Specific Genomic Regions Are Differentially Affected by Copy Number Alterations across Distinct Cancer Types, in Aggregated Cytogenetic Data

Kumar, Nitin; Cai, Haoyang; Mering, Christian von; Baudis, Michael

doi:10.1371/journal.pone.0043689

Cited by 6 publications

(6 citation statements)

References 28 publications

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“…The tens of thousands of tumor samples profiled by genomic arrays and deposited in public repositories allow researchers to identify patterns of non-random CNA events related to different cancer types, and to pinpoint involvement of specific cancer genes ( 6 , 11 , 12 ). A number of databases providing curated CNA data are available online, such as CaSNP ( 13 ), CanGEM ( 14 ) and Progenetix ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

arrayMap 2014: an updated cancer genome resource

Cai

Gupta

Rath

et al. 2014

Nucleic Acids Research

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Somatic copy number aberrations (CNA) represent a mutation type encountered in the majority of cancer genomes. Here, we present the 2014 edition of arrayMap (http://www.arraymap.org), a publicly accessible collection of pre-processed oncogenomic array data sets and CNA profiles, representing a vast range of human malignancies. Since the initial release, we have enhanced this resource both in content and especially with regard to data mining support. The 2014 release of arrayMap contains more than 64 000 genomic array data sets, representing about 250 tumor diagnoses. Data sets included in arrayMap have been assembled from public repositories as well as additional resources, and integrated by applying custom processing pipelines. Online tools have been upgraded for a more flexible array data visualization, including options for processing user provided, non-public data sets. Data integration has been improved by mapping to multiple editions of the human reference genome, with the majority of the data now being available for the UCSC hg18 as well as GRCh37 versions. The large amount of tumor CNA data in arrayMap can be freely downloaded by users to promote data mining projects, and to explore special events such as chromothripsis-like genome patterns.

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Section: Introductionmentioning

confidence: 99%

arrayMap 2014: an updated cancer genome resource

Cai

Gupta

Rath

et al. 2014

Nucleic Acids Research

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“…Earlier research by our group [7, 8] and others [9, 10] has described amplification and deletion hotspots among multiple cancer types. However, a systematic multi-cancer analysis for CNA-exerted susceptibility discovery is needed to compare between cancer types, extract relevant changes and delineate their functional impact.…”

Section: Introductionmentioning

confidence: 99%

“…Earlier research has described amplification and deletion hotspots among multiple cancer types [14, 15, 16, 17]. CNA-derived gene discovery can complement the knowledge of functional landscape during oncogenesis and pinpoint new genes previously unknown from point mutation analysis [18].…”

Section: Introductionmentioning

confidence: 99%

Candidate targets of copy number deletion events across 17 cancer types

Huang

Baudis

2022

Preprint

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Genome variation is the direct cause of cancer and driver of its clonal evolution. While the impact of many point mutations can be evaluated through their modification of individual genomic elements, even single copy number aberrations (CNAs) may encompass hundreds of genes and therefore pose challenges to untangle potentially complex functional effects. However, consistent, recurring and disease-specific patterns in the genome-wide CNA landscape imply that particular CNA may promote cancer type-specific characteristics. Discerning essential cancer-promoting alterations from the inherent co-dependency in CNA would improve the understanding of mechanisms of CNA and provide new insights into cancer biology and potential therapeutic targets. Here we implement a model using segment breakpoints to discover non-random gene coverage by copy number deletion (CND). With a diverse set of cancer types from multiple resources, this model identified common and cancer type-specific oncogenes and tumor suppressor genes as well as cancer-promoting functional pathways. Confirmed by differential expression analysis of data from corresponding cancer types, the results show that for most cancer types, despite dissimilarity of their CND landscapes, similar canonical pathways are affected. In 25 analyses of 17 cancer types, we have identified 20-170 significant genes by copy deletion, including RB1, PTEN and CDKN2A as the most significantly deleted genes among all cancer types. We have also shown a shared dependence on core pathways for cancer progression in different cancers as well as cancer-type separation by genome-wide significance scores. While this work provides a reference for gene specific significance in many cancers, it chiefly contributes a general framework to derive genome-wide significance and molecular insights in CND profiles with a potential for the analysis of rare cancer types as well as non-coding regions.

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“…Aneuploidy is a frequent observation across virtually all types of cancer and a characteristic of all solid tumors (e.g. Supplemental Figure 7 in 19 , Figure 3 in 20 and Supplemental Figure S1 (Supplemental Note A). The works of David Paul von Hansemann 21 that were later taken up by Theodor Heinrich Boveri 3 recognized many years ago that an incorrect number of chromosomes was caused by errors during mitosis and that this was related to the cancerous state of a cell 22 .…”

Section: Introductionmentioning

confidence: 99%

The disruption of trace element homeostasis due to aneuploidy as a unifying theme in the etiology of cancer

Engelken

Altmeyer

2014

Preprint

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Abstracts Abstract for ScientistsWhile decades of cancer research have firmly established multiple "hallmarks of cancer" 1,2 , cancer's genomic landscape remains to be fully understood. Particularly, the phenomenon of aneuploidy -gains and losses of large genomic regions, i.e. whole chromosomes or chromosome arms -and why most cancer cells are aneuploid remains enigmatic 3 . Another frequent observation in many different types of cancer is the deregulation of the homeostasis of the trace elements copper, zinc and iron. Concentrations of copper are markedly increased in cancer tissue and the blood plasma of cancer patients, while zinc levels are typically decreased [4][5][6][7][8][9] . Here we discuss the hypothesis that the disruption of trace element homeostasis and the phenomenon of aneuploidy might be linked. Our tentative analysis of genomic data from diverse tumor types mainly from The Cancer Genome Atlas (TCGA) project suggests that gains and losses of metal transporter genes occur frequently and correlate well with transporter gene expression levels. Hereby they may confer a cancer-driving selective growth advantage at early and possibly also later stages during cancer development. This idea is consistent with recent observations in yeast, which suggest that through chromosomal gains and losses cells can adapt quickly to new carbon sources 10 , nutrient starvation 11 as well as to copper toxicity 12 . In human cancer development, candidate driving events may include, among others, the gains of zinc transporter genes SLC39A1 and SLC39A4 on chromosome arms 1q and 8q, respectively, and the losses of zinc transporter genes SLC30A5, SLC39A14 and SLC39A6 on 5q, 8p and 18q. The recurrent gain of 3q might be associated with the iron transporter gene TFRC and the loss of 13q with the copper transporter gene ATP7B. By altering cellular trace element homeostasis such events might contribute to the initiation of the malignant transformation. Intriguingly, attenuation or overexpression of several of these metal transporter genes has been shown to lead to malignant cellular behavior in vitro. Consistently, it has been shown that zinc affects a number of the observed "hallmarks of cancer" characteristics including DNA repair, inflammation and apoptosis, e.g. through its effects on NF-kappa B signaling. We term this model the "aneuploidy metal transporter cancer" (AMTC) hypothesis and find it compatible with the cancer-promoting role of point mutations and focal copy number alterations in established tumor suppressor genes and oncogenes (e.g. MYC, MYCN, TP53, PIK3CA, BRCA1, ERBB2). We suggest a number of approaches for how this hypothesis could be tested experimentally and briefly touch on possible implications for cancer etiology, metastasis, drug resistance and therapy.. CC-BY-NC 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/002105 doi: bioRxiv preprint first posted online Jan. 29, 2014; [3...

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Specific Genomic Regions Are Differentially Affected by Copy Number Alterations across Distinct Cancer Types, in Aggregated Cytogenetic Data

Cited by 6 publications

References 28 publications

arrayMap 2014: an updated cancer genome resource

arrayMap 2014: an updated cancer genome resource

Candidate targets of copy number deletion events across 17 cancer types

The disruption of trace element homeostasis due to aneuploidy as a unifying theme in the etiology of cancer

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