A research group made up of Professor Junko Takita and Assistant Professor Yoshinori Uchihara of the Department of Pediatrics, Graduate School of Medicine at Kyoto University, Professor Katsutsugu Umeda of the Department of Pediatrics, Faculty of Medical Sciences at the University of Fukui and Division Director Keiji Tasaka of the Department of Hematology and Oncology at Shizuoka Children's Hospital, supported by the Liver Tumor Committee of the Japan Children's Cancer Group (JCCG), a certified non-profit organization, clarified detailed mechanisms by which undifferentiated embryonal sarcoma of the liver (UESL), a rare pediatric liver tumor, undergoes stepwise malignancy from mesenchymal hamartoma of the liver (MHL), a benign tumor. Discovering that both share structural anomalies in the C19MC region on chromosome 19, they pinpointed that acquiring new genetic anomalies leads to malignancy into UESL. Furthermore, it was found that highly precise diagnosis and verification of treatment efficacy are possible via blood tests. The findings were published online in npj Precision Oncology.
Among cancers that develop in children's livers, UESL, ranking third most common, makes treatment extremely difficult when surgery is difficult or anticancer drugs are ineffective. This cancer develops as a portion of benign MHL seen in infants undergoes malignancy. Both are deeply related diseases sharing genetic anomalies in chromosome 19, but what triggered the change from benign to malignant, and its mechanism, were not understood.
Because these tumors are extremely rare cancers, the JCCG Liver Tumor Committee, uniting pediatric cancer specialized medical institutions nationwide, provided full cooperation to launch a joint research project utilizing a nationwide specimen network. To clarify detailed mechanisms changing from benign to malignant, Kyoto University, University of Fukui, and Shizuoka Children's Hospital collaborated to conduct research.
The joint research group performed integrated multi-omics analysis using clinical specimens of UESL and MHL. Furthermore, they established an original analysis system detecting and quantifying trace cancer-derived DNA and RNA contained in blood with high precision.
Comparing both benign tumors (MHL) and malignant tumors (UESL) in detail, it was found that accompanied by structural anomalies in a specific microRNA (C19MC) region on chromosome 19 in both tumors, expression of this microRNA increased abnormally.
On the other hand, anomalies in TP53, an important gene that suppresses cancer occurrence, were observed with 100% probability only in patients with malignant tumors, and were not observed at all in patients with benign tumors. Thereby, they pinpointed that addition of TP53 gene anomalies to benign tumors is the decisive cause triggering stepwise malignancy.
In addition, they conducted liquid biopsies on patients where malignant tumors were suspected in imaging tests, but tumor rupture risk was high and biopsy was difficult. As a result, from blood, microRNA derived from the C19MC region characteristic of this tumor was detected at high values, and they also succeeded in detecting TP53 gene anomalies. Furthermore, examining progress during anticancer drug treatment, they confirmed that microRNA values decreased as treatment progressed, and became undetectable after completely resecting tumors via surgery.
Uchihara: "The greatest achievement of this research lies in scientifically proving that the addition of a single genetic change, an 'anomaly in the TP53 gene,' to benign tumors serves as the decisive trigger for stepwise malignancy. This discovery not only solves the mystery of pediatric liver cancer, which was extremely difficult to diagnose, but should also be a major step toward developing new therapeutic drugs."
"Through introduction of liquid biopsy, a cutting-edge technology, we were able to open up possibilities for 'safe cancer monitoring via blood,' which had been impossible until now. Research on rare cancers can only be established with support from patients and families who provided precious specimens, as well as joint researchers nationwide. Not leaving these achievements as 'past discoveries,' we will vigorously advance prospective validation to develop them into practical medical technologies to save future patients."
Journal Information
Publication: npj Precision Oncology
Title: Stepwise malignant transformation from MHL to UESL via activation of C19MC and loss of TP53
DOI: 10.1038/s41698-026-01563-2
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.