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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Tumor irradiation may facilitate the detection of tumor-specific mutations in plasma
Ekaterina Kuligina, Fedor Moiseyenko, Sergey Belukhin, Ekaterina Stepanova, Maria Zakharova, Vera Chernobrivtseva, Ikram Aliev, Tatiana Sharabura, Vladimir Moiseyenko, Svetlana Aleksakhina, Tatiana Laidus, Aleksandr Martianov, Maksim Kholmatov, Aldon Whitehead, Grigoriy Yanus, Evgeny Imyanitov
Ekaterina Kuligina, Svetlana Aleksakhina, Tatiana Laidus, Aleksandr Martianov, Maksim Kholmatov, Grigoriy Yanus, Evgeny Imyanitov, Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
Ekaterina Kuligina, Svetlana Aleksakhina, Aleksandr Martianov, Grigoriy Yanus, Evgeny Imyanitov, Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
Fedor Moiseyenko, Vladimir Moiseyenko, Department of Therapy, City Cancer Center, St.-Petersburg 197758, Russia
Sergey Belukhin, Ikram Aliev, Department of Surgery, City Cancer Center, St.-Petersburg 197758, Russia
Ekaterina Stepanova, Maria Zakharova, Vera Chernobrivtseva, Tatiana Sharabura, Department of Radiology, City Cancer Center, St.-Petersburg 197758, Russia
Aldon Whitehead, Internal Medicine Residency Program, The University of Illinois College of Medicine, Chicago, IL 60612, United States
Evgeny Imyanitov, Department of Oncology, I.I. Mechnikov Northwestern Medical University, St.-Petersburg 191015, Russia
Author contributions: Kuligina ES, Moiseyenko FV, Moiseyenko VM, Yanus GA and Imyanitov EN designed and coordinated the study; Belukhin SA, Stepanova EO, Zakharova MS, Chernobrivtseva VV, Aliev II, Tatiana M Sharabura TM, Laidus TA, Martianov AS and Kholmatov MM performed the experiments, acquired the data and analyzed the results; Kuligina ES, Moiseenko FV, Aleksakhina SN, Laidus TA and Whitehead AJ interpreted the data; Kuligina ES, Moiseenko FV, Moiseyenko VM, Whitehead AJ and Imyanitov EN prepared the manuscript; all authors approved the final version of the article.
Supported by the Russian Science Foundation, No. 20-75-10163.
Institutional review board statement: The study was approved by the local Ethics Committee.
Conflict-of-interest statement: All authors have nothing to disclose.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Evgeny Imyanitov, DSc, Professor, Department of Tumor Biology, N.N. Petrov Institute of Oncology, Pesochny, St.-Petersburg 19775, Russia.
evgeny@imyanitov.spb.ru
Received: April 28, 2021
Peer-review started: April 28, 2021
First decision: June 13, 2021
Revised: June 26, 2021
Accepted: November 28, 2021
Article in press: November 28, 2021
Published online: December 24, 2021
Processing time: 239 Days and 16.7 Hours
BACKGROUND
The mutation-based analysis of circulating tumor DNA (ctDNA) is a promising diagnostic tool for clinical oncology. However, it has low success rate because many cancer patients do not have detectable ctDNA in the bloodstream.
AIM
To evaluate whether preoperative tumor irradiation results in a transient increase of plasma ctDNA concentration due to the induction of apoptosis in radiation-exposed cells.
METHODS
This study focused on patients with locally advanced rectal cancer, because preoperative tumor irradiation is a part of their standard treatment plan. Nine subjects, whose tumors contained KRAS, NRAS or BRAF mutations, donated serial blood samples 1 h prior to the first fraction of irradiation (at baseline), immediately after the first fraction (time 0), and 1, 3, 6, 12, 24, 36, 48, 72 and 96 h after the first fraction. The amount of mutated gene copies was measured by droplet digital PCR.
RESULTS
Five out of nine patients were mutation-negative by ctDNA test at baseline; two of these subjects demonstrated an emergence of the mutated DNA copies in the bloodstream within the follow-up period. There were 4 patients, who had detectable ctDNA in the plasma at the start of the experiment; three of them showed an evident treatment-induced increase of the content of mutated RAS/RAF alleles.
CONCLUSION
Local tumor irradiation may facilitate the detection of tumor-specific DNA in the bloodstream. These data justify further assessment of the clinical feasibility of irradiation-assisted liquid biopsy.
Core Tip: The detection of circulating tumor DNA (ctDNA) in cancer patients is compromised by the low sensitivity of this assay. We hypothesized that tumor irradiation may lead to the transient increase of ctDNA content due to induction of cell death. Nine patients with locally advanced RAS/RAF-mutated rectal cancer provided serial blood samples at baseline and during the first 96 h after the first dose of tumor irradiation. Treatment-induced elevation of the concentration of mutated RAS/RAF alleles in the blood was revealed in five of these subjects. In conclusion, local tumor irradiation may facilitate the detection of plasma ctDNA and thus improve the efficacy of liquid biopsy.
