The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis
There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells (PSCs) into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53R175H induced cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. Culture conditions are also defined for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture, phenotypic heterogeneity of the primary tumor, and retain patient-specific physiologic changes including hypoxia, oxygen consumption, epigenetic marks, and differential sensitivity to EZH2 inhibition. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.
To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype ( = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. expression in tumor measured by RNA hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. .
Pancreas cancer (PC), a highly aggressive tumour type with uniformly poor prognosis, is an exemplar of the classical view of cancer development based on stepwise progression1. The current progression model, based on analyses of precursor lesions termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: 1) PC develops through a particular sequence of genetic alterations2–5 (KRAS > CDKN2A > TP53/SMAD4); and 2) the evolutionary trajectory of PC progression is gradual because each alteration is acquired independently. One shortcoming of this nearly two decade old contention is that clonally expanded precursor lesions have been identified that do not always belong to the tumour lineage2,5–9, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing view of tumourigenesis has contributed to the clinical notion that PC evolves slowly and presents at a late stage10. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes despite efforts aimed at early detection11, argue that PC progression is anything but gradual. By tracking DNA copy number changes and their associated rearrangements from tumour-enriched genomes using novel informatics tools, we found that PC tumourigenesis neither is gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory12. In a subset of cases, the consequence of such errors was the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that likely set-off invasive cancer growth. These findings challenge the current model of PC tumourigenesis and provide novel insights into the mutational processes giving rise to these aggressive tumours.
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