Comparative analysis of somatic copy-number alterations across different human cancer types reveals two distinct classes of breakpoint hotspots

MicroRNAs (miRNAs) are key molecules that regulate biological processes such as cell proliferation, differentiation, and apoptosis in cancer. Somatic copy number alterations (SCNAs) are common genetic mutations that play essential roles in cancer development. Here, we investigated the association between miRNAs and SCNAs in cancer. We collected 2538 tumor samples for seven cancer types from The Cancer Genome Atlas. We found that 32−84% of miRNAs are in SCNA regions, with the rate depending on the cancer type. In these regions, we identified 80 SCNA-miRNAs whose expression was mainly associated with SCNAs in at least one cancer type and showed that these SCNA-miRNAs are related to cancer by survival analysis and literature searching. We also identified 58 SCNA-miRNAs common in the seven cancer types (CC-SCNA-miRNAs) and showed that these CC-SCNA-miRNAs are more likely to be related with protein and gene expression than other miRNAs. Furthermore, we experimentally validated the oncogenic role of miR-589. In conclusion, our results suggest that SCNA-miRNAs significantly alter biological processes related to cancer development, confirming the importance of SCNAs in non-coding regions in cancer.

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Signatures of copy number alterations in human cancer

10.1101/2021.04.30.441940 ◽

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.

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Somatic Copy Number Alterations in Human Cancers: An Analysis of Publicly Available Data From The Cancer Genome Atlas

Frontiers in Oncology ◽

10.3389/fonc.2021.700568 ◽

2021 ◽

Vol 11 ◽

Author(s):

Luuk Harbers ◽

Federico Agostini ◽

Marcin Nicos ◽

Dimitri Poddighe ◽

Magda Bienko ◽

...

Keyword(s):

Copy Number ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Copy Number Alterations ◽

Multiple Cancer ◽

Human Cancers ◽

Cancer Genome Atlas ◽

Cancer Types ◽

Somatic Copy Number Alterations ◽

Genome Atlas

Somatic copy number alterations (SCNAs) are a pervasive trait of human cancers that contributes to tumorigenesis by affecting the dosage of multiple genes at the same time. In the past decade, The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) initiatives have generated and made publicly available SCNA genomic profiles from thousands of tumor samples across multiple cancer types. Here, we present a comprehensive analysis of 853,218 SCNAs across 10,729 tumor samples belonging to 32 cancer types using TCGA data. We then discuss current models for how SCNAs likely arise during carcinogenesis and how genomic SCNA profiles can inform clinical practice. Lastly, we highlight open questions in the field of cancer-associated SCNAs.

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

eLife ◽

10.7554/elife.23268 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 38

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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Comparative analysis of methods for identifying somatic copy number alterations from deep sequencing data

Briefings in Bioinformatics ◽

10.1093/bib/bbu004 ◽

2014 ◽

Vol 16 (2) ◽

pp. 242-254 ◽

Cited By ~ 36

Author(s):

A. Alkodsi ◽

R. Louhimo ◽

S. Hautaniemi

Keyword(s):

Comparative Analysis ◽

Deep Sequencing ◽

Copy Number ◽

Copy Number Alterations ◽

Sequencing Data ◽

Deep Sequencing Data ◽

Somatic Copy Number Alterations

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LiquidCNA: tracking subclonal evolution from longitudinal liquid biopsies using somatic copy number alterations

10.1101/2021.01.05.425414 ◽

2021 ◽

Author(s):

Eszter Lakatos ◽

Helen Hockings ◽

Maximilian Mossner ◽

Michelle Lockley ◽

Trevor A. Graham

Keyword(s):

Copy Number ◽

Evolutionary Dynamics ◽

Cost Effective ◽

Copy Number Alterations ◽

Liquid Biopsies ◽

Metastatic Lung ◽

Low Pass ◽

Somatic Copy Number Alterations

AbstractCell-free DNA (cfDNA) measured via liquid biopsies provides a way for minimally-invasive monitoring of tumour evolutionary dynamics during therapy. Here we present liquidCNA, a method to track subclonal evolution from longitudinally collected cfDNA samples based on somatic copy number alterations (SCNAs). LiquidCNA utilises SCNA profiles derived through cost-effective low-pass whole genome sequencing to automatically and simultaneously genotype and quantify the size of the dominant subclone without requiring prior knowledge of the genetic identity of the emerging clone. We demonstrate the accuracy of liquidCNA in synthetically generated sample sets and in vitro and in silico mixtures of cancer cell lines. Application in vivo in patients with metastatic lung cancer reveals the progressive emergence of a novel tumour sub-population. LiquidCNA is straightforward to use, computationally inexpensive and enables continuous monitoring of subclonal evolution to understand and control therapy-induced resistance.

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