Background: Alpha-fetoprotein (AFP) blood level in Hepatocellular carcinoma (HCC)is an important marker widely used in clinical practice. Although different AFP levels indicate the different prognosis of HCC patients, the gene mutation profile is still unclear. The research was to conduct a comprehensive study of the gene mutation profile in HCC patients with different AFP levels at diagnosis.

Methods: Retrospective analysis was carried out on medical records of HCC patients who had received a hepatectomy between January 2016 and December 2018. Formalin-fixed, paraffin-embedded (FFPE) HCC tissues and matched blood samples were collected for targeted next-generation sequencing (NGS) assay at OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic variants including single nucleotide variations (SNV), short/long insertion/deletions (Indel), copy number alterations and gene rearrangements were analyzed.

Results: A total of 180 HCC cases were enrolled in the study. The patients were categorized into AFP<10ng/ml (n=63) group, 10ng/ml≤AFP<1000ng/ml (n=71) group, and AFP≥1000ng/ml (n=46) group. The higher AFP level at diagnosis was positively correlated with younger incidence age (P=0.012), lower blood glucose (P=0.008), larger diameter of tumor nodules (P=0.006), more microvascular invasion (P=0.01), higher grade of tumor differentiation (P<0.001), poorer overall survival (P=0.023), and recurrence free survival (P=0.007). AXIN1 mutation frequency significantly increased with the rise of the APF level: AFP<10ng/ml (7.9%), 10ng/ml≤AFP<1000ng/ml (25.4%), and AFP≥1000ng/ml (42.2%, P<0.001), while TP53 mutation frequency decreased with the rise of the AFP level: AFP<10ng/ml (65.1%), 10ng/ml≤AFP<1000ng/ml (57.7%), and AFP≥1000ng/ml (48.9%) with only near significance (P=0.095) among three groups. Furthermore, we identified 11q13 (FGF3, FGF4, FGF19, CCND1) amplification frequency increased with AFP level: AFP<10ng/ml 4.8%, 10ng/ml≤AFP<1000ng/ml 12.7%, and AFP≥1000ng/ml 20.9%, P=0.015.

Conclusion: We demonstrated AXIN1 mutation frequency increased with the rise of the AFP level. Because these AXIN1 mutations can result in inactivating the AXIN1 protein and the AXIN1 is a known negative regulator of the Wnt/β-catenin signaling pathway, we reason that the Wnt/β-catenin signaling pathway has a deleterious effect on the poor prognosis in the higher AFP groups, and/or directly on the rise of the AFP level.

Citation Format: Xiang Kui, Liqun Wu, Yang Ke, Yan Wang, Hai Li, Juan Zhao, Tingting He, Lin Wang. The gene mutation profile in HCC patients with different AFP levels at diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2660.