Feasibility of multiplexed gene mutation detection in plasma samples of colorectal cancer patients by mass spectrometric genotyping

Shin, Su‐Jin; Chun, Sung-Min; Kim, Tae Im; Kim, Yu Jin; Choi, Hyun-Jeung; Jang, Se Jin; Kim, Jihun

doi:10.1371/journal.pone.0176340

Cited by 17 publications

(22 citation statements)

References 30 publications

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“…Pre- and post-operative ctDNA levels have also been evaluated for clinical utility in determining survival. Shin et al assessed KRAS mutations in 62 stage III/IV CRC patients undergoing surgery and found a higher rate of ctDNA mutation detection in patients with metastases, and that detectable ctDNA KRAS mutations correlated with a shorter overall survival ( p = 0.03) ( 97 ).…”

Section: Ctdna Biomarkers For Prognosis Of Colorectal Cancermentioning

confidence: 99%

The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers

Saluja

Karapetis

Pedersen³

et al. 2018

Front. Oncol.

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Gastrointestinal cancers, including oesophageal, gastric and colorectal cancers (CRC) have high rates of disease recurrence despite curative resection. There are a number of recent studies that have investigated the use of circulating tumor DNA (ctDNA) for prognostic value in these cancers. We reviewed studies that had been published prior to March 2018 that assessed the prognostic values of ctDNA in patients with oesophageal and gastric cancers, gastrointestinal stromal tumors (GIST) and CRC. We identified 63 eligible clinical studies that focussed on recurrence and survival. Studies assessed investigated various ctDNA biomarkers in patients with different stages of cancer undergoing surgical resection, chemotherapy and no treatment. For oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, methylation of certain genes such as APC and DAPK have been highlighted as promising biomarkers for prognostication, but these studies are limited and more comprehensive research is needed. Studies focusing on gastric cancer patients showed that methylation of ctDNA in SOX17 and APC were independently associated with poor survival. Two studies demonstrated an association between ctDNA and recurrence and survival in GIST patients, but more studies are needed for this type of gastrointestinal cancer. A large proportion of the literature was on CRC which identified both somatic mutations and DNA methylation biomarkers to determine prognosis. ctDNA biomarkers that identified somatic mutations were more effective if they were personalized based on mutations found in the primary tumor tissue, but ctDNA methylation studies identified various biomarkers that predicted increased risk of recurrence, poor disease free survival and overall survival. While the use of non-invasive ctDNA biomarkers for prognosis is promising, larger studies are needed to validate the clinical utility for optimizing treatment and surveillance strategies to reduce mortality from gastrointestinal cancers.

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Section: Ctdna Biomarkers For Prognosis Of Colorectal Cancermentioning

confidence: 99%

The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers

Saluja

Karapetis

Pedersen³

et al. 2018

Front. Oncol.

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“…However, this study did not use quantitative analysis and did not have matched tumor and serum samples for all cases. Another recent study on non-metastatic CRC was able to detect 5.6% of tumor mutations by dPCR 25 , which is not satisfactory as an early diagnostic biomarker. Thus, further improvement of techniques is required to define patients with early-stage CRC.…”

Section: Discussionmentioning

confidence: 89%

Enrichment technique to allow early detection and monitor emergence of KRAS mutation in response to treatment

Kitagawa

Okumura

Watanabe

et al. 2019

Sci Rep

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Sensitivity of cell-free circulating tumour DNA (ctDNA) assays is often hampered by the limited quantity of intact mutant nucleotide fragments. To overcome the issue of substrate limitation in clinical applications, we developed an enrichment method utilizing pyrrole-imidazole (PI) polyamides and their ability to bind the minor groove of B-DNA. We present here a proof-of-concept experiment to enrich specific mutant KRAS alleles with biotinylated PI polyamides. We investigated the clinical feasibility of incorporating PI polyamides to detect KRAS mutations in ctDNA from 40 colorectal cancer (CRC) patients, of whom 17 carried mutations in KRAS . After enriching ctDNA with those polyamides, we used digital PCR to detect several common KRAS codon 12 mutations. Enrichment by biotinylated PI polyamides improved the sensitivity of ctDNA analysis (88.9% vs. 11.1%, P < 0.01) in 9 non-metastatic mutation-positive patients. We observed no differences in performance for the 8 metastatic subjects (100% vs. 75%, P = 0.47). In the remaining 23/40 patients with wild type KRAS codon 12, no mutant alleles were detected with or without polyamide-facilitated enrichment. Enriching B-form of ctDNA with PI polyamides significantly improved the assay sensitivity in detecting KRAS mutations in non-metastatic CRC patient samples.

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“…This integrated technique could provide the advantage of high-throughput detection of multiplex genetic variations [24]. The sensitivity of mutant ctDNA detection in this technique was comparable to that of dPCR-based techniques in patients with CRC [34]. Therefore, the MassARRAY platform is employed in this study to analyze RAS mutations in the ctDNA of patients during and after anti-EGFR therapy.…”

Section: Discussionmentioning

confidence: 99%

Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment: a study protocol

et al. 2019

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Background In the management of patients with RAS wild-type metastatic colorectal cancer (mCRC), anti-epidermal growth factor receptor (EGFR) therapies have demonstrated a clinical benefit, with longer survival. However, the correlation between the emergence of circulating RAS mutations and secondary resistance to anti-EGFR therapies requires further elucidation. In this study, we aim to examine evolutionary changes in RAS mutations through liquid biopsy in patients with mCRC during and after anti-EGFR therapy. Methods A total of 120 patients diagnosed with RAS wild-type mCRC will be enrolled in this study. Patients will receive a cetuximab-based infusional 5-fluorouracil regimen as first-line treatment. Cetuximab-based treatment is expected to continue until disease progression, intolerable toxic effects, or withdrawal of consent. Blood samples from enrolled patients will be collected before and then every 3 months during cetuximab-based treatment and also at disease progression. These blood samples will be evaluated for RAS resistance mutations by using the MassARRAY platform. The primary endpoint is the percentage of RAS mutations detected in circulating DNA from patients during cetuximab treatment. The correlation between the tumor response and survival outcomes of these patients and the emergence of circulating RAS mutations will be further analyzed. Discussion Liquid biopsy is a powerful technology that can represent tumor heterogeneity in a relatively noninvasive manner. Because RAS mutations play a major role in resistance to anti-EGFR therapy for mCRC, examining evolutionary changes in these mutations during such treatment through liquid biopsy would be useful. After comprehensively analyzing the emergence of circulating RAS mutations and its clinical relevance in this study, our results should provide practical guidance on anti-EGFR therapy for mCRC. Trial registration The date of trial registration ( NCT03401957 ) in this study was January 17, 2018. Electronic supplementary material The online version of this article (10.1186/s12885-019-5826-7) contains supplementary material, which is available to authorized users.

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Feasibility of multiplexed gene mutation detection in plasma samples of colorectal cancer patients by mass spectrometric genotyping

Cited by 17 publications

References 30 publications

The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers

The Use of Circulating Tumor DNA for Prognosis of Gastrointestinal Cancers

Enrichment technique to allow early detection and monitor emergence of KRAS mutation in response to treatment

Emergence of RAS mutations in patients with metastatic colorectal cancer receiving cetuximab-based treatment: a study protocol

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