To the editor,
We followed with interest the report by Liao et al. that METTL1 conferred resistance to radiotherapy in hepatocellular carcinoma (HCC) through its involvement in nonhomologous end joining repair (NHEJ).1 The treatment of HCC has been challenging because of the complex tumor immune microenvironment (TIME). Traditional external beam radiation therapy was limited in managing HCC because of resistance to radiation. We appreciated the authors' work in discovering the causes of radiotherapy resistance and proposing treatments for the future. However, after reading this article, we would like to highlight some critical issues in this study.
First, in this study, samples for experimental research were obtained from patients with HCC mainly by biopsy. Previous studies have shown that HCC could be divided into multiple subtypes based on differences in their intratumoral components.2 Although biopsy was the best method to obtain specimens from nonsurgical patients, because of the intratumoral heterogeneity of HCC, specimens obtained by biopsy might not represent the overall status of the tumor. Therefore, obtaining more samples in a limited space might reduce errors because of internal heterogeneity. We recommend that authors clarify specific methods and criteria for obtaining samples in the manuscript.
Second, the authors lacked information on whether patients received antiviral therapy, transarterial chemoembolization, targeted therapy, or immunotherapy before the biopsy. In particular, immunotherapy before the biopsy was the most crucial factor affecting the outcome. Radiation had both positive and negative effects on the tumor immune microenvironment. The combined use of immune checkpoint inhibitors and radiotherapy may provide synergistic effects.3 Therefore, samples should be obtained after determining whether a patient had received systemic therapy for HCC.
Finally, we noted that the authors used the patient‐derived xenograft (PDX). PDX was an essential tool for tumor biology research. Because of the immunodeficiency, the application of PDX in the study was affected to a certain extent. In addition, in tumor tissue grown in mice, it was inevitable that tumor cells would mix with mouse cells. Whether performing quantitative gene expression analysis or immunohistochemical analysis, components derived from mouse cells will impact the final result.
In conclusion, METTL1 was an essential enhancer of NHEJ‐based DNA repair in HCC cells after ionizing radiation. Because of the unique intratumoral heterogeneity, the quality of the specimen and the effects of changes in the TIME must be considered when interpreting the findings.
Supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2020‐I2M‐C&T‐B‐026, No. 2020‐I2M‐C&T‐B‐019), CHEN XIAO‐PING Foundation for the Development of Science and Technology of Hubei province (CXPJJH1200008‐10), and Beijing Municipal Natural Science Foundation Project (Grant No. 7222130).
CONFLICTS OF INTEREST
Nothing to report.
1. Liao J, Yi Y, Yue X, Wu X, Zhu M, Chen Y, et al. Methyltransferase 1 is required for nonhomologous end‐joining repair and renders hepatocellular carcinoma resistant to radiotherapy. Hepatology. 2022 Jun 14. https://doi.org/10.1002/hep.32615
. [Epub ahead of print]
2. Wu R, Guo W, Qiu X, Wang S, Sui C, Lian Q, et al. Comprehensive analysis of spatial architecture in primary liver cancer. Sci Adv. 2021;7(51):eabg3750.
3. Pérez‐Romasanta LA, González‐Del Portillo E, Rodríguez‐Gutiérrez A, Matías‐Pérez á. Stereotactic radiotherapy for hepatocellular carcinoma, radiosensitization strategies and radiation‐immunotherapy combination. Cancers (Basel). 2021;13(2):192.