Proteomic identifies heterogeneity of AFP-negative hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Alpha-fetoprotein (AFP) is the most commonly used diagnostic marker for HCC. However, over 30% of HCC patients are negative for AFP ( < 20 ng/mL), which makes early diagnosis difficult and leads to complex heterogeneity and poor prognosis. Therefore, AFP-negative-specific heterogeneity is of great value in HCC study. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-associated mortality worldwide. Alpha-fetoprotein (AFP) is the most commonly used diagnostic marker for HCC. However, over 30% of HCC patients are negative for AFP ( < 20 ng/mL), which makes early diagnosis difficult and leads to complex heterogeneity and poor prognosis. Therefore, AFP-negative-specific heterogeneity is of great value in HCC study.

Quantitative proteomic profiling was performed to characterize paired tumor and non-tumor tissues of 124 AFP-negative HCC patients and 76 AFP-positive HCC patients.

The proteomic data showed the specific proteins expression profile of AFP-negative HCC. Furthermore, we identified heterogeneity in AFP-negative HCC, and classified the cohort into the subtype I, II and III, which showed significant difference in clinical outcome. Subtype II, which is characterized by immunoreactivity and proliferation, is associated with the shortest overall survival and disease-free survival. Meanwhile, based on the patient-derived tumor organoids and xenograft mouse model of HCC, we found that the above stratification is valuable on distinguishing individual differences in patients response to chemotherapeutic and molecular targeted agents.

Through this study, the proteomic stratification of AFP-negative HCC yielded new insight into the tumor biology, and provided new possibility for personalized therapies.

The authors.

This study was supported by grants from the National Natural Science Foundation of China (No. 82070652), the Key Research and Development Plan of Zhejiang Province (No. 2020C04003), Research Unit Project of the Chinese Academy of Medical Sciences (2019-I2M-5-030) and the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (JNL-2022007B).

All authors have declared no conflicts of interest.