Genomic variations in plasma cell free DNA differentiate early stage lung cancers from normal controls

Xia, Shu; Huang, Chiang Ching; Le, Min; Dittmar, Rachel L.; Du, Meijun; Yuan, Tiezheng; Guo, Yanning; Wang, Yuan; Wang, Xuexia; Tsai, Susan; Suster, Saul; Mackinnon, Alexander C.; Wang, Liang

doi:10.1016/j.lungcan.2015.07.002

Cited by 39 publications

(29 citation statements)

References 33 publications

(10 reference statements)

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“…For instance, in a study to compare NGS results from plasma cfDNA and tumor samples using whole genome sequencing and targeted NGS, Xia et al developed a plasma genomic abnormality (PGA) score to reflect mutational status and tumor burden. Patients with lung cancer had a higher plasma cfDNA concentration (4.9 ng per 400 μL, range 2.25-26.98 ng per 400 μL versus 2.32 ng per 400 μL, range 1.30-2.81 ng per 400 μL) and a higher PGA score (19.50, range 5.89-64.47 versus 9.28, range 7.38-11.08) than control patients, and targeted NGS revealed 14 point mutations in 12 genes in solid tumor tissue [65]. Also, to determine the mutations found in plasma and serum cfDNA samples of NSCLC patients, Paweletz et al developed a targeted NGS panel for 11 oncogenes commonly associated with NSCLC.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

et al. 2016

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Personalized medicine has emerged as the future of cancer care to ensure that patients receive individualized treatment specific to their needs. In order to provide such care, molecular techniques that enable oncologists to diagnose, treat, and monitor tumors are necessary. In the field of lung cancer, cell free DNA (cfDNA) shows great potential as a less invasive liquid biopsy technique, and next-generation sequencing (NGS) is a promising tool for analysis of tumor mutations. In this review, we outline the evolution of cfDNA and NGS and discuss the progress of using them in a clinical setting for patients with lung cancer. We also present an analysis of the role of cfDNA as a liquid biopsy technique and NGS as an analytical tool in studying EGFR and MET, two frequently mutated genes in lung cancer. Ultimately, we hope that using cfDNA and NGS for cancer diagnosis and treatment will become standard for patients with lung cancer and across the field of oncology.

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Section: Next-generation Sequencingmentioning

confidence: 99%

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

et al. 2016

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“…This phenomenon was previously reported as an accidental finding in a lung cancer patient who received neoadjuvant treatment during ccfDNA sampling [26]. Here, the finding was hypothetically explained by rapid tumor shrinkage leading to de-attachment of tumor from adjacent blood supply, and thus to limited release of ccfDNA into the blood stream.…”

Section: Discussionmentioning

confidence: 67%

“…Recently, advances in next-generation sequencing (NGS) have enabled whole-genome/exome sequencing (WGS, WES) of ccfDNA and depicted complex tumor profiles from ccfDNA [4], [14]. NGS has also been applied for detection of particular somatic copy number alterations (SCNAs) [11], [21] or genome-wide SCNA profiles [19], [26] in tumor samples, as well as, in plasma [10]. Even though advances in bioinformatics in principle allow for transformation of sequencing reads into quantitative assessment of copy numbers, the derived SCNAs are sensitive to the quality of the ccfDNA and the choice of processing algorithms and thresholds [10].…”

Section: Introductionmentioning

confidence: 99%

Detection of copy number alterations in cell-free tumor DNA from plasma

2017

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BackgroundSomatic copy number alterations (SCNAs) occurring in tumors can provide information about tumor classification, patient's outcome or treatment targets. Liquid biopsies, incl. plasma samples containing circulating cell-free tumor DNA (ccfDNA) can be used to assess SCNAs for clinical purposes, however specify and reliability of methods have to be tested.MethodsSNP microarrays (Affymetrix) were used to generate whole-genome copy number profiles from plasma ccfDNA (OncoScan) and paired tumor biopsies (CytoScan) from ten patients with metastatic cancers. Numerical, segmental and focal SCNAs were assessed using ASCAT/TuScan and SNP-FASST2.ResultsAberrations in ccfDNA in 4 patients resembled numerical (76%) and segmental (80%) aberrations in tDNA. Three patients represented low correlation due to postponed sampling time, ccfDNA quality and possible treatment interference. Breakpoints of high-amplitude amplification were assessed with high accuracy and relative breakpoints difference of only 7% (0.02–37%). Similarly, biallelic losses were reliably detected. Array was 100% successful in detection of SCNAs on clinically relevant genes compared to SCNAs in tumor biopsies. Tracking of SCNAs changes during the treatment course of one patient also indicated that apoptosis/necrosis of non-cancerous cells presumably induced by treatment can influence ccfDNA composition and introduce false-negative findings into the analysis of liquid biopsies.ConclusionsGenomic alterations detected in ccfDNA from liquid biopsies by comprehensive SNP array are reliable source for information for stratification of patients for targeted treatment.General significanceClinically relevant SCNAs can be detected in ccfDNA with high resolution and can therefore serve as an alternative to tumor biopsy in defining treatment targets.

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“…Cell‐free DNA extraction was published previously (Xia et al ., ,b). In brief, prior to DNA extraction, samples were removed from the freezer and thawed on ice.…”

Section: Methodsmentioning

confidence: 97%

Cell‐free DNA copy number variations in plasma from colorectal cancer patients

Dittmar

Xia

et al. 2017

Molecular Oncology

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To evaluate the clinical utility of cell‐free DNA (cfDNA), we performed whole‐genome sequencing to systematically examine plasma cfDNA copy number variations (CNVs) in a cohort of patients with colorectal cancer (CRC, n = 80), polyps (n = 20), and healthy controls (n = 35). We initially compared cfDNA yield in 20 paired serum–plasma samples and observed significantly higher cfDNA concentration in serum (median = 81.20 ng, range 7.18–500 ng·mL−1) than in plasma (median = 5.09 ng, range 3.76–62.8 ng·mL−1) (P < 0.0001). However, tumor‐derived cfDNA content was significantly lower in serum than in matched plasma samples tested. With ~10 million reads per sample, the sequencing‐based copy number analysis showed common CNVs in multiple chromosomal regions, including amplifications on 1q, 8q, and 5q and deletions on 1p, 4q, 8p, 17p, 18q, and 22q. Copy number changes were also evident in genes critical to the cell cycle, DNA repair, and WNT signaling pathways. To evaluate whether cumulative copy number changes were associated with tumor stages, we calculated plasma genomic abnormality in colon cancer (PGA‐C) score by summing the most significant CNVs. The PGA‐C score showed predictive performance with an area under the curve from 0.54 to 0.84 for CRC stages I‐IV. Locus‐specific copy number analysis identified nine genomic regions where CNVs were significantly associated with survival in stage III‐IV CRC patients. A multivariate model using six of nine genomic regions demonstrated a significant association of high‐risk score with shorter survival (HR = 5.33, 95% CI = 6.76–94.44, P < 0.0001). Our study demonstrates the importance of using plasma (rather than serum) to test tumor‐related genomic variations. Plasma cfDNA‐based tests can capture tumor‐specific genetic changes and may provide a measurable classifier for assessing clinical outcomes in advanced CRC patients.

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Genomic variations in plasma cell free DNA differentiate early stage lung cancers from normal controls

Cited by 39 publications

References 33 publications

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

Detection of copy number alterations in cell-free tumor DNA from plasma

Cell‐free DNA copy number variations in plasma from colorectal cancer patients

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