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Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

ABSTRACT: Oesophageal cancer (OC) has high mortality. This study aims at determining the feasibility of liquid biopsies for genomic profiling in early stage OC, comparing two different technologies for mutational analysis in circulating cell -free DNA (ccfDNA) and evaluating the clinical impact of these somatic alterations during primary staging. In 25 patients with locally advanced OC, endoscopic tumour biopsies and simultaneous blood samples were taken during primary staging. Genomic DNA from biopsies and ccfDNA were analysed for mutations using a 12 gene panel next-generation sequencing (NGS) assay as well as digital droplet PCR (ddPCR). Genetic data was correlated with patients' outcome. In 21 of the tested biopsies (84%) at least one somatic mutation was detected by NGS. Mutations detected by NGS were detectable by ddPCR with similar allele frequencies. In three out of the 21 patients with proven mutations, the same mutations were also detectable in ccfDNA using NGS (14%). In contrast, ddPCR detected mutations in ccfDNA of five additional patients (8/21, 38%). Post-surgical outcome analysis was performed for those patients who had received complete tumour resection (n?=?16). Five of them suffered from an early relapse within the first year after surgery, including four with detectable somatic mutations in ccfDNA during primary staging. Taken together, we showed a higher sensitivity for ddPCR compared to NGS in detecting mutated ccfDNA in OC. Detection of somatically altered ccfDNA during primary staging seems to be indicative for post-surgical tumour recurrence.

SUBMITTER: Pasternack H

PROVIDER: S-EPMC6175817 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

Pasternack Helen H Fassunke Jana J Plum Patrick Sven PS Chon Seung-Hun SH Hescheler Daniel Alexander DA Gassa Asmae A Merkelbach-Bruse Sabine S Bruns Christiane Josephine CJ Perner Sven S Hallek Michael M Büttner Reinhard R Bollschweiler Elfriede E Hölscher Arnulf Heinrich AH Quaas Alexander A Zander Thomas T Weiss Jonathan J Alakus Hakan H

Scientific reports 20181008 1

Oesophageal cancer (OC) has high mortality. This study aims at determining the feasibility of liquid biopsies for genomic profiling in early stage OC, comparing two different technologies for mutational analysis in circulating cell -free DNA (ccfDNA) and evaluating the clinical impact of these somatic alterations during primary staging. In 25 patients with locally advanced OC, endoscopic tumour biopsies and simultaneous blood samples were taken during primary staging. Genomic DNA from biopsies a ...[more]

PMID: 30297788

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Project description:Background18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) may improve cancer staging by combining sensitive cancer detection with high-contrast resolution and detail. We compared the diagnostic performance of 18F-FDG PET/MRI to 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for staging oesophageal/gastro-oesophageal cancer. Following ethical approval and informed consent, participants with newly diagnosed primary oesophageal/gastro-oesophageal cancer were enrolled. Exclusions included prior/concurrent malignancy. Following 324 ± 28 MBq 18F-FDG administration and 60-min uptake, PET/CT was performed, immediately followed by integrated PET/MRI from skull base to mid-thigh. PET/CT was interpreted by two dual-accredited nuclear medicine physicians and PET/MRI by a dual-accredited nuclear medicine physician/radiologist and cancer radiologist in consensus. Per-participant staging was compared with the tumour board consensus staging using the McNemar test, with statistical significance at 5%.ResultsOut of 26 participants, 22 (20 males; mean ± SD age 68.8 ± 8.7 years) completed 18F-FDG PET/CT and PET/MRI. Compared to the tumour board, the primary tumour was staged concordantly in 55% (12/22) with PET/MRI and 36% (8/22) with PET/CT; the nodal stage was concordant in 45% (10/22) with PET/MRI and 50% (11/22) with PET/CT. There was no statistical difference in PET/CT and PET/MRI staging performance (p > 0.05, for T and N staging). The staging of distant metastases was concordant with the tumour board in 95% (21/22) with both PET/MRI and PET/CT. Of participants with distant metastatic disease, PET/MRI detected additional metastases in 30% (3/10).ConclusionIn this preliminary study, compared to 18F-FDG PET/CT, 18F-FDG PET/MRI showed non-significant higher concordance with T-staging, but no difference with N or M-staging. Additional metastases detected by 18F-FDG PET/MRI may be of additive clinical value.

Project description:Abstract Rationale A high risk of post‐operative recurrence contributes to the poor prognosis and low survival rate of oesophageal squamous cell carcinoma (ESCC) patients. Increasing experimental evidence suggests that integrin adhesion receptors, in particular integrin αv (ITGAV), are important for cancer cell survival, proliferation and migration. Therefore, targeting ITGAV may be a rational approach for preventing ESCC recurrence. Materials and methods Protein levels of ITGAV were determined in human ESCC tumour tissues using immunohistochemistry. MTT, propidium iodide staining, and annexin V staining were utilized to investigate cell viability, cell cycle progression, and induction of apoptosis, respectively. Computational docking was performed with the Schrödinger Suite software to visualize the interaction between indomethacin and ITGAV. Cell‐derived xenograft mouse models, patient‐derived xenograft (PDX) mouse models, and a humanized mouse model were employed for in vivo studies. Results ITGAV was upregulated in human ESCC tumour tissues and increased ITGAV protein levels were associated with poor prognosis. ITGAV silencing or knockout suppressed ESCC cell growth and metastatic potential. Interestingly, we identified that indomethacin can bind to ITGAV and enhance synovial apoptosis inhibitor 1 (SYVN1)‐mediated degradation of ITGAV. Integrin β3, one of the β subunits of ITGAV, was also decreased at the protein level in the indomethacin treatment group. Importantly, indomethacin treatment suppressed ESCC tumour growth and prevented recurrence in a PDX mouse model. Moreover, indomethacin inhibited the activation of cytokine TGFβ, reduced SMAD2/3 phosphorylation, and increased anti‐tumour immune responses in a humanized mouse model. Conclusion ITGAV is a promising therapeutic target for ESCC. Indomethacin can attenuate ESCC growth through binding to ITGAV, promoting SYVN1‐mediated ubiquitination of ITGAV, and potentiating cytotoxic CD8+ T cell responses. Integrin αvβ3 was upregulated in ESCC tumour tissue compared to adjacent tissue. Indomethacin binds to ITGAV and promotes SYVN1‐mediated ubiquitination of ITGAV, thereby attenuating the αvβ3/PI3K/AKT/GS3Kβ signalling pathway. Inhibition of αvβ3 by indomethacin treatment blocks TGFβ/SMAD2/SMAD3 signalling and increases anti‐tumour immune responses in a humanized mouse model. Indomethacin suppresses ESCC tumour growth and recurrence in a PDX mouse model.

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Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

Publications

Somatic alterations in circulating cell-free DNA of oesophageal carcinoma patients during primary staging are indicative for post-surgical tumour recurrence.

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