The spatial landscape of clonal somatic mutations in benign and malignant tissue

Abstract Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. Here, we provide an unsupervised approach to study spatial genome integrity in situ to describe previously unidentified clonal relationships. We employed spatially resolved transcriptomics to infer spatial copy number variations in >120 000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.

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The spatial landscape of clonal somatic mutations in benign and malignant tissue

10.1101/2021.07.12.452018 ◽

2021 ◽

Author(s):

Andrew Erickson ◽

Emelie Berglund ◽

Mengxiao He ◽

Maja Marklund ◽

Reza Mirzazadeh ◽

...

Keyword(s):

Copy Number ◽

Focal Therapy ◽

Copy Number Variations ◽

Cancer Evolution ◽

Malignant Tissue ◽

Spatially Resolved ◽

Early Diagnosis Of Cancer ◽

Multiple Organs ◽

Benign Tissue ◽

Unsupervised Approach

Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. Here, we provide an unsupervised approach to study spatial genome integrity in situ to gain molecular insight into clonal relationships. We employed spatially resolved transcriptomics to infer spatial copy number variations in >120 000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of an unsupervised approach to capture the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.

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Application of Copy Number Variation Sequencing in Genetic Analysis of Miscarriages in Early and Middle Pregnancy

Cytogenetic and Genome Research ◽

10.1159/000512801 ◽

2020 ◽

Vol 160 (11-12) ◽

pp. 634-642

Author(s):

Shiqiang Luo ◽

Xingyuan Chen ◽

Tizhen Yan ◽

Jiaolian Ya ◽

Zehui Xu ◽

...

Keyword(s):

Copy Number Variation ◽

High Throughput ◽

Copy Number ◽

High Throughput Sequencing ◽

Chromosomal Abnormalities ◽

Pregnancy Termination ◽

Mendelian Inheritance ◽

Copy Number Variations ◽

Abnormal Chromosome ◽

Number Variation

High-throughput sequencing based on copy number variation (CNV-seq) is commonly used to detect chromosomal abnormalities. This study identifies chromosomal abnormalities in aborted embryos/fetuses in early and middle pregnancy and explores the application value of CNV-seq in determining the causes of pregnancy termination. High-throughput sequencing was used to detect chromosome copy number variations (CNVs) in 116 aborted embryos in early and middle pregnancy. The detection data were compared with the Database of Genomic Variants (DGV), the Database of Chromosomal Imbalance and Phenotype in Humans using Ensemble Resources (DECIPHER), and the Online Mendelian Inheritance in Man (OMIM) database to determine the CNV type and the clinical significance. High-throughput sequencing results were successfully obtained in 109 out of 116 specimens, with a detection success rate of 93.97%. In brief, there were 64 cases with abnormal chromosome numbers and 23 cases with CNVs, in which 10 were pathogenic mutations and 13 were variants of uncertain significance. An abnormal chromosome number is the most important reason for embryo termination in early and middle pregnancy, followed by pathogenic chromosome CNVs. CNV-seq can quickly and accurately detect chromosome abnormalities and identify microdeletion and microduplication CNVs that cannot be detected by conventional chromosome analysis, which is convenient and efficient for genetic etiology diagnosis in miscarriage.

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Carcinosarcoma of the prostate: case report with molecular and histological characterization

The International Journal of Biological Markers ◽

10.1177/1724600818791463 ◽

2018 ◽

Vol 33 (4) ◽

pp. 540-544 ◽

Cited By ~ 3

Author(s):

Samanta Salvi ◽

Valentina Casadio ◽

Filippo Martignano ◽

Giorgia Gurioli ◽

Maria Maddalena Tumedei ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Copy Number Variations ◽

Molecular Characteristics ◽

Glutathione S Transferase ◽

Molecular Alterations ◽

Positive Expression ◽

Molecular Pattern ◽

Programmed Death ◽

Number Variation

Background: We report a case of prostatic carcinosarcoma, a rare variant of prostatic cancer, which is composed of a mixture of epithelial and mesenchymal components with a generally poor outcome. Aims and methods: We aim to identify molecular alterations, in particular copy number variations of AR and c -MYC genes, methylation and expression of glutathione S-transferase P1 (GSTP1), programmed death-ligand 1 (PD-L1), AR, and phosphorylated AR expression. Results: We found a distinct molecular pattern between adenocarcinoma and carcinosarcoma, which was characterized by high AR copy number variation gain; positive expression of PD-L1, AR, and phosphorylated AR; low espression of GSTP1 in epithelial component. The sarcomatoid component had a lower gain of the AR gene, and no expression of PD-L1, AR, phosphorylated AR, or GSTP1. Both components had a gain of c-MYC copy number variation. Conclusions: Our findings suggest that carcinosarcoma has specific molecular characteristics that could be indicative for early diagnosis and treatment selection.

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Identification of prognostic values defined by copy number variation, mRNA and protein expression of LANCL2 and EGFR in IDH1/2-wild-type glioblastoma

10.21203/rs.3.rs-276679/v1 ◽

2021 ◽

Author(s):

Hua-fu Zhao ◽

Xiu-ming Zhou ◽

Jing Wang ◽

Fan-fan Chen ◽

Chang-peng Wu ◽

...

Keyword(s):

Protein Expression ◽

Copy Number ◽

Intracellular Localization ◽

Methylation Status ◽

Growth Factor Receptor ◽

Copy Number Variations ◽

Wild Type ◽

Number Variation ◽

Newly Diagnosed Glioblastoma ◽

Mrna And Protein Expression

Abstract Background Epidermal growth factor receptor (EGFR) and lanthionine synthetase C-like 2 (LanCL2) genes locate in the same amplicon, and co-amplification of EGFR and LANCL2 is frequent in glioblastoma. However, the prognostic value of LANCL2 and EGFR co-amplification, and their mRNA and protein expression in glioblastoma remain unclear yet. Methods This study analyzed the prognostic values of the copy number variations (CNVs), mRNA and protein expression of LANCL2 and EGFR in glioblastoma specimens from TCGA database or our tumor banks. Results The amplification of LANCL2 or EGFR, and their co-amplification were frequent in glioblastoma of TCGA database and our tumor banks. CNVs of LANCL2 or EGFR were significantly correlated with IDH1/2 mutation but not MGMT promoter methylation status. LANCL2 or EGFR amplification, and their co-amplification were significantly associated with reduced overall survival (OS) of glioblastoma patients, rather than IDH1/2-wild-type glioblastoma patients. mRNA and protein overexpression of LANCL2 and EGFR was also frequently found in glioblastoma. LANCL2, rather than EGFR, was overexpressed in relapsing glioblastoma, compared with newly diagnosed glioblastoma. However, mRNA or protein expression of EGFR and LANCL2 was not significantly correlated with OS of glioblastoma patients. In addition, the intracellular localization of LanCL2, not EGFR, was associated with the grade of gliomas. Conclusions Taken together, amplification and mRNA overexpression of LANCL2 and EGFR, and their co-amplification and co-expression were frequent in glioblastoma patients. Our findings suggest that CNVs of LANCL2 and EGFR were the independent diagnostic and prognostic biomarkers for histological glioblastoma patients, but not for IDH1/2-wild-type glioblastoma patients.

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Hadoop-CNV-RF: a clinically validated and scalable copy number variation detection tool for next-generation sequencing data

10.21203/rs.2.22176/v1 ◽

2020 ◽

Author(s):

Getiria Onsongo ◽

Ham Ching Lam ◽

Matthew Bower ◽

Bharat Thyagarajan

Keyword(s):

Copy Number ◽

Copy Number Variations ◽

Next Generation Sequencing Data ◽

Sequencing Data ◽

Large Gene ◽

Data Framework ◽

Number Variation ◽

Targeted Capture ◽

Objective Detection ◽

Gene Panels

Abstract Objective : Detection of small copy number variations (CNVs) in clinically relevant genes is routinely being used to aid diagnosis. We recently developed a tool, CNV-RF , capable of detecting small clinically relevant CNVs. CNV-RF was designed for small gene panels and did not scale well to large gene panels. On large gene panels, CNV-RF routinely failed due to memory limitations. When successful, it took about 2 days to complete a single analysis, making it impractical for routinely analyzing large gene panels. We need a reliable tool capable of detecting CNVs in the clinic that scales well to large gene panels. Results : We have developed Hadoop-CNV-RF, a scalable implementation of CNV-RF . Hadoop-CNV-RF is a freely available tool capable of rapidly analyzing large gene panels. It takes advantage of Hadoop, a big data framework developed to analyze large amounts of data. Preliminary results show it reduces analysis time from about 2 days to less than 4 hours and can seamlessly scale to large gene panels. Hadoop-CNV-RF has been clinically validated for targeted capture data and is currently being used in a CLIA molecular diagnostics laboratory. Its availability and usage instructions are publicly available at: https://github.com/getiria-onsongo/hadoop-cnvrf-public .

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Copy Number Variations of Four Y-Linked Genes in Swamp Buffaloes

Animals ◽

10.3390/ani10010031 ◽

2019 ◽

Vol 10 (1) ◽

pp. 31

Author(s):

Ting Sun ◽

Quratulain Hanif ◽

Hong Chen ◽

Chuzhao Lei ◽

Ruihua Dang

Keyword(s):

Y Chromosome ◽

Copy Number ◽

Water Buffalo ◽

Single Copy ◽

Copy Number Variations ◽

Tetratricopeptide Repeat ◽

Dead Box ◽

Complex Phenotypes ◽

Swamp Buffaloes ◽

Number Variation

Copy number variation (CNV), a significant source of genetic diversity in the mammalian Y chromosome, is associated with the development of many complex phenotypes, such as spermatogenesis and male fertility. The contribution of Y-linked CNVs has been studied in various species, however, water buffalo has not been explored in this area and the genetic information still remains unknown. The aim of the current study was to investigate the CNVs of four Y-linked genes, including, sex determining Region of Y-Chromosome (SRY), ubiquitously transcribed tetratricopeptide repeat gene protein on the chromosome Y (UTY), DEAD-box helicase 3 Y-linked (DDX3Y, also known as DBY), and oral-facial-digital syndrome 1 Y-linked (OFD1Y) in 254 swamp buffaloes from 15 populations distributed across China, Vietnam, and Laos using quantitative real-time PCR (qPCR). Our results revealed the prevalence of a single-copy UTY gene in buffaloes. The DBY and OFD1Y represented CNVs among and within different buffalo breeds. The SRY showed CNVs only in Vietnamese and Laotian buffaloes. In conclusion, this study indicated that DBY, OFD1Y, and SRY showed CNVs, while the UTY was a single-copy gene in swamp buffaloes.

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Copy Number Variation at 16p11.2 Imparts Transcriptional Alterations in Neural Development in an hiPSC-derived Model of Corticogenesis

10.1101/2020.04.22.055731 ◽

2020 ◽

Author(s):

Julien G. Roth ◽

Kristin L. Muench ◽

Aditya Asokan ◽

Victoria M. Mallett ◽

Hui Gai ◽

...

Keyword(s):

Neural Development ◽

Copy Number ◽

Developmental Disorders ◽

Neural Progenitor Cells ◽

Copy Number Variations ◽

Chromosomal Locus ◽

Research Initiative ◽

Transcriptional Alterations ◽

Number Variation ◽

Induced Pluripotent

ABSTRACTMicrodeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations of these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). Cortical neural progenitor cells derived from these hiPSCs were profiled using RNA-Seq, which identified alterations in radial glial gene expression that precede morphological abnormalities reported at later neurodevelopmental stages. Moreover, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of “footprint”-free hiPSC clones that are available by request from the Simons Foundation Autism Research Initiative. This publicly available resource of 65 human hiPSC clones can serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.

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Phenome-wide burden of copy number variation in UK Biobank

10.1101/545996 ◽

2019 ◽

Cited By ~ 2

Author(s):

Matthew Aguirre ◽

Manuel Rivas ◽

James Priest

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Significant Proportion ◽

High Body Mass Index ◽

Population Level ◽

Copy Number Variations ◽

Uk Biobank ◽

Number Variation ◽

Artery Disease ◽

The Uk

AbstractCopy number variations (CNV) represent a significant proportion of the genetic differences between individuals and many CNVs associate causally with syndromic disease and clinical outcomes. Here, we characterize the landscape of copy number variation and their phenome-wide effects in a sample of 472,228 array-genotyped individuals from the UK Biobank. In addition to population-level selection effects against genic loci conferring high-mortality, we describe genetic burden from syndromic and previously uncharacterized CNV loci across nearly 2,000 quantitative and dichotomous traits, with separate analyses for common and rare classes of variation. Specifically, we highlight the effects of CNVs at two well-known syndromic loci 16p11.2 and 22q11.2, as well as novel associations at 9p23, in the context of acute coronary artery disease and high body mass index. Our data constitute a deeply contextualized portrait of population-wide burden of copy number variation, as well as a series of known and novel dosage-mediated genic associations across the medical phenome.

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CoDEX2: full-spectrum copy number variation detection by high-throughput DNA sequencing

10.1101/211698 ◽

2017 ◽

Cited By ~ 1

Author(s):

Yuchao Jiang ◽

Rujin Wang ◽

Eugene Urrutia ◽

Ioannis N. Anastopoulos ◽

Katherine L. Nathanson ◽

...

Keyword(s):

Dna Sequencing ◽

High Throughput ◽

Copy Number ◽

Copy Number Variations ◽

Negative Control ◽

Sequencing Data ◽

Full Spectrum ◽

Number Variation ◽

High Throughput Dna Sequencing ◽

Low Sensitivity

AbstractHigh-throughput DNA sequencing enables detection of copy number variations (CNVs) on the genome-wide scale with finer resolution compared to array-based methods, but suffers from biases and artifacts that lead to false discoveries and low sensitivity. We describe CODEX2, a statistical framework for full-spectrum CNV profiling that is sensitive for variants with both common and rare population frequencies and that is applicable to study designs with and without negative control samples. We demonstrate and evaluate CODEX2 on whole-exome and targeted sequencing data, where biases are the most prominent. CODEX2 outperforms existing methods and, in particular, significantly improves sensitivity for common CNVs.

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Frequency of CDK2 , CCNE1 Copy Number Variation in Acral Melanoma and Implications for CDK Inhibitor in Targeted Therapy

10.21203/rs.2.23330/v1 ◽

2020 ◽

Author(s):

Xiaowen Wu ◽

Junya Yan ◽

Jiayi Yu ◽

Jinyu Yu ◽

Zhiyuan Cheng ◽

...

Keyword(s):

Cell Cycle ◽

Targeted Therapy ◽

Copy Number Variation ◽

Copy Number ◽

Melanoma Cells ◽

Copy Number Variations ◽

Gene Copy ◽

Cdk Inhibitor ◽

Acral Melanoma ◽

Number Variation

Abstract Background: Acral melanoma have a high frequency of cell cycle-related gene copy number variation. However, the status and clinical significance of CNVs of CDK 2 and CCNE1 have not been fully elucidated. Methods: A total of 490 acral melanoma samples were examined for CNVs of CDK 2 and CCNE1 using QuantiGenePlex DNA Assay. Correlations of CDK2 and CCNE1 CNVs to clinicopathologic features and prognosis of acral melanoma were evaluated.The sensitivity of cell lines and cell-derived xenograft (CDX) containing CCNE1 CNVs to CDK inhibitor AT7519,Dinaciclib and proteasome inhibitor Bortezomib were also analyzed. Results: Among the 490 samples,140 cases, 139 cases and 39 cases respectively showed CDK2 gain (28.5%), CCNE1 gain (28.3%) and CDK2 gain plus CCNE1 gain (8.0%).The median progression-free survival (PFS) time for acral patients with CCNE1 gain was significantly shorter than that for patients without CCNE1 gain (17.0 versus 27.0 months; P =0.002). Furthermore, CCNE1 gain was an independent prognostic factor for patients receiving chemotherapy. The pan-CDK inhibitor AT7519 could inhibit the cell proliferation, induce apoptosis and cause cell cycle arrest in G2 phase of acral melanoma cells and inhibit the tumor growth of CDX with CCNE1 gain. Dinaciclib and Bortezomib showed CCNE1 copy number independent inhibitory effects on the proliferation of melanoma cells. Conclusions: CDK2 and CCNE1 copy number variations were frequent in acral melanoma and CCNE1 gain may be a useful biomarker to predict the outcome of receiving chemotherapy in patients with acral melanoma. In addition, our study provides a basis for the use of CDK inhibitor in the treatment of acral melanoma. Keywords: acral melanoma, targeted therapy, CDK2 , CCNE1 , copy number variation

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