scholarly journals Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

2019 ◽  
Author(s):  
Xing Yi Woo ◽  
Jessica Giordano ◽  
Anuj Srivastava ◽  
Zi-Ming Zhao ◽  
Michael W. Lloyd ◽  
...  
Keyword(s):  
Microarray Data ◽  
Copy Number ◽  
Dynamic Range ◽  
Human Cancer ◽  
Tumor Evolution ◽  
Copy Number Alterations ◽  
Recurrence Analysis ◽  
Late Passage ◽  
Significant Enrichment ◽  
Pdx Models

ABSTRACTPatient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multi-region samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

scholarly journals Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

2018 ◽  
Author(s):  
Nitin Roper ◽  
Shaojian Gao ◽  
Tapan K. Maity ◽  
A. Rouf Banday ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Copy Number ◽  
Thymic Carcinoma ◽  
Patient Specific ◽  
Tumor Evolution ◽  
Copy Number Alterations ◽  
Immune Microenvironment ◽  
Mutation Status ◽  
Whole Exome ◽  
Rapid Autopsy ◽  
Insight Into

ABSTRACTElucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.

scholarly journals Integrated sequence and gene expression analysis of mouse models of breast cancer reveals critical events with human parallels

2018 ◽  
Author(s):  
Jonathan P Rennhack ◽  
Matthew Swiatnicki ◽  
Yueqi Zhang ◽  
Caralynn Li ◽  
Evan Bylett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Cancer Patients ◽  
Mouse Models ◽  
Copy Number ◽  
Human Breast Cancer ◽  
Human Cancer ◽  
Copy Number Alterations ◽  
Human Breast ◽  
Lung Cancer Patients

AbstractMouse models have an essential role in cancer research, yet little is known about how various models resemble human cancer at a genomic level. However, the shared genomic alterations in each model and corresponding human cancer are critical for translating findings in mice to the clinic. We have completed whole genome sequencing and transcriptome profiling of two widely used mouse models of breast cancer, MMTV-Neu and MMTV-PyMT. This genomic information was integrated with phenotypic data and CRISPR/Cas9 studies to understand the impact of key events on tumor biology. Despite the engineered initiating transgenic event in these mouse models, they contain similar copy number alterations, single nucleotide variants, and translocation events as human breast cancer. Through integrative in vitro and in vivo studies, we identified copy number alterations in key extracellular matrix proteins including Collagen 1 Type 1 alpha 1 (Col1a1) and Chondroadherin (CHAD) that drive metastasis in these mouse models. Importantly this amplification is also found in 25% of HER2+ human breast cancer and is associated with increased metastasis. In addition to copy number alterations, we observed a propensity of the tumors to modulate tyrosine kinase mediated signaling through mutation of phosphatases. Specifically, we found that 81% of MMTV-PyMT tumors have a mutation in the EGFR regulatory phosphatase, PTPRH. Mutation in PTPRH led to increased phospho-EGFR levels and decreased latency. Moreover, PTPRH mutations increased response to EGFR kinase inhibitors. Analogous PTPRH mutations are present in lung cancer patients and together this data suggests that a previously unidentified population of human lung cancer patients may respond to EGFR targeted therapy. These findings underscore the importance of understanding the complete genomic landscape of a mouse model and illustrate the utility this has in understanding human cancers.

Frequent extrachromosomal oncogene amplification drives aggressive tumors

2019 ◽  
Author(s):  
Hoon Kim ◽  
Nam Nguyen ◽  
Kristen Turner ◽  
Sihan Wu ◽  
Jihe Liu ◽  
...  
Keyword(s):  
Copy Number ◽  
Computational Analysis ◽  
Chromatin Accessibility ◽  
Tissue Type ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Sequencing Data ◽  
Oncogene Amplification ◽  
Significant Enrichment ◽  
Aggressive Tumors

Extrachromosomal DNA (ecDNA) amplification promotes high oncogene copy number, intratumoral genetic heterogeneity, and accelerated tumor evolution1–3, but its frequency and clinical impact are not well understood. Here we show, using computational analysis of whole-genome sequencing data from 1,979 cancer patients, that ecDNA amplification occurs in at least 26% of human cancers, of a wide variety of histological types, but not in whole blood or normal tissue. We demonstrate a highly significant enrichment for oncogenes on amplified ecDNA and that the most common recurrent oncogene amplifications arise on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number matched linear DNA, coupled with enhanced chromatin accessibility. Patients whose tumors have ecDNA-based oncogene amplification showed increase of cell proliferation signature activity, greater likelihood of lymph node spread at initial diagnosis, and significantly shorter survival, even when controlled for tissue type, than do patients whose cancers are not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification plays a central role in driving the poor outcome for patients with some of the most aggressive forms of cancers.

scholarly journals Sparse representation and Bayesian detection of genome copy number alterations from microarray data

2008 ◽  
Vol 24 (3) ◽  
pp. 309-318 ◽  
Author(s):  
Roger Pique-Regi ◽  
Jordi Monso-Varona ◽  
Antonio Ortega ◽  
Robert C. Seeger ◽  
Timothy J. Triche ◽  
...  
Keyword(s):  
Sparse Representation ◽  
Microarray Data ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Genome Copy ◽  
Genome Copy Number

scholarly journals Patient-derived xenografts undergo murine-specific tumor evolution

2017 ◽  
Author(s):  
Uri Ben-David ◽  
Gavin Ha ◽  
Yuen-Yi Tseng ◽  
Noah F. Greenwald ◽  
Coyin Oh ◽  
...  
Keyword(s):  
Drug Testing ◽  
Human Cancer ◽  
Genomic Stability ◽  
Molecular Characteristics ◽  
Tumor Evolution ◽  
Underlying Assumption ◽  
Primary Tumors ◽  
Specific Tumor ◽  
Pdx Models

AbstractPatient-derived xenografts (PDXs) have become a prominent model for studying human cancer in vivo. The underlying assumption is that PDXs faithfully represent the genomic features of primary tumors, retaining their molecular characteristics throughout propagation. However, the genomic stability of PDXs during passaging has not yet been evaluated systematically. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We found that new CNAs accumulated quickly, such that within four passages an average of 12% of the genome was affected by newly acquired CNAs. Selection for preexisting minor clones was a major contributor to these changes, leading to both gains and losses of CNAs. The rate of CNA acquisition in PDX models was correlated with the extent of both aneuploidy and genetic heterogeneity observed in primary tumors of the same tissue. However, the specific CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients, suggesting that PDX tumors are subjected to distinct selection pressures compared to those that exist in human hosts. Specifically, several recurrent CNAs observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Finally, we found that the genomic stability of PDX models also affected their responses to chemotherapy and targeted drugs. Our findings thus highlight the need to couple the timing of PDX molecular characterization to that of drug testing experiments. These results suggest that while PDX models are powerful tools, they should be used with caution.

scholarly journals Targeted genomic screen reveals focal long non-coding RNA copy number alterations in cancer

2017 ◽  
Author(s):  
Pieter-Jan Volders ◽  
Jo Vandesompele ◽  
Steve Lefever ◽  
Shalina Baute ◽  
Justine Nuytens ◽  
...  
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Microarray Platform ◽  
Copy Number Alterations ◽  
Protein Coding ◽  
Lncrna Gene ◽  
Cancer Pathogenesis ◽  
Non Coding Rna ◽  
Long Non Coding Rna

AbstractThe landscape of somatic copy-number alterations (SCNAs) affecting long non-coding RNAs (lncRNAs) in human cancer remains largely unexplored. While the majority of lncRNAs remains to be functionally characterized, several have been implicated in cancer development and metastasis. Considering the plethora of lncRNAs genes that is currently reported, it is conceivable that several lncRNAs might function as oncogenes or tumor suppressor genes.We devised a strategy to detect focal lncRNA SCNAs using a custom DNA microarray platform probing 20 418 lncRNA genes. By screening a panel of 80 cancer cell lines, we detected numerous focal aberrations targeting one or multiple lncRNAs without affecting neighboring protein-coding genes. These focal aberrations are highly suggestive for a tumor suppressive or oncogenic role of the targeted lncRNA gene. Although functional validation remains an essential step in the further characterization of the involved candidate cancer lncRNAs, our results provide a direct way of prioritizing candidate lncRNAs involved in cancer pathogenesis.

scholarly journals APOBEC Mutagenesis and Copy-Number Alterations Are Drivers of Proteogenomic Tumor Evolution and Heterogeneity in Metastatic Thoracic Tumors

Cell Reports ◽  
2019 ◽  
Vol 26 (10) ◽  
pp. 2651-2666.e6 ◽  
Author(s):  
Nitin Roper ◽  
Shaojian Gao ◽  
Tapan K. Maity ◽  
A. Rouf Banday ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Copy Number ◽  
Tumor Evolution ◽  
Copy Number Alterations

scholarly journals Signatures of copy number alterations in human cancer

2021 ◽  
Author(s):  
Christopher D Steele ◽  
Ammal Abbasi ◽  
Ashiqul S M Islam ◽  
Azhar Khandekar ◽  
Kerstin Haase ◽  
...  
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Cancer Risk Factors ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Cancer Types ◽  
Copy Number Changes ◽  
Gains And Losses

The gains and losses of DNA that emerge as a consequence of mitotic errors and chromosomal instability are prevalent in cancer. These copy number alterations contribute to cancer initiaition, progression and therapeutic resistance. Here, we present a conceptual framework for examining the patterns of copy number alterations in human cancer using whole-genome sequencing, whole-exome sequencing, and SNP6 microarray data making it widely applicable to diverse datasets. Deploying this framework to 9,873 cancers representing 33 human cancer types from the TCGA project revealed a set of 19 copy number signatures that explain the copy number patterns of 93% of TCGA samples. 15 copy number signatures were attributed to biological processes of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, and chromothripsis. The aetiology of four copy number signatures are unexplained and some cancer types have unique patterns of amplicon signatures associated with extrachromosomal DNA, disease-specific survival, and gains of proto-oncogenes such as MDM2. In contrast to base-scale mutational signatures, no copy number signature associated with known cancer risk factors. The results provide a foundation for exploring patterns of copy number changes in cancer genomes and synthesise the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes giving rise to copy number changes.

scholarly journals Copy-number and gene dependency analysis reveals partial copy loss of wild-type SF3B1 as a novel cancer vulnerability

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Brenton R Paolella ◽  
William J Gibson ◽  
Laura M Urbanski ◽  
John A Alberta ◽  
Travis I Zack ◽  
...  
Keyword(s):  
Copy Number ◽  
Human Cancer ◽  
Copy Number Alterations ◽  
Wild Type ◽  
Partial Loss ◽  
Human Cancer Cell Lines ◽  
Human Cancer Cells ◽  
A Genome ◽  
Genome Scale ◽  
Somatic Copy Number Alterations

Genomic instability is a hallmark of human cancer, and results in widespread somatic copy number alterations. We used a genome-scale shRNA viability screen in human cancer cell lines to systematically identify genes that are essential in the context of particular copy-number alterations (copy-number associated gene dependencies). The most enriched class of copy-number associated gene dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes, and spliceosome components were the most prevalent. One of these, the pre-mRNA splicing factor SF3B1, is also frequently mutated in cancer. We validated SF3B1 as a CYCLOPS gene and found that human cancer cells harboring partial SF3B1 copy-loss lack a reservoir of SF3b complex that protects cells with normal SF3B1 copy number from cell death upon partial SF3B1 suppression. These data provide a catalog of copy-number associated gene dependencies and identify partial copy-loss of wild-type SF3B1 as a novel, non-driver cancer gene dependency.

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