Genomic profiling identified novel prognostic biomarker in Chinsese glioma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14538-e14538
Author(s):  
Hainan Li ◽  
Changguo Shan ◽  
Chongzhu Fan ◽  
Shengnan Wu ◽  
Mingyao Lai ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Overall Survival ◽  
Survival Data ◽  
Copy Number ◽  
Copy Number Variations ◽  
Occurrence Rate ◽  
Molecular Diagnostic ◽  
Poor Overall Survival ◽  
Tissue Samples ◽  
Pik3ca Mutations

e14538 Background: Molecular charactersitcs are essential for the classification and grading of gliomas. However, majority of current understanding is based on public databases that might not accurately reflect the Asian population. Here, we studied the mutation landscape of Chinese glioma patients in hope to provide new insights for glioma prognosis and treatment. Methods: Tissue samples from 112 glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their prognostic effect using overall survival data. Pathway-based survival analysis was peformed using top ten predefined oncogenic pathways. Results: We identified similar prevalence of currently established molecular diagnostic markers of glioma, including TP53 (33%), EGFR(26%), TERT (24%), PTEN (21%), ATRX (14%), BRAF (13%) and IDH1/2 (6%). Among all genetic abberations with more than 5% occurrence rate, four mutations and four copy number gains were significantly associated with poor overall survival (univariate, P < 0.05). Of these, TERT mutations (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.31 to 7.49; P = 0.01) and EGFR amplification (HR, 2.67; 95% CI, 1.20 to 5.95; P = 0.02) remained significant after adjusting for clinical parameters. Similarly, PIK3CA mutations, which was also frequently mutated in glioma but not used for clinical classification, were found to correlate with poor prognosis (HR, 2.61; 95% CI, 1.19 to 5.74; P = 0.02). Additionally, we have also identified MCL1 amplification as a potential novel biomarker for glioma (HR, 2.73; 95% CI, 1.47 to 5.07; P < 0.001), which was seldom reported in the TCGA database and might possibly be ancestral specific giving its high prevelance in our cohort (found in 32% patients). Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12 to 2.95; P = 0.02) and cell cycle pathways (HR, 2.04; 95% CI, 1.2 to 3.47; P < 0.001), both of which stayed meaningful after adjusting for clinical factors. Conclusions: In this study, we discovered PIK3CA mutations and MCL1 amplification as novel prognostic markers of glioma. We also demonstrated shorter survival with abnormal PI3K and cell cycle pathways that provided an intergrative understanding of glioma.

scholarly journals Genomic Profiling Identified Novel Prognostic Biomarkers in Chinese Midline Glioma Patients

2021 ◽  
Vol 10 ◽  
Author(s):  
Hainan Li ◽  
Changguo Shan ◽  
Shengnan Wu ◽  
Baijie Cheng ◽  
Chongzu Fan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Overall Survival ◽  
Survival Data ◽  
Copy Number ◽  
Copy Number Variations ◽  
Prognostic Biomarkers ◽  
Occurrence Rate ◽  
Molecular Characteristics ◽  
Poor Overall Survival ◽  
Tissue Samples

BackgroundMolecular characteristics are essential for the classification and grading of gliomas. However, diagnostic classification of midline glioma is still debatable and substantial molecular and clinical heterogeneity within each subgroup suggested that they should be further stratified. Here, we studied the mutation landscape of Chinese midline glioma patients in hope to provide new insights for glioma prognosis and treatment.MethodsTissue samples from 112 midline glioma patients underwent next-generation sequencing targeting 425 cancer-relevant genes. Gene mutations and copy number variations were investigated for their somatic interactions and prognostic effect using overall survival data. Pathway-based survival analysis was performed for ten canonical oncogenic pathways.ResultsWe identified several currently established diagnostic and prognostic biomarkers of glioma, including TP53 (33%), EGFR (26%), TERT (24%), PTEN (21%), PIK3CA (14%), ATRX (14%), BRAF (13%), and IDH1/2 (6%). Among all genetic aberrations with more than 5% occurrence rate, six mutations and three copy number gains were greatly associated with poor overall survival (univariate, P &lt; 0.1). Of these, TERT mutations (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.37–6.61; P = 0.01) and PIK3CA mutations (HR, 2.04; 95% CI, 1.08–3.84; P = 0.02) remained significant in multivariate analyses. Additionally, we have also identified a novel MCL1 amplification (found in 31% patients) as a potential independent biomarker for glioma (multivariate HR, 2.78; 95% CI, 1.53–5.08; P &lt; 0.001), which was seldom reported in public databases. Pathway analyses revealed significantly worse prognosis with abnormal PI3K (HR, 1.81; 95% CI, 1.12–2.95; P = 0.01) and cell cycle pathways (HR, 1.97; 95% CI, 1.15–3.37; P = 0.01), both of which stayed meaningful after multivariate adjustment.ConclusionsIn this study, we discovered shorter survival in midline glioma patients with PIK3CA and TERT mutations and with abnormal PI3K and cell cycle pathways. We also revealed a novel prognostic marker, MCL1 amplification that collectively provided new insights and opportunities in understanding and treating midline gliomas.

BIOM-34. GENOMIC PROFILING IDENTIFIED COPY NUMBER VARIATIONS OF CDK4/6 AS A NOVEL PROGNOSTIC BIOMARKER FOR THALAMIC GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi18-vi18
Author(s):  
Mingyao Lai ◽  
zhaoming Zhou ◽  
Hainan Li ◽  
Jiangfen Zhou ◽  
Juan Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
Copy Number Variation ◽  
Copy Number ◽  
Prognostic Biomarker ◽  
Gene Mutations ◽  
Copy Number Variations ◽  
Occurrence Rate ◽  
Number Variation ◽  
Thalamic Glioma ◽  
Astrocyte Differentiation

Abstract BACKGROUND Thalamic glioma is a rare tumor, which is poorly understood in adults. The genetic variation of this tumor is still unknown. In this study, we investigated the mutation landscape of thalamic glioma and compared the clinical outcomes between different mutation situations in thalamic glioma. METHODS Next-generation sequencing targeting 425 cancer-relevant genes was performed with 34 thalamic glioma tissue samples. Gene mutations and copy number variations were investigated for prognostic effect with overall survival data. RESULTS Several diagnostic and prognostic biomarkers appeared in our thalamic glioma cohort, including TP53 (56%), EGFR (41%), TERT (35%), M CL1 (26%), PDGFRA (26%), PTEN (26%), CDK4/6 (24%), POLE (24%), PIK3CA (24%), NF1 (21%), ATR (21%), ATRX (18%), BRAF (15%), and ROS1 (12%). Among all genetic aberrations with a more than 10% occurrence rate, two mutations (TERT and PTEN) were associated with poor overall survival and one copy number variation (CDK4/6) was associated with favorable overall survival (univariate P &lt; 0.1). Among these genes, CDK4/6 copy number variations (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.035–0.704; P = 0.016) remained significant survival associated in multivariate analyses. Copy number variations of CDK4/6 was seldom reported as a prognostic biomarker for glioma, especially for thalamic glioma in public databases. Besides, several gene mutations (BRIP1, MRE11A, MAP2K1, ROS1, MUTYH, JARID2, CTCF, and EGFR) were found positively associated with CDK4/6 copy number variations. Gene enrichment analysis demonstrated that those genes were related to astrocyte differentiation. CONCLUSIONS In our study, CDK4/6 copy number variation was determined as a favorable overall survival biomarker for thalamic glioma, and CDK4/6 copy number variation associated mutant genes were related to astrocyte differentiation, which could be the potential therapeutic targets for thalamic glioma.

scholarly journals Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2426
Author(s):  
Pankita H. Pandya ◽  
Lijun Cheng ◽  
M. Reza Saadatzadeh ◽  
Khadijeh Bijangi-Vishehsaraei ◽  
Shan Tang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Systems Biology ◽  
Copy Number ◽  
Therapeutic Option ◽  
Replication Stress ◽  
Copy Number Variations ◽  
Chromosome 8 ◽  
Adolescent And Young Adult ◽  
Poor Overall Survival

Osteosarcoma (OS) patients exhibit poor overall survival, partly due to copy number variations (CNVs) resulting in dysregulated gene expression and therapeutic resistance. To identify actionable prognostic signatures of poor overall survival, we employed a systems biology approach using public databases to integrate CNVs, gene expression, and survival outcomes in pediatric, adolescent, and young adult OS patients. Chromosome 8 was a hotspot for poor prognostic signatures. The MYC-RAD21 copy number gain (8q24) correlated with increased gene expression and poor overall survival in 90% of the patients (n = 85). MYC and RAD21 play a role in replication-stress, which is a therapeutically actionable network. We prioritized replication-stress regulators, bromodomain and extra-terminal proteins (BETs), and CHK1, in order to test the hypothesis that the inhibition of BET + CHK1 in MYC-RAD21+ pediatric OS models would be efficacious and safe. We demonstrate that MYC-RAD21+ pediatric OS cell lines were sensitive to the inhibition of BET (BETi) and CHK1 (CHK1i) at clinically achievable concentrations. While the potentiation of CHK1i-mediated effects by BETi was BET-BRD4-dependent, MYC expression was BET-BRD4-independent. In MYC-RAD21+ pediatric OS xenografts, BETi + CHK1i significantly decreased tumor growth, increased survival, and was well tolerated. Therefore, targeting replication stress is a promising strategy to pursue as a therapeutic option for this devastating disease.

scholarly journals Development and Validation of a Unique Gignature of Cancer Stemness-related Genes for Predicting the Overall survival of Colorectal Cancer Patients

2020 ◽  
Author(s):  
Ran Wei ◽  
Jichuan Quan ◽  
Shuofeng Li ◽  
Zhao Lu ◽  
Xu Guan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
Cancer Stemness ◽  
Poor Overall Survival ◽  
Tissue Samples ◽  
Cox Regression Analysis ◽  
Rna Methylation ◽  
M6a Rna Methylation

Abstract Background: Cancer stem cells (CSCs), which are characterized by self-renewal and plasticity, are highly correlated with tumor metastasis and drug resistance. To fully understand the role of CSCs in colorectal cancer (CRC), we evaluated the stemness traits and prognostic value of stemness-related genes in CRC.Methods: In this study, the data from 616 CRC patients from The Cancer Genome Atlas (TCGA) were assessed and subtyped based on the mRNA expression-based stemness index (mRNAsi). The correlations of cancer stemness with the immune microenvironment, tumor mutational burden (TMB) and N6-methyladenosine (m6A) RNA methylation regulators were analyzed. Weighted gene co-expression network analysis (WGCNA) was performed to identify the crucial stemness-related genes and modules. Furthermore, a prognostic expression signature was constructed using Lasso-penalized Cox regression analysis. The signature was validated via multiplex immunofluorescence staining of tissue samples in an independent cohort of 48 CRC patients.Results: This study suggests that high mRNAsi scores are associated with poor overall survival in stage Ⅳ CRC patients. Moreover, the levels of TMB and m6A RNA methylation regulators were positively correlated with mRNAsi scores, and low mRNAsi scores were characterized by increased immune activity in CRC. The analysis identified 2 key modules and 34 key genes as prognosis-related candidate biomarkers. Finally, a 3-gene prognostic signature (PARPBP, KNSTRN and KIF2C) was explored together with specific clinical features to construct a nomogram, which was successfully validated in an external cohort. Conclusions: There is a unique correlation between CSCs and the prognosis of CRC patients, and the novel biomarkers related to cell stemness could accurately predict the clinical outcomes of these patients.

Application of Restriction Site-Associated DNA Sequencing (RAD-Seq) for Copy Number Variation and Triploidy Detection in Human

2021 ◽  
pp. 1-8
Author(s):  
Jian-Chun He ◽  
Shao-Ying Li ◽  
Wen-Zhi He ◽  
Jia-Jia Xian ◽  
Xiao-Yan Ma ◽  
...  
Keyword(s):  
Dna Sequencing ◽  
Cell Lines ◽  
Genome Sequencing ◽  
Copy Number ◽  
Restriction Site ◽  
Chromosomal Abnormalities ◽  
Copy Number Variations ◽  
Str Analysis ◽  
Tissue Samples ◽  
Low Pass

At present, low-pass whole-genome sequencing (WGS) is frequently used in clinical research and in the screening of copy number variations (CNVs). However, there are still some challenges in the detection of triploids. Restriction site-associated DNA sequencing (RAD-Seq) technology is a reduced-representation genome sequencing technology developed based on next-generation sequencing. Here, we verified whether RAD-Seq could be employed to detect CNVs and triploids. In this study, genomic DNA of 11 samples was extracted employing a routine method and used to build libraries. Five cell lines of known karyotypes and 6 triploid abortion tissue samples were included for RAD-Seq testing. The triploid samples were confirmed by STR analysis and also tested by low-pass WGS. The accuracy and efficiency of detecting CNVs and triploids by RAD-Seq were then assessed, compared with low-pass WGS. In our results, RAD-Seq detected 11 out of 11 (100%) chromosomal abnormalities, including 4 deletions and 1 aneuploidy in the purchased cell lines and all triploid samples. By contrast, these triploids were missed by low-pass WGS. Furthermore, RAD-Seq showed a higher resolution and more accurate allele frequency in the detection of triploids than low-pass WGS. Our study shows that, compared with low-pass WGS, RAD-Seq has relatively higher accuracy in CNV detection at a similar cost and is capable of identifying triploids. Therefore, the application of this technique in medical genetics has a significant potential value.

Phenotypes Associated with 16p11.2 Copy Number Gains and Losses at a Single Institution

2020 ◽  
Vol 51 (6) ◽  
pp. 642-648
Author(s):  
Caleb Chu ◽  
Haotian Wu ◽  
Fangling Xu ◽  
Joseph W Ray ◽  
Allison Britt ◽  
...  
Keyword(s):  
Behavioral Problems ◽  
Copy Number ◽  
Copy Number Variations ◽  
Molecular Diagnostic ◽  
Segmental Duplications ◽  
Diagnostic Laboratory ◽  
University Of Texas ◽  
Recombination Hotspots ◽  
Study Results ◽  
Gains And Losses

Abstract Chromosome 16p11.2 is one of the susceptible sites for recurrent copy number variations (CNVs) due to flanking near-identical segmental duplications. Five segmental duplications, named breakpoints 1 to 5 (BP1–BP5), have been defined as recombination hotspots within 16p11.2. Common CNVs on 16p11.2 include a proximal ~593 kb between BP4 and BP5, and a distal ~220 kb between BP2 and BP3. We performed a search for patients carrying 16p11.2 CNVs, as detected using chromosome microarray (CMA), in the Molecular Diagnostic Laboratory at the University of Texas Medical Branch (UTMB), in Galveston. From March 2013 through April 2018, a total of 1200 CMA results were generated for germline testing, and 14 patients tested positive for 16p11.2 CNVs, of whom 7 had proximal deletion, 2 had distal deletion, 4 had proximal duplication, and 1 had distal duplication. Herein, we provide detailed phenotype data for these patients. Our study results show that developmental delay, abnormal body weight, behavioral problems, and hypotonia are common phenotypes associated with 16p11.2 CNVs.

Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer

2018 ◽  
Vol 71 (9) ◽  
pp. 787-794 ◽  
Author(s):  
Stephanie Robertson ◽  
Gustav Stålhammar ◽  
Eva Darai-Ramqvist ◽  
Mattias Rantalainen ◽  
Nicholas P Tobin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Overall Survival ◽  
Survival Data ◽  
Prognostic Value ◽  
Molecular Subtype ◽  
Axillary Lymph Node Metastasis ◽  
Axillary Lymph ◽  
Poor Overall Survival ◽  
Breast Tumours

AimsThe accuracy of biomarker assessment in breast pathology is vital for therapy decisions. The therapy predictive and prognostic biomarkers oestrogen receptor (ER), progesterone receptor, HER2 and Ki67 may act as surrogates to gene expression profiling of breast cancer. The aims of this study were to investigate the concordance of consecutive biomarker assessment by immunocytochemistry on preoperative fine-needle aspiration cytology versus immunohistochemistry (IHC) on the corresponding resected breast tumours. Further, to investigate the concordance with molecular subtype and correlation to stage and outcome.MethodsTwo retrospective cohorts comprising 385 breast tumours with clinicopathological data including gene expression-based subtype and up to 10-year overall survival data were evaluated.ResultsIn both cohorts, we identified a substantial variation in Ki67 index between cytology and histology and a switch between low and high proliferation within the same tumour in 121/360 cases. ER evaluations were discordant in only 1.5% of the tumours. From cohort 2, gene expression data with PAM50 subtype were used to correlate surrogate subtypes. IHC-based surrogate classification could identify the correct molecular subtype in 60% and 64% of patients by cytology (n=63) and surgical resections (n=73), respectively. Furthermore, high Ki67 in surgical resections but not in cytology was associated with poor overall survival and higher probability for axillary lymph node metastasis.ConclusionsThis study shows considerable differences in the prognostic value of Ki67 but not ER in breast cancer depending on the diagnostic method. Furthermore, our findings show that both methods are insufficient in predicting true molecular subtypes.

scholarly journals Copy Number Variations Analysis Identifies QPRT as a Candidate Gene Associated With Susceptibility for Solitary Functioning Kidney

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao Y. Zhou ◽  
Hao Y. Zheng ◽  
Li Han ◽  
Yan Wang ◽  
Li Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Candidate Gene ◽  
Copy Number ◽  
Copy Number Variations ◽  
Renal Tubules ◽  
Human Embryonic Kidney ◽  
Solitary Functioning Kidney ◽  
Triple X Syndrome ◽  
Pathogenic Cnvs ◽  
Functioning Kidney

BackgroundThe lack of understanding of molecular pathologies of the solitary functioning kidney makes improving and strengthening the continuity of care between pediatric and adult nephrological patients difficult. Copy number variations (CNVs) account for a molecular cause of solitary functioning kidney, but characterization of the pathogenic genes remains challenging.MethodsIn our prospective cohort study, 99 fetuses clinically diagnosed with a solitary functioning kidney were enrolled and evaluated using chromosomal microarray analysis (CMA). The genetic drivers for the pathogenic CNVs were analyzed. We characterized QPRT localization in fetal kidneys using immunohistochemistry and its expression in adult kidneys using quantitative RT-PCR. Further, QPRT was knocked down using siRNA in human embryonic kidney (HEK293T) cells, and the cell cycle and proliferation were tested.ResultsBesides one Triple X syndrome and one Down syndrome, we identified a total of 45 CNVs out of 34 subjects. Among the 14 pathogenic CNVs, CNV 16p11.2 reached the highest number of records with the phenotype of kidney anomalies in the Decipher database. Among the 26 genes within the 16p11.2 region, as a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, QPRT was distinctly localized in renal tubules but was barely observed in renal interstitial and glomeruli in fetal kidneys. The loss of QPRT prevented cells’ efficient transition into S phase, affected cell-cycle progression, and abrogated proliferation of human embryonic kidney cells.ConclusionOur data suggest that QPRT is a candidate gene associated with susceptibility for solitary functioning kidney. The CNVs discovered in our study exhibit great potential for future applications in genetic counseling and pregnancy management.

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

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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