Yu Xian, Lei Xuezhong
Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu 610041, China.
Diagnostics (Basel). 2023 Jul 26;13(15):2484. doi: 10.3390/diagnostics13152484.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with low rates of early diagnosis and surgical resection. In recent years, with the rapid development of liquid biopsy technology, circulating tumor DNA (ctDNA) has emerged as a research hotspot in the field of precision medicine for liver cancer. Existing studies have demonstrated the suitability of ctDNA for combined detection with other liver cancer diagnostic markers, enabling a multi-index analysis. In recent years, a novel prediction model has been developed for early liver cancer screening based on ctDNA liquid biopsy, M2P-HCC (methylation, mutation, and protein-HCC), mainly incorporating methylation changes, gene mutations, and protein markers associated with liver cancer. Preliminary validation in the HCCscreenTM Investigational (HIT, ChiCTR1800020233) study, which focused on screening early liver cancer in communities with Hepatitis B surface antigen (HBsAg) positivity, yielded promising results with 100% sensitivity and 94% specificity. However, it remains uncertain whether M2P-HCC can be effectively applied in high-risk populations for Hepatitis B-associated liver cancer, warranting further research.
Patients who were under long-term follow-up at the outpatient clinic of the Infectious Diseases Center of West China Hospital of Sichuan University from December 2020 to January 2023 were recruited in this prospective observational study and underwent the M2P-HCC test. The study population consisted of high-risk patients with Hepatitis B-related liver cancer who met the inclusion criteria. Patients with a history of previous malignancy, recent blood transfusion, autoimmune diseases, and human immunodeficiency virus (HIV) infection were excluded. Clinical data were collected at a baseline, and all patients underwent the M2P-HCC blood test. Based on the test results, they were categorized into positive, early-warning, and negative groups. Prospective cohort observation and regular follow-ups were performed for 6-8 months.
313 patients met the inclusion criteria and were included in the study. After 6-8 months of follow-up, HCC occurred in 41(13.1%) participants. The M2P-HCC test demonstrated good predictive performance with an area under the curve (AUC) of 0.88 (95% CI: 0.81-0.95, < 0.001) and a cutoff value of 83 points (sensitivity 82.9% and specificity 85.7%). In contrast, the combination of alpha-fetoprotein (AFP) and ultrasound (US) yielded an inferior predictive performance (AUC 0.76 (95% CI: 0.69-0.84, < 0.001), sensitivity 58.5%, and specificity 94.1%). Multivariate analyses revealed that M2P-HCC was an independent predictor of increased risk of HCC (OR = 1.16 [1.09-1.22], < 0.001).
M2P-HCC liquid biopsy demonstrated good performance for early liver cancer screening in high-risk populations of Hepatitis B-related liver cancer, exhibiting better sensitivity than the combination of AFP and US.
肝细胞癌（HCC）是全球最常见的恶性肿瘤之一，早期诊断和手术切除率较低。近年来，随着液体活检技术的快速发展，循环肿瘤DNA（ctDNA）已成为肝癌精准医学领域的研究热点。现有研究表明，ctDNA适用于与其他肝癌诊断标志物联合检测，可进行多指标分析。近年来，基于ctDNA液体活检开发了一种用于早期肝癌筛查的新型预测模型，即M2P-HCC（甲基化、突变和蛋白-HCC），主要纳入了与肝癌相关的甲基化变化、基因突变和蛋白标志物。在HCCscreenTM研究（HIT，ChiCTR1800020233）中进行的初步验证聚焦于在乙型肝炎表面抗原（HBsAg）阳性的社区中筛查早期肝癌，结果显示其敏感性为100%，特异性为94%，效果良好。然而，M2P-HCC能否有效应用于乙型肝炎相关肝癌的高危人群仍不确定，有待进一步研究。
本前瞻性观察性研究招募了2020年12月至2023年1月在四川大学华西医院传染病中心门诊接受长期随访的患者，并进行了M2P-HCC检测。研究人群包括符合纳入标准的乙型肝炎相关肝癌高危患者。排除有既往恶性肿瘤史、近期输血史、自身免疫性疾病和人类免疫缺陷病毒（HIV）感染的患者。在基线时收集临床数据，所有患者均接受M2P-HCC血液检测。根据检测结果，将他们分为阳性、预警和阴性组。进行了6-8个月的前瞻性队列观察和定期随访。
313例患者符合纳入标准并纳入研究。随访6-8个月后，41例（13.1%）参与者发生了肝癌。M2P-HCC检测显示出良好的预测性能，曲线下面积（AUC）为0.88（95%CI：0.81-0.95，P<0.001），临界值为83分（敏感性82.9%，特异性85.7%）。相比之下，甲胎蛋白（AFP）和超声（US）联合检测的预测性能较差（AUC 0.76（95%CI：0.69-0.84，P<0.001），敏感性58.5%，特异性94.1%）。多变量分析显示，M2P-HCC是肝癌风险增加的独立预测因素（OR = 1.16 [1.09-1.22]，P<0.001）。
M2P-HCC液体活检在乙型肝炎相关肝癌高危人群的早期肝癌筛查中表现良好，其敏感性优于AFP和US联合检测。
