scholarly journals Multiple-level copy number variations in circulating cell-free DNA for prognostic prediction of hepatocellular carcinoma with radical treatments

2020 ◽  
Author(s):  
Yang Wang ◽  
Xiangxu Wang ◽  
Kaixiang Zhou ◽  
Yang Liu ◽  
Zhenyuan Bian ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Copy Number Variations ◽  
Prognostic Biomarkers ◽  
Multiple Level ◽  
Circulating Free Dna ◽  
Free Dna ◽  
Kaplan Meier ◽  
Genome Wide ◽  
Low Coverage

Abstract Background Copy number variations (CNVs) in circulating free DNA (cfDNA) are emerging as minimally invasive prognostic biomarkers for various cancers. However, little has been reported on the multiple-level analysis of cfDNA CNVs for hepatocellular carcinoma (HCC) patients with radical treatments. Methods Here, CNVs at genome-wide, chromosomal-arm and bin levels were analyzed in cfDNA from 117 HCC patients receiving radical treatments via low-coverage whole genome sequencing. Then, the relationship between cfDNA CNVs and clinical outcomes was explored. Our results showed that a concordant profile of CNVs was observed between cfDNA and tumor tissue DNA. Three genome-wide CNV indicators including tumor fraction (TFx), prediction score (P-score) and stability score (S-score) were calculated based on genome-wide cfDNA CNVs. Results Kaplan-Meier analysis showed that the patients with high TFx, P-score and S-score exhibited a significantly poorer overall survival (OS) and recurrence free survival (RFS) than those with low TFx, P-score and S-score, respectively (All P < 0.05). Furthermore, a group of high frequency cfDNA CNVs at chromosomal-arm level including loss of 4q, 17p, 19p and the gain of 8q, 1q clearly predicted prognosis of HCC patients. Finally, a bin-level risk score was constructed based on three most relevant prognostic bin regions identified by a LASSO model. Patients with high bin-score had a significantly poorer OS than those with low bin-score (P < 0.001). Conclusion Altogether, our study indicates that the multiple-level cfDNA CNVs are significantly associated with OS and RFS in HCC patients with radical treatments, suggesting that cfDNA CNVs detected by low-coverage WGS may be used as potential prognostic biomarkers of HCC patients.

scholarly journals Copy number variations of MMP-9 are prognostic biomarkers for hepatocellular carcinoma

2020 ◽  
Vol 9 (2) ◽  
pp. 698-706
Author(s):  
Xi Yu ◽  
Jing Huang ◽  
Shengdong Wu ◽  
Yi Huang ◽  
Yuying Shan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Copy Number Variations ◽  
Prognostic Biomarkers

scholarly journals Multiple‐level copy number variations in cell‐free DNA for prognostic prediction of HCC with radical treatments

2021 ◽  
Author(s):  
Yang Wang ◽  
Kaixiang Zhou ◽  
Xiangxu Wang ◽  
Yang Liu ◽  
Dongnan Guo ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Multiple Level ◽  
Cell Free Dna ◽  
Free Dna ◽  
Prognostic Prediction

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

scholarly journals Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

2021 ◽  
Vol 9 (5) ◽  
pp. e001942
Author(s):  
Xu Yang ◽  
Ying Hu ◽  
Keyan Yang ◽  
Dongxu Wang ◽  
Jianzhen Lin ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Outcome ◽  
Risk Score ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Copy Number Variations ◽  
Risk Scores ◽  
Free Dna

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.ResultsBased on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).ConclusionsThe CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.

scholarly journals Genome-wide copy number variations as molecular diagnostic tool for cutaneous intermediate melanocytic lesions: a systematic review and individual patient data meta-analysis

2021 ◽  
Author(s):  
Chiel F. Ebbelaar ◽  
Anne M. L. Jansen ◽  
Lourens T. Bloem ◽  
Willeke A. M. Blokx
Keyword(s):  
Systematic Review ◽  
Sensitivity And Specificity ◽  
Copy Number ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Copy Number Variations ◽  
Patient Data ◽  
Melanocytic Lesions ◽  
Genome Wide ◽  
Malignant Lesions

AbstractCutaneous intermediate melanocytic neoplasms with ambiguous histopathological features are diagnostically challenging. Ancillary cytogenetic techniques to detect genome-wide copy number variations (CNVs) might provide a valuable tool to allow accurate classification as benign (nevus) or malignant (melanoma). However, the CNV cut-off value to distinguish intermediate lesions from melanoma is not well defined. We performed a systematic review and individual patient data meta-analysis to evaluate the use of CNVs to classify intermediate melanocytic lesions. A total of 31 studies and 431 individual lesions were included. The CNV number in intermediate lesions (median 1, interquartile range [IQR] 0–2) was significantly higher (p<0.001) compared to that in benign lesions (median 0, IQR 0–1) and lower (p<0.001) compared to that in malignant lesions (median 6, IQR 4–11). The CNV number displayed excellent ability to differentiate between intermediate and malignant lesions (0.90, 95% CI 0.86–0.94, p<0.001). Two CNV cut-off points demonstrated a sensitivity and specificity higher than 80%. A cut-off of ≥3 CNVs corresponded to 85% sensitivity and 84% specificity, and a cut-off of ≥4 CNVs corresponded to 81% sensitivity and 91% specificity, respectively. This individual patient data meta-analysis provides a comprehensive overview of CNVs in cutaneous intermediate melanocytic lesions, based on the largest pooled cohort of ambiguous melanocytic neoplasms to date. Our meta-analysis suggests that a cut-off of ≥3 CNVs might represent the optimal trade-off between sensitivity and specificity in clinical practice to differentiate intermediate lesions from melanoma.

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