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Tytuł:
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Whole genome copy number analyses reveal a highly aberrant genome in TP53 mutant lung adenocarcinoma tumors.
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Autorzy:
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Bjaanæs MM; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway. .; Department of Oncology, Oslo University Hospital, 4950 Nydalen, Oslo, Norway. .
Nilsen G; Department of Computer Science, University of Oslo, Oslo, Norway.; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Halvorsen AR; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.
Russnes HG; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.; Department of Pathology, Oslo University Hospital, Oslo, Norway.
Solberg S; Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway.
Jørgensen L; Department of Cardiothoracic Surgery, Oslo University Hospital, Oslo, Norway.
Brustugun OT; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.; Section of Oncology, Vestre Viken Hospital, Drammen, Norway.
Lingjærde OC; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.; Department of Computer Science, University of Oslo, Oslo, Norway.; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Helland Å; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway.; Department of Oncology, Oslo University Hospital, 4950 Nydalen, Oslo, Norway.
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Źródło:
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BMC cancer [BMC Cancer] 2021 Oct 09; Vol. 21 (1), pp. 1089. Date of Electronic Publication: 2021 Oct 09.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: London : BioMed Central, [2001-
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MeSH Terms:
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Gene Dosage*
Genes, p53*
Adenocarcinoma of Lung/*genetics
Carcinoma, Non-Small-Cell Lung/*genetics
Lung Neoplasms/*genetics
Adenocarcinoma of Lung/pathology ; Alleles ; Carcinoma, Non-Small-Cell Lung/pathology ; Chromosomes, Human, Pair 7 ; Chromosomes, Human, Pair 9 ; Class I Phosphatidylinositol 3-Kinases/genetics ; DNA Copy Number Variations ; Ex-Smokers ; Female ; Gene Expression ; Genes, erbB-1/genetics ; Genes, ras/genetics ; Humans ; Lung Neoplasms/pathology ; Male ; Non-Smokers ; Polymorphism, Single Nucleotide ; Signal Transduction/genetics ; Smokers ; TOR Serine-Threonine Kinases/genetics
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References:
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Contributed Indexing:
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Keywords: Copy number; Lung cancer; NSCLC; mTOR; p53
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Substance Nomenclature:
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EC 2.7.1.1 (MTOR protein, human)
EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
EC 2.7.1.137 (PIK3CA protein, human)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
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Entry Date(s):
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Date Created: 20211009 Date Completed: 20211020 Latest Revision: 20231102
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Update Code:
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20240104
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PubMed Central ID:
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PMC8501630
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DOI:
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10.1186/s12885-021-08811-7
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PMID:
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34625038
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Background: Genetic alterations are common in non-small cell lung cancer (NSCLC), and DNA mutations and translocations are targets for therapy. Copy number aberrations occur frequently in NSCLC tumors and may influence gene expression and further alter signaling pathways. In this study we aimed to characterize the genomic architecture of NSCLC tumors and to identify genomic differences between tumors stratified by histology and mutation status. Furthermore, we sought to integrate DNA copy number data with mRNA expression to find genes with expression putatively regulated by copy number aberrations and the oncogenic pathways associated with these affected genes.
Methods: Copy number data were obtained from 190 resected early-stage NSCLC tumors and gene expression data were available from 113 of the adenocarcinomas. Clinical and histopathological data were known, and EGFR-, KRAS- and TP53 mutation status was determined. Allele-specific copy number profiles were calculated using ASCAT, and regional copy number aberration were subsequently obtained and analyzed jointly with the gene expression data.
Results: The NSCLC tumors tissue displayed overall complex DNA copy number profiles with numerous recurrent aberrations. Despite histological differences, tissue samples from squamous cell carcinomas and adenocarcinomas had remarkably similar copy number patterns. The TP53-mutated lung adenocarcinomas displayed a highly aberrant genome, with significantly altered copy number profiles including gains, losses and focal complex events. The EGFR-mutant lung adenocarcinomas had specific arm-wise aberrations particularly at chromosome7p and 9q. A large number of genes displayed correlation between copy number and expression level, and the PI(3)K-mTOR pathway was highly enriched for such genes.
Conclusions: The genomic architecture in NSCLC tumors is complex, and particularly TP53-mutated lung adenocarcinomas displayed highly aberrant copy number profiles. We suggest to always include TP53-mutation status when studying copy number aberrations in NSCLC tumors. Copy number may further impact gene expression and alter cellular signaling pathways.
(© 2021. The Author(s).)