Genome-Wide Analysis of Circulating Cell-Free DNA Copy Number Detects Active Melanoma and Predicts Survival

Silva, Shobha; Danson, Sarah; Teare, M. Dawn; Taylor, Fiona; Bradford, James R.; McDonagh, A.J.G.; Salawu, Abdulazeez; Wells, Greg; Burghel, George J.; Brock, Ian W.; Connley, Daniel; Cramp, Helen; Hughes, D. E.; Tiffin, Nick; Cox, Angela

doi:10.1373/clinchem.2018.290023

Cited by 9 publications

(5 citation statements)

References 28 publications

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“…Similarly, we showed that in SKCM, the CN gain of PDGFRA pathway caused a lower enrichment of multiple immune cell subpopulations, resulting in worse survival. It has been demonstrated that while the immune microenvironment is critical to the treatment of SKCM patients, CNV has the potential of being a biomarker for active melanoma disease and survival (Silva et al 2018 ; Pozniak et al 2019 ). Overall, the present study not only prove the previous observations, but also provide new insights into mechanisms underlying the effects of PDGFRA pathway CN gain on the immune microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Liu

Shan

et al. 2022

Mol Genet Genomics

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We investigated the copy number variation (CNV) of PDGFRA pathway across all common cancer types as well as its clinical relevance. This study included a total of 10,678 patients with pan-cancerous species involving 33 types of cancers and patient information was obtained from The Cancer Genome Atlas. According to the PDGFRA pathway CNV, all samples were divided into copy number gain (CN gain) group and No CN gain group. The analysis of loss of heterozygosity (LOH) fraction, CNV burden, tumor mutation burden (TMB), and the number of immunogenic mutations were performed, as well as the correlation analysis of PDGFRA pathway CN gain with tumor-related signaling pathways and tumor-infiltrating immune cell subpopulations. The results showed that CN gain of PDGFRA pathway in the cancer patients was associated with significantly shorter overall survival. The CN gain of PDGFRA pathway was identified as a prognostic risk factor for some tumors. CN gain was accompanied by an altered percentage of LOH, CNV burden, TMB, the number of immunogenic mutations were increased and tumor-infiltrating immune cell subpopulations were less. While certain tumor-related signaling pathways, such as hypoxia, cell cycle, DNA repair, and epithelial-mesenchymal transition were more enriched in the CN gain group, quiescence, and inflammation pathways were more enriched in the No CN gain group. In conclusion, PDGFRA pathway CNV gain may be a poor prognostic factor in cancer patients.

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Section: Discussionmentioning

confidence: 99%

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Liu

Shan

et al. 2022

Mol Genet Genomics

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“…Numerous studies have shown that ctDNA profiling was able to identify and track cancerspecific mutations, which is helpful in diagnosis, prediction of prognosis, and treatment response, and guiding personalized therapeutics [11,[13][14][15]. Emerging evidence suggested the ability of genome-wide or exome-wide ctDNA sequencing to capture genetic diversity including aberrations of copy number and chromosome structure in addition to single nucleotide variants [16,17].…”

Section: Introductionmentioning

confidence: 99%

Genome‐wide profiling of circulating tumor DNA depicts landscape of copy number alterations in pancreatic cancer with liver metastasis

Tao

Zhang

et al. 2020

Molecular Oncology

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We used whole‐genome sequencing of cell‐free DNA (cfDNA) to obtain copy number alteration (CNA) profiles from the plasma of patients with metastatic pancreatic cancer (PC). These profiles were compared with TCGA‐derived CNA profiles of primary pancreatic tumors. CNA analysis enabled the prediction of tumor burden and tumor prognosis, and assessment of therapeutic response and clonal evolution.

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“…In this study, we developed an algorithm that utilized cfDNA LD-WGS data to differentiate between benign and malignant pulmonary nodules. Cancer-associated CNAs have been detected in the cfDNA of patients with cancer, underscoring their potential clinical applications for the screening, early detection, and monitoring of human cancer (23,24,(42)(43)(44). However, CNAs only reflect copy number variation relative to normal controls in some specific locations in the genome.…”

Section: Discussionmentioning

confidence: 99%

A novel approach for the non-invasive diagnosis of pulmonary nodules using low-depth whole-genome sequencing of cell-free DNA

Zhang¹,

Liang²,

Liu³

et al. 2022

Transl Lung Cancer Res

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Background: Differentiating between benign and malignant pulmonary nodules is a diagnostic challenge, and inaccurate detection can result in unnecessary invasive procedures. Cell-free DNA (cfDNA) has been successfully utilized to detect various solid tumors. In this study, we developed a genome-wide approach to explore the characteristics of cfDNA sequencing reads obtained by low-depth whole-genome sequencing (LD-WGS) to diagnose pulmonary nodules.Methods: LD-WGS was performed on cfDNA extracted from 420 plasma samples from individuals with pulmonary nodules that were no more than 30 mm in diameter, as determined by computed tomography (CT). The sequencing read distribution patterns of cfDNA were analyzed and used to establish a model for distinguishing benign from malignant pulmonary nodules.Results: We proposed the concept of weighted reads distribution difference (WRDD) based on the copy number alterations (CNAs) of cfDNA to construct a benign and malignant diagnostic (BEMAD) algorithm model. In a training cohort of 360 plasma samples, the model achieved an average area under the receiver operating characteristic (ROC) curve (AUC) value of 0.84 in 10-fold cross-validation. The model was validated in an independent cohort of 60 plasma samples, obtaining an AUC value of 0.87. The BEMAD model could distinguish benign from malignant nodules at a sensitivity of 74% and a specificity of 86%.Furthermore, analysis of the critical features of the cfDNA using the BEMAD model identified repeat regions that were associated with microsatellite instability, which is an important indicator of tumorigenesis.

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Genome-Wide Analysis of Circulating Cell-Free DNA Copy Number Detects Active Melanoma and Predicts Survival

Abstract: This study demonstrates the potential of a de novo approach utilizing copy-number profiling of cfDNA as a biomarker of active disease and survival in melanoma. Longitudinal analysis of copy-number profiles as an early marker of relapsed disease is warranted.

Cited by 9 publications

References 28 publications

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Characterization and clinical relevance of PDGFRA pathway copy number variation gains across human cancers

Genome‐wide profiling of circulating tumor DNA depicts landscape of copy number alterations in pancreatic cancer with liver metastasis

A novel approach for the non-invasive diagnosis of pulmonary nodules using low-depth whole-genome sequencing of cell-free DNA

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