Editor’s Note:
Liver cancer is one of the malignant tumors with a high incidence and mortality rate in China. Most patients are clinically diagnosed late, with a high rate of postoperative recurrence and metastasis, which has become a significant factor affecting patient prognosis. There is an urgent need for technology that can effectively detect early liver cancer, monitor treatment effects in real-time, and prevent metastasis. Liquid biopsy technology has attracted attention in recent years as a new detection method. It is non-invasive, sensitive, and dynamic, showing promise in early tumor diagnosis, personalized medication guidance, and treatment monitoring. At the 17th International Liver Cancer Association Annual Meeting (ILCA 2023), Dr. Issei Saeki from School of Medicine of Yamaguchi University,Japan, reported a study (Abstract number: O-11) that assessed the clinical application value of liquid biopsy technology based on the methylated SEPT9 test for early diagnosis of non-viral hepatitis-related hepatocellular carcinoma (N-HCC).
Previous studies have shown that the loss of DNA methylation is a crucial cause of cancer. Methylation testing of circulating tumor DNA (ctDNA) may be the most suitable liquid biopsy technology for early cancer screening. There is already a successful application example: the abnormal methylation detection of the SEPT9 gene is highly valuable for diagnosing colorectal cancer, with a sensitivity of 72%-90% and a specificity of 88%-90%.
Currently, as the incidence of metabolic-associated fatty liver disease (MAFLD) is increasing globally, the proportion of N-HCC is also rising. However, most HCC patients are usually diagnosed in advanced stages, and establishing a new diagnostic system capable of early detection remains challenging.
At the ILCA conference, Dr. Issei Saeki reported a more sensitive method for detecting methylated DNA. This method employs three methylation-sensitive restriction enzymes combined with droplet digital PCR technology to evaluate the diagnostic ability of methylated SEPT9 (m-SEPT9) for early N-HCC.
This study included 80 healthy controls and 136 HCC patients diagnosed between 2015 and 2018 as a training set. The m-SEPT9 levels of the participants were measured, and the best cut-off value was set using the Youden Index in the ROC analysis. In the validation set, 1,248 participants were included from 2018 to 2022, with 464 healthy controls and 784 HCC patients. The diagnostic ability of m-SEPT9 was assessed using the threshold value obtained from the training set.
Results showed:
– In the training set of 136 HCC patients, 98 (72.1%) were male (median age: 73 years). The number of patients at BCLC stages 0, A, B, C, and D were 12, 50, 31, 41, and 2, respectively. The median levels of AFP, DCP, and m-SEPT9 were 10.1 ng/mL, 144 mAU/mL, and 160 copies/mL, respectively. When 115 copies/mL was set as the best cut-off value for m-SEPT9, the sensitivity and specificity were 63.2% and 90.0%, respectively (AUC: 0.81).
– In the validation set of 784 HCC patients, 568 (71.4%) were male, with a median age of 73 years. The number of patients at BCLC stages 0, A, B, C, and D were 107, 250, 142, 268, and 17, respectively. The median levels of AFP, DCP, and m-SEPT9 were 11.4 ng/mL, 102.4 mAU/mL, and 220 copies/mL, respectively. The diagnostic ability of m-SEPT9 for HCC in the validation set was almost the same as in the training set (AUC: 0.83), with a sensitivity and specificity of 68.1% and 84.9%, respectively. The sensitivity of m-SEPT9 for N-HCC and virus-related HCC were 67.8% and 68.4%, respectively, with no significant difference between the two groups. Furthermore, the sensitivity of m-SEPT9 for early HCC (BCLC-0 or BCLC-A) was 55.9%.
Dr. Issei Saeki stated that because m-SEPT9 complements the currently applied biological markers AFP and DCP, combining all three could significantly increase the detection rate of early HCC. Analysis revealed that testing AFP alone for early N-HCC had very low sensitivity (18.6%). However, the combined detection of m-SEPT9, AFP, and DCP for early N-HCC had a sensitivity of 80.9%. In conclusion, the results of this study validate the performance of the liquid biopsy based on the methylated SEPT9 test in the early diagnosis of N-HCC. It is hopeful for establishing a new HCC diagnostic system based on various risk factors.
Reference:
- Issei Saeki, Takahiro Yamasaki, Yutaka Suehiro, et al. Validating liquid biopsy test based on a methylated SEPT9 assay for diagnosing hepatocellular carcinoma. ILCA 2023 Abstract O-11.
- Kotoh Y, Suehiro Y, Saeki I, et al. Novel liquid biopsy test based on a sensitive methylated SEPT9 assay for diagnosing hepatocellular carcinoma. Hepatol Commun. 2020 Jan 2;4(3):461-470. doi: 10.1002/hep4.1469. PMID: 32140662; PMCID: PMC7049671.
TAG: ILCA 2023, Commentary, HCC
