtSNVs in 2 separate mitochondrial genes (ND4 and ND6) were associated with shorter overall survival time. This association appeared to depend on the level of mtSNV heteroplasmy. Non-random co-occurrence between mtSNVs and mutations in nuclear genes indicates interactions between nuclear and mitochondrial DNA. In an analysis of primary tumors and metastases from 6 patients, we found tumors to accumulate mitochondrial mutational mutations as they progress.
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Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified ...based on the spectrum of response to platinum/PARP inhibition: (i) refractory overall survival (OS) <6 months, (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions.
glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
Abstract
Single cell RNA-sequencing (scRNAseq) of the murine cerebellum at nine fetal and immediate post-natal (E10-P14) times points on >60,000 individual cells to identified >30 transcriptionally ...distinct cell clusters. Based on marker gene expression, many clusters resemble known cerebellar stem, progenitor, and differentiated cell types, while other clusters are more novel. Pseudo-time trajectory assisted in the reconstruction of known and novel developmental lineages, including the lineage of the cerebellar radial glia. A population of stem cells in the ventricular zone (VZ) gives rise to the progenitors of the GABAergic cerebellar interneurons, as well as the gliogenic progenitor cells, which subsequently become Bergmann glia and astrocytes. A novel, but clearly distinct and robust cluster of cells with transcriptional similarity to both the roof plate and the rhombic lip was identified. Comparison of bulk RNA-seq from human PFA, PFB, and cerebellar pilocytic astrocytomas (C-PA) reveals that all three-tumor types best transcriptionally match the gliogenic progenitor cells, with some similarity to VZ progenitor cells and ‘roof plate like’ stem cells. Furthermore, PFA and PFB temporally match to the gliogenic progenitors at E16, while C-PA resemble the E16-E18 the progenitor population. Subclustering of gliogenic progenitors reveals significant intra-cluster heterogeneity, with the ependymomas transcriptionally matching one subcluster, and the C-PA clearly matching a very different subcluster. scRNAseq of human PFA and C-PA reveals multiple tumor cell clusters within a given human ependymoma, with some clusters matching most closely to the gliogenic progenitors, and others matching best to the ‘roof plate like’ stem cells. Similarity to the ‘roof plate stem cells’ (E10-E14), and gliogenic progenitors (E14-E18) suggests an embryonic origin for PFA, PFB, and C-PA, suggests specific novel cells of origin, and offers a novel opportunity to understand posterior fossa tumor transcriptomic targets for novel therapy.
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