Detection of mutations in circulating cell‐free DNA in relation to disease stage in colorectal cancer

Liebs, Sandra; Keilholz, Ulrich; Kehler, Inge; Schweiger, Caroline; Haybäck, Johannes; Nonnenmacher, Anika

doi:10.1002/cam4.2219

Cited by 37 publications

(42 citation statements)

References 22 publications

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“…Thus, specificity is affected to some extent. Therefore, nucleic acid markers are now largely developed towards based on their biology, such as methylation 35,36 and mutation, [37][38][39] to provide insight into treatment choice or potential drug resistance. As complete cells, CTCs can provide all the same information as nucleic acids.…”

Section: Discussionmentioning

confidence: 99%

<p>Dynamic Changes in Serum Markers and Their Utility in the Early Diagnosis of All Stages of Hepatitis B-Associated Hepatocellular Carcinoma</p>

Wu¹,

Liu²,

Li³

et al. 2020

OTT

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Objective: This study aimed to evaluate the individual and combined diagnostic values of serum alpha-fetoprotein (AFP), des-gamma-carboxyprothrombin (DCP), glypican-3 (GPC3) and golgi protein 73 (GP73) in diagnosing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods: Participants from Beijing YouAn Hospital were enrolled and divided into seven groups. Serum was collected and the levels of AFP, GPC3, GP73 and DCP were simultaneously measured with a protein array. Pearson's χ 2 test was applied to compare the clinicopathological characteristics. Receiver operating characteristic (ROC) curves were used to analyse the diagnostic performance of the four markers. Results: As a single biomarker for differentiating HCC from all controls, AFP had a larger area under the curve (AUC) (0.798, 95% CI (0.754-0.838) than the other biomarkers, with a sensitivity of 77.3% and a specificity of 71.1%. Among the other combinations, AFP plus GPC3 and DCP (0.871, 95% CI (0.833-0.903)) was the best at differentiating HCC from all controls. In discriminating very early stage and early stage HCC from all controls, the AUC of GPC3 (0.744, 95% CI (0.690-0.793); sensitivity 62.8%; specificity 83.3%) was better than that of AFP (0.723, 95% CI (0.668-0.774); sensitivity 67.3%; specificity 71.7%). Among all biomarker combinations, the combination of AFP, GPC3 and GP73 had the largest AUC (0.843, 95% CI (0.796-0.883); sensitivity 84.1%; specificity 71.7%). AFP (AUC 0.726, 95% CI (0.662-0.784)) showed the best performance in the very early diagnosis of HBV-related HCC. Conclusion: As a single biomarker, AFP has an advantage in the very early and early diagnosis of HBV-related HCC. The combination of AFP, GPC3 and GP73 is the most suitable marker for the early diagnosis of HBV-related HCC. However, AFP remains the best biomarker for the very early diagnosis of HBV-related HCC, and the adding of one or more markers does not significantly improve the diagnostic accuracy.

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Section: Discussionmentioning

confidence: 99%

<p>Dynamic Changes in Serum Markers and Their Utility in the Early Diagnosis of All Stages of Hepatitis B-Associated Hepatocellular Carcinoma</p>

Wu¹,

Liu²,

Li³

et al. 2020

OTT

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“…Therefore, it is vital to detect these gene mutations in an individualized manner. We believe this strategy can support the establishment of reasonable treatment plan for each patient (11)(12)(13)(14).…”

Section: Discussionmentioning

confidence: 83%

Circulating Tumor DNA Is Capable of Monitoring the Therapeutic Response and Resistance in Advanced Colorectal Cancer Patients Undergoing Combined Target and Chemotherapy

Cao

Liu²,

Chen

et al. 2020

Front. Oncol.

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Colorectal cancer (CRC) is a highly lethal disease worldwide. The majority of patients receiving targeted therapy or chemotherapy develop drug resistance, while its molecular mechanism remains to be elucidated. The plasma circulating tumor DNA (ctDNA) exhibited the potential in identifying gene variations and monitoring drug resistance in CRC treatment. In this study, we monitored the ctDNA mutational changes in advanced CRC patients underwent first-line therapy with bevacizumab and cetuximab combined with chemotherapy. The mutation spectrum of 43 patients was established by a 605gene next-generation sequencing (NGS) panel. The baseline measurement shows that genes with the highest mutation frequency were TP53 (74%), APC (58%), KRAS (40%), SYNE1 (33%), LRP1B (23%), TOP1 (23%), and PIK3CA (21%). Mutations in TP53, APC, and KRAS were detected in 29 paired plasma and tissue samples with the consistency of 81, 67, and 42%, respectively. Clinically targetable gene mutations, such as APC, RNF43, SMAD4, BRAD1, KRAS, RAF1, and TP53, were also identified in ctDNA. The overall consistency between ctDNA and tissue samples was 54.6%. Alleviation of mutational burden in BRAF, KRAS, AMER1, and other major driving genes was observed following the first-line therapy. Patients with KRAS and TP53 mutations in tissues appeared to benefit more than the wild-type counterpart. The dynamic change of plasma mutation status was consistent with the tissue tumor burden and was closely correlated with disease progression. In conclusion, ctDNA monitoring is a useful method for molecular genotyping of colorectal cancer patients. Dynamic changes in resistance can be sensitively monitored by gene variation status, which potentially helps to develop treatment strategy.

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“…Results of this study indicate that the fractionation of cfDNA from CRC patients offers sensitive genetic detection by dPCR and NGS analysis, which would provide a less-invasive method to obtain the genetic tumor profiles. The sensitivity of cfDNA in detecting tumor mutations is currently reported to be 51-97% with digital PCR (dPCR) 13,18,19,[24][25][26][27]39 and 35-86% with NGS. 19,22,23,28,40,41 In our study, the sensitivity in detecting mutations in cfDNA from serum using dPCR was 85% and 93% when cut-off values of MAFs were set at >0% and >0.1%, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, liquid biopsy, a process that identifies the presence of tumor genetic abnormalities using cell-free DNA (cfDNA), [9][10][11] circulating tumor cells, [12][13][14] and microRNA [15][16][17] that are extracted from body fluids such as plasma, serum, and urine, is gaining significant attention because of its less-invasive method to obtain genetic profiles. 11 In fact, and owing to its profound advantages, liquid biopsy is expected to be used clinically in cases such as early tumors detection, 18,19 tumor monitoring, [20][21][22][23][24] treatment effect prediction, 20 detection of drug resistance, and as a sensitivity marker. 18,21,[25][26][27][28] cfDNA normally exists in blood at a length of approximately 170 bp.…”

Section: Introductionmentioning

confidence: 99%

“…11 In fact, and owing to its profound advantages, liquid biopsy is expected to be used clinically in cases such as early tumors detection, 18,19 tumor monitoring, [20][21][22][23][24] treatment effect prediction, 20 detection of drug resistance, and as a sensitivity marker. 18,21,[25][26][27][28] cfDNA normally exists in blood at a length of approximately 170 bp. Furthermore, it is bound to histones, and its half time in blood is reported to be 16 minutes to several hours.…”

Section: Introductionmentioning

confidence: 99%

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Fractionated small cell‐free DNA increases possibility to detect cancer‐related gene mutations in advanced colorectal cancer

et al. 2020

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Background and Aim: Liquid biopsy is a method that can efficiently detect tumor genetic abnormalities from body fluids such as blood and urine. Detection sensitivity and the available number of mutations in cell-free DNA (cfDNA) are limited. In this study, we develop a highly sensitive and comprehensive method to detect mutations from cfDNA by concentrating tumor fractions of small cfDNA in advanced colorectal cancers. Methods: Biopsied specimens and 37 serum samples were collected from 27 patients with advanced colorectal carcinoma. A serum-extracted cfDNA was divided into enriched fractionated small cfDNA and unfractionated cfDNA. Both cfDNAs were subjected to digital polymerase chain reaction (PCR) to evaluate their KRAS, BRAF, CDKN2A, and TP53 status. Consequently, their mutant allele frequencies (MAFs) were compared and analyzed by next-generation sequencing (NGS) in conjunction with tissue-derived DNA. Results: NGS analyses revealed mutations in TP53 (63%), KRAS (63%), APC (30%), and PIK3CA (22%). Digital PCR could detect mutations in 25 of 27 samples (93%) of unfractionated cfDNA, a rate that increased to 100% when samples were enriched with fractionated small cfDNA (6.8 vs 10.7%, P < 0.001). NGS also showed increased MAFs in fractionated small cfDNA compared to unfractionated cfDNA (16.3 vs 18.8%, P = 0.012) and a tendency to detect a greater number of cancerrelated genes in fractionated cfDNA. Conclusions: Fractionated small cfDNA increased MAFs of gene mutations and increases the possibilities to detect cancer-related genes even in advanced cancer patients from whom it is difficult to obtain tissue samples.

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Detection of mutations in circulating cell‐free DNA in relation to disease stage in colorectal cancer

Cited by 37 publications

References 22 publications

<p>Dynamic Changes in Serum Markers and Their Utility in the Early Diagnosis of All Stages of Hepatitis B-Associated Hepatocellular Carcinoma</p>

<p>Dynamic Changes in Serum Markers and Their Utility in the Early Diagnosis of All Stages of Hepatitis B-Associated Hepatocellular Carcinoma</p>

Circulating Tumor DNA Is Capable of Monitoring the Therapeutic Response and Resistance in Advanced Colorectal Cancer Patients Undergoing Combined Target and Chemotherapy

Fractionated small cell‐free DNA increases possibility to detect cancer‐related gene mutations in advanced colorectal cancer

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