scholarly journals A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members

2021 ◽  
Vol 23 (1) ◽  
pp. 84
Author(s):  
Rubi Campos Gudiño ◽  
Ally C. Farrell ◽  
Nicole M. Neudorf ◽  
Kirk J. McManus
Keyword(s):  
Copy Number ◽  
26S Proteasome ◽  
Gene Copy ◽  
Cancer Type ◽  
Dependent Manner ◽  
Epigenetic Alterations ◽  
Copy Number Alterations ◽  
Scf Complex ◽  
Protein Substrates ◽  
Cancer Types

The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types.

scholarly journals Identification and Characterization of MicroRNAs Associated with Somatic Copy Number Alterations in Cancer

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 475 ◽  
Author(s):  
Jihee Soh ◽  
Hyejin Cho ◽  
Chan-Hun Choi ◽  
Hyunju Lee
Keyword(s):  
Copy Number ◽  
The Cancer Genome Atlas ◽  
Cancer Development ◽  
Cancer Type ◽  
Biological Processes ◽  
Copy Number Alterations ◽  
Coding Regions ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Somatic Copy Number Alterations

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.

scholarly journals CNApp, a tool for the quantification of copy number alterations and integrative analysis revealing clinical implications

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sebastià Franch-Expósito ◽  
Laia Bassaganyas ◽  
Maria Vila-Casadesús ◽  
Eva Hernández-Illán ◽  
Roger Esteban-Fabró ◽  
...  
Keyword(s):  
Copy Number ◽  
Clinical Implications ◽  
Cancer Type ◽  
Copy Number Alterations ◽  
Cancer Dataset ◽  
Web Based ◽  
Genomic Imbalances ◽  
Genome Wide ◽  
Cancer Types ◽  
Unique Framework

Somatic copy number alterations (CNAs) are a hallmark of cancer, but their role in tumorigenesis and clinical relevance remain largely unclear. Here, we developed CNApp, a web-based tool that allows a comprehensive exploration of CNAs by using purity-corrected segmented data from multiple genomic platforms. CNApp generates genome-wide profiles, computes CNA scores for broad, focal and global CNA burdens, and uses machine learning-based predictions to classify samples. We applied CNApp to the TCGA pan-cancer dataset of 10,635 genomes showing that CNAs classify cancer types according to their tissue-of-origin, and that each cancer type shows specific ranges of broad and focal CNA scores. Moreover, CNApp reproduces recurrent CNAs in hepatocellular carcinoma and predicts colon cancer molecular subtypes and microsatellite instability based on broad CNA scores and discrete genomic imbalances. In summary, CNApp facilitates CNA-driven research by providing a unique framework to identify relevant clinical implications. CNApp is hosted at https://tools.idibaps.org/CNApp/.

Comprehensive genomic profiling of circulating cell-free DNA (cfDNA) distinguishes focal amplification (amp) from aneuploidy among MET amps in diverse advanced cancer types.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3046-3046
Author(s):  
Yuichi Kumaki ◽  
Sadakatsu Ikeda ◽  
Thereasa A. Rich ◽  
Jing Zhao ◽  
Takayuki Yoshino ◽  
...  
Keyword(s):  
Copy Number ◽  
Gene Copy Number ◽  
Copy Number Gain ◽  
Chromosome 7 ◽  
Gene Copy ◽  
Cancer Type ◽  
Single Nucleotide Variants ◽  
Gene Assay ◽  
Cancer Types ◽  
Egfr Mutated

3046 Background: MET amps can occur from focal gene copy number gain (e.g. MET-driven) or gain of chromosome 7 (e.g. aneuploidy); however, the contribution of each to MET amp is not well established. MET inhibitor-sensitive lung cancers harboring high-level MET amp have been reported in the absence of other sensitizing MET alterations (alts), e.g. exon 14 skipping, particularly among those with higher MET to chromosome 7 ratios. Methods: 3,114 samples from 2,902 Asian patients with advanced solid tumors were tested with a comprehensive cfDNA NGS panel (Guardant360) between Oct 2015-Dec 2018. This 70-73 gene assay evaluates single nucleotide variants (SNV), selected insertion-deletions (indels), fusions, and copy number gains. Focal amp was determined bioinformatically as having statistically higher copy number relative to other genes, such as BRAF, or CDK6, in the same chromosome arm. Results: MET alts associated with aberrant signaling were found in 223 pts (7.7%) with 18 different cancer types, most commonly lung (128/1,678), colorectal (36/349), and prostate (11/48). Among 223 pts, 189 pts (84.8%) had amps, 38(17.0%) had exon 14 skipping, and 8 (3.6%) had activating SNVs. 39.7% of MET amp was focal but differed by cancer type; highest prevalence was in gastroesophageal (80%) and lowest in prostate cancers (9%). Samples with focal MET amp had higher plasma copy number compared to those with non-focal MET amp (mean 5.8 vs. 2.5; p < 0.0001) and lower total number of alts per sample (8.8 vs. 11; p = 0.0122). Focal MET amp was more common than non-focal MET amp among 419 EGFR mutated samples (6.9% vs. 3.8%, p = 0.05) suggesting focal MET amp may be biologically more relevant as a mechanism of EGFR TKI resistance. Conclusions: This is the first study to use cfDNA to examine focal vs. non-focal MET amp. Focal MET amp accounted for ~40% of all MET amps, was found in 2.6% of pts with diverse cancers, was associated with higher plasma copy number, and found in a higher proportion of EGFR mutated lung cancer samples. The ability to differentiate may be clinically relevant given higher MET to chromosome 7 ratios have been associated with improved therapeutic response.

scholarly journals POFUT1 as a Promising Novel Biomarker of Colorectal Cancer

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 411 ◽  
Author(s):  
Julien Chabanais ◽  
François Labrousse ◽  
Alain Chaunavel ◽  
Agnès Germot ◽  
Abderrahman Maftah
Keyword(s):  
Colorectal Cancer ◽  
Mucinous Adenocarcinoma ◽  
Copy Number ◽  
Notch Pathway ◽  
Gene Copy Number ◽  
Stage I ◽  
Gene Copy ◽  
Pathway Activation ◽  
Potential Biomarker ◽  
Cancer Types

Background: While protein O-fucosyltransferase 1 (POFUT1) overexpression has been recently proposed as a potential biomarker for different cancer types, no study was carried out on POFUT1 implication in colorectal cancer (CRC). Methods: Data from 626 tumors and 51 non-tumor adjacent tissues available in FireBrowse had been used in this study. Statistical analyses on POFUT1 expression and gene copy number, NOTCH receptors (main targets of POFUT1 enzymatic activity) expression and association of POFUT1 and NOTCH1 expressions with clinical parameters were investigated. Data were completed by POFUT1 histological labeling on six tumor tissues from patients with CRC. Results: We found that POFUT1 is overexpressed from the stage I (p < 0.001) and 76.02% of tumors have a 20q11.21 amplification, associated in 90.13% of cases with a POFUT1 overexpression, compared to non-tumor adjacent tissues. The POFUT1 copy number in tumors is mainly between 2 and 3. POFUT1 is positively correlated with NOTCH1 (rs = 0.34, p < 0.001), NOTCH3 (rs = 0.087, p = 0.0297), and NOTCH4 (rs = 0.097, p = 0.0148) expressions, while negatively correlated with NOTCH2 expression (rs = −0.098, p = 0.0142). POFUT1 overexpression is markedly associated with rectal location, non-mucinous adenocarcinoma and cancer stages IV and M1. NOTCH1 overexpression is only associated with rectal location and non-mucinous adenocarcinoma. Conclusion: We conclude that POFUT1 is overexpressed in CRC from stage I, and its high expression is associated with metastatic process, probably through NOTCH pathway activation. Then, POFUT1 could represent a potential novel biomarker for CRC diagnosis.

scholarly journals ASF1B Promotes Oncogenesis in Lung Adenocarcinoma and Other Cancer Types

2021 ◽  
Vol 11 ◽  
Author(s):  
Wencheng Zhang ◽  
Zhouyong Gao ◽  
Mingxiu Guan ◽  
Ning Liu ◽  
Fanjie Meng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Tumor Promoter ◽  
Regulatory Subunit ◽  
Cell Cycle Distribution ◽  
Cancer Type ◽  
Dependent Manner ◽  
Cancer Types

Anti-silencing function 1B histone chaperone (ASF1B) is known to be an important modulator of oncogenic processes, yet its role in lung adenocarcinoma (LUAD) remains to be defined. In this study, an integrated assessment of The Cancer Genome Atlas (TCGA) and genotype-tissue expression (GTEx) datasets revealed the overexpression of ASF1B in all analyzed cancer types other than LAML. Genetic, epigenetic, microsatellite instability (MSI), and tumor mutational burden (TMB) analysis showed that ASF1B was regulated by single or multiple factors. Kaplan-Meier survival curves suggested that elevated ASF1B expression was associated with better or worse survival in a cancer type-dependent manner. The CIBERSORT algorithm was used to evaluate immune microenvironment composition, and distinct correlations between ASF1B expression and immune cell infiltration were evident when comparing tumor and normal tissue samples. Gene set enrichment analysis (GSEA) indicated that ASF1B was associated with proliferation- and immunity-related pathways. Knocking down ASF1B impaired the proliferation, affected cell cycle distribution, and induced cell apoptosis in LUAD cell lines. In contrast, ASF1B overexpression had no impact on the malignant characteristics of LUAD cells. At the mechanistic level, ASF1B served as an indirect regulator of DNA Polymerase Epsilon 3, Accessory Subunit (POLE3), CDC28 protein kinase regulatory subunit 1(CKS1B), Dihydrofolate reductase (DHFR), as established through proteomic profiling and Immunoprecipitation-Mass Spectrometry (IP-MS) analyses. Overall, these data suggested that ASF1B serves as a tumor promoter and potential target for cancer therapy and provided us with clues to better understand the importance of ASF1B in many types of cancer.

scholarly journals Increased gene copy number of DEFA1/DEFA3 worsens sepsis by inducing endothelial pyroptosis

2019 ◽  
Vol 116 (8) ◽  
pp. 3161-3170 ◽  
Author(s):  
QiXing Chen ◽  
Yang Yang ◽  
JinChao Hou ◽  
Qiang Shu ◽  
YiXuan Yin ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Copy Number ◽  
Treatment Options ◽  
Gene Copy Number ◽  
High Copy Number ◽  
Gene Copy ◽  
Dependent Manner ◽  
Barrier Dysfunction ◽  
Specific Expression

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1–3 (HNP1–3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.

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