Genomic profiling of cell-free circulating tumor DNA in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy

Li, Gerald; Pavlick, Dean C.; Chung, Jon; Bauer, Todd M.; Tan, Bradford A.; Peguero, Julio; Ward, Patrick; Kallab, Andre M.; Bufill, José A.; Hoffman, Ari; Sadiq, Ahad A.; Edenfield, Jeff; He, Jie; Cooke, Matthew; Hughes, Jason D.; Forcier, Brady; Nahas, Michelle; Stephens, Phil; Ali, Siraj M.; Schrock, Alexa B.; Ross, Jeffrey S.; Miller, Vincent A.; Gregg, Jeffrey P.

doi:10.21037/jgo.2019.05.05

Cited by 33 publications

(25 citation statements)

References 26 publications

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“…In our study, 23 (36%) of the 64 mutations that were identified from plasma were undetected in the tumor tissues. In addition, similar discordance rates of 28-84% have been reported in several previous studies (Barata et al, 2017;Chae et al, 2016;Li et al, 2019). A study conducted by Rothwell et al (2019) demonstrated that NGS of cfDNA and patient's corresponding tumor tissues from 39 patients with advanced-stage solid tumor revealed up to 30% of mutations identified from plasma samples were not detected in tumor tissues.…”

Section: Discussionsupporting

confidence: 82%

Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy

et al. 2020

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As the use of next‐generation sequencing (NGS) for plasma cell‐free DNA (cfDNA) continues to expand in clinical settings, accurate identification of circulating tumor DNA mutations is important to validate its use in the clinical management for cancer patients. Here, we aimed to characterize mutations including clonal hematopoiesis (CH)‐related mutations in plasma cfDNA and tumor tissues using the same ultradeep NGS assay and evaluate the clinical significance of CH‐related mutations on the interpretation of liquid biopsy results. Ultradeep targeted NGS using Oncomine Pan‐Cancer Panel was performed on matched surgically resected tumor tissues, peripheral blood cells (PBCs), and 120 plasma cfDNA samples from 38 colorectal cancer patients. The clinical significance of the CH‐related mutations in plasma cfDNA was evaluated by longitudinal monitoring of the postoperative plasma samples. Among the 38 patients, 74 nonsynonymous mutations were identified from tumor tissues and 64 mutations from the preoperative plasma samples. Eleven (17%) of the 64 mutations identified in plasma cfDNA were also detected in PBC DNA and were identified to be CH‐related mutations. Overall, 11 of 38 (29%) patients in this cohort harbored at least one CH‐related mutation in plasma cfDNA. These CH‐related mutations were continuously detected in subsequent postoperative plasma samples from three patients which could be misinterpreted as the presence of residual disease or as lack of treatment response. Our results indicated that it is essential to integrate the mutational information of PBCs to differentiate tumor‐derived from CH‐related mutations in liquid biopsy analysis. This would prevent the misinterpretation of results to avoid misinformed clinical management for cancer patients.

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Section: Discussionsupporting

confidence: 82%

Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy

et al. 2020

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“…DNA extracted from the serum is variably fragmented, but representative sequences with characteristic cancer-related aberrations could reproducibly demonstrate suitable amplification and accurate sequencing (Ma et al, 2017). Recently, there has been consensus in the literature that ctDNA obtained by liquid biopsy is a convenient carrier of the actual genetic composition and is potentially more informative than tissue-derived nucleic acids archived from the time of diagnosis (Li et al, 2019;Remon et al, 2019;Vitiello et al, 2019). Additionally, ctDNA is useful for finding therapeutic targets after several cycles of therapy (Bhangu et al, 2018;Garlan et al, 2017).…”

Section: Using Ctdna To Follow-up Cancer Treatment and Recurrencementioning

confidence: 99%

“…The overall concordance between plasma and matched tumor tissues assessed by NGS is only approximately 25% (Pishvaian et al, 2017). Internal quality control guidelines and ctDNA reference materials are still not available to support strong and reliable liquid biopsy-based cancer diagnostics and followup (Li et al, 2019). To date, there are no cross-platform validations, and therefore, the clinical predictive value of variant detection must be considered with caution (Merker et al, 2018).…”

Section: The "Bottle Neck" Of Ctdna Analysismentioning

confidence: 99%

ctDNA as a Cancer Biomarker: A Broad Overview

Pessôa

Heringer²,

Ferrer

2020

Preprint

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Circulating tumor DNA (ctDNA) in fluids has gained attention because ctDNA seems to identify tumor-specific abnormalities, which could be used for diagnosis, follow-up of treatment, and prognosis: the so-called liquid biopsy. Liquid biopsy is a minimally invasive approach and presents the sum of ctDNA from primary and secondary tumor sites. It has been possible not only to quantify the amount of ctDNA but also to identify (epi)genetic changes. Specific mutations in genes have been identified in the plasma of patients with several types of cancer, which highlights ctDNA as a possible cancer biomarker. However, achieving detectable concentrations of ctDNA in body fluids is not an easy task. ctDNA fragments present a short half-life, and there are no cut-off values to discriminate high and low ctDNA concentrations. Here, we discuss the use of ctDNA as a cancer biomarker, the main methodologies, the inherent difficulties, and the clinical predictive value of ctDNA.

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“…Additionally, liquid biopsies may allow the capturing of ctDNA released from multiple tumor regions and could reflect intratumoral-heterogeneity that might be missed in tissue biopsy [ 28 , 29 ]. The development of next-generation sequencing (NGS) has assisted the validation of clinical applications of ctDNA in cancer management, including, tumor profiling [ 30 , 31 ], early cancer detection [ 32 , 33 ], minimal residual disease detection [ 34 , 35 ] and treatment monitoring [ 36 , 37 , 38 ].…”

Section: Circulating Cell-free Dna (Cfdna) and Circulating Tumor Dmentioning

confidence: 99%

Clonal Hematopoiesis in Liquid Biopsy: From Biological Noise to Valuable Clinical Implications

Chan

Chin

Nakamura

et al. 2020

Cancers

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The use of blood liquid biopsy is being gradually incorporated into the clinical setting of cancer management. The minimally invasive nature of the usage of cell-free DNA (cfDNA) and its ability to capture the molecular alterations of tumors are great advantages for their clinical applications. However, somatic mosaicism in plasma remains an immense challenge for accurate interpretation of liquid biopsy results. Clonal hematopoiesis (CH) is part of the normal process of aging with the accumulation of somatic mutations and clonal expansion of hematopoietic stem cells. The detection of these non-tumor derived CH-mutations has been repeatedly reported as a source of biological background noise of blood liquid biopsy. Incorrect classification of CH mutations as tumor-derived mutations could lead to inappropriate therapeutic management. CH has also been associated with an increased risk of developing cardiovascular disease and hematological malignancies. Cancer patients, who are CH carriers, are more prone to develop therapy-related myeloid neoplasms after chemotherapy than non-carriers. The detection of CH mutations from plasma cfDNA analysis should be cautiously evaluated for their potential pathological relevance. Although CH mutations are currently considered as “false-positives” in cfDNA analysis, future studies should evaluate their clinical significance in healthy individuals and cancer patients.

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Genomic profiling of cell-free circulating tumor DNA in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy

Cited by 33 publications

References 26 publications

Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy

Clinical significance of clonal hematopoiesis in the interpretation of blood liquid biopsy

ctDNA as a Cancer Biomarker: A Broad Overview

Clonal Hematopoiesis in Liquid Biopsy: From Biological Noise to Valuable Clinical Implications

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