Reconstructing the evolutionary history of metastases is critical for understanding their basic biological principles and has profound clinical implications 1-3 . Genome-wide sequencing data has enabled modern phylogenomic methods to accurately dissect subclones and their phylogenies from noisy and impure bulk tumor samples at unprecedented depth 4-7 . However, existing methods are not designed to infer metastatic seeding patterns. We have developed a tool, called Treeomics, that utilizes Bayesian inference and Integer Linear Programming to reconstruct the phylogeny of metastases. Treeomics allowed us to infer comprehensive seeding patterns for pancreatic 8 , ovarian 9 , and prostate cancers 10,11 . Moreover, Treeomics correctly disambiguated true seeding patterns from sequencing artifacts; 7% of variants were misclassified by conventional statistical methods. These artifacts can skew phylogenies by creating illusory tumor heterogeneity among distinct samples. Last, we performed in silico benchmarking on simulated tumor phylogenies across a wide range of sample purities (30-90%) and sequencing depths (50-800x) to demonstrate the high accuracy of Treeomics compared to existing methods.Genetic evolution underlies our current understanding of cancer 12-14 and the development of resistance to therapies 15,16 . The principles governing this evolution are still an active area of research, particularly for metastasis, the final biological stage of cancer that is responsible for the vast majority of deaths from the disease. Although many insights into the nature of metastasis have emerged 2,17,18 , we do not yet know how
words) 28Recent studies indicate that pancreatic cancer expression profiles are variable and largely 29 reflect a classical or basal-type phenotype. We performed genetic sequencing, RNA-seq, and 30 histologic review of multiregion sampled pancreatic cancers and found that squamous and 31 squamoid features, indicators of poor prognosis, correlate with a "basal -like" expressional type. 32Cancers with squamous features were more likely to have truncal mutations in chromatin modifier 33 genes and intercellular heterogeneity for MYC amplification that was associated with entosis. In 34 most patients the basal phenotype coexisted with a glandular component, and phylogenetic studies 35 indicated that it arose from a subclonal population in the tumor. These data provide a unifying 36 paradigm for understanding the interrelationship of basal-type features, squamous histology, and 37 somatic mutations in chromatin modifier genes in the context of the clonal evolution of pancreatic 38 cancer. 39 40 41 4 Text: 42 Despite advances in diagnostic tools, surgery, chemotherapy and radiation therapy, pancreatic 43 ductal adenocarcinoma (PDAC) remains one of the most lethal tumor types 1 . The five-year 44 survival is less than 10% with 56,770 new cases diagnosed and 45,750 deaths estimated for 2019 45 in the United States alone 2,3 . Large scale sequencing studies have revealed the recurrent genomic 46features of this disease that target a defined number of core pathways 4-8 . In some patients a genome 47 pattern (Figure 2a). Principal component analysis using this same gene set revealed a similar 130 distribution based on morphologic features or expression subtype, whereas no relationship was 131 found for site of harvesting of each sample (primary or metastasis) ( Figure 2b). Finally, we 132 compared the morphologic features to the transcriptional subtypes of each sample analyzed for 23 133
Humans have an increased incidence of epithelial neoplasia compared to non-human primates. We performed a comparative analysis of 21 non-human primate genomes and 54 ancient human genomes to identify variations in known cancer genes that may explain this difference. We identified 299 human-specific fixed non-silent single nucleotide polymorphisms. Bioinformatics analyses for functional consequences identified a number of variants predicted to have altered protein function, one of which was located at the most evolutionarily conserved domain of human BRCA2. This variant, in which a polar threonine residue replaces a hydrophobic methionine residue to codon 2662 within the DSS1 binding domain, decreases the interactions of BRCA2 with other proteins, specifically the binding of BRCA2 and RAD51, as well as the repairing ability of cells for DNA double-strand breaks. We conclude that a 20% reduction in BRCA2 DNA repair ability was positively selected for in the course of human evolution.One Sentence SummaryReduction of BRCA2 functional activity has been selected for during human evolution since the chimpanzee-human last common ancestor.
We investigated tumor-cell-intrinsic chromatin accessibility patterns of pancreatic ductal adenocarcinoma (PDAC) by ATAC-seq on EpCAM+ PDAC malignant epithelial cells, sorted from 54 freshly resected human tumors, and discovered a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identified two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further developed a novel chromatin accessibility microarray methodology termed ATAC-Array, an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this novel methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validated ATAC-array technology in both the original ATAC-Seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a novel, low-cost, clinically feasible technology for assessing chromatin accessibility profiles.
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