Chemoresistance and genetic mutations in hepatocellular carcinoma: a pharmacogenomic atlas of 51 patients

Chemoresistance remains a major barrier in hepatocellular carcinoma (HCC) treatment, and research on personalized therapies for resistant patients is still nascent. This study aimed to construct a preliminary gene-drug resistance map for HCC to advance research in personalized treatment. Tumor tissues from 51 HCC patients who underwent surgical resection at the First Affiliated Hospital of Chongqing Medical University (December 2019 to June 2021) were used to establish in vitro models. High-throughput drug sensitivity screening (HDSS) and whole-exome sequencing (WES) were performed to identify key resistance-associated genes. Integrated analysis with TCGA database data generated a pharmacogenomic atlas of HCC. Mutational frequencies of key oncogenes and tumor suppressor genes in HCC patients were elevated and largely consistent with The Cancer Genome Atlas (TCGA) data. FAT4 mutations were significantly associated with resistance to epirubicin, doxorubicin, 5-fluorouracil, and XELOX regimens (p < 0.05). KMT2D mutations showed significant correlations with resistance to gemcitabine, 5-FU + cisplatin, ADM + L-OHP, and L-OHP + irinotecan (p < 0.05). PABPC1 mutations were linked to resistance in doxorubicin, apatinib, and ADM + L-OHP regimens (p < 0.05). FAT4, KMT2D, and PABPC1 are potential key drivers of chemoresistance in HCC, demonstrating cross-regimen associations. These findings may inform personalized chemotherapy strategies for advanced HCC, although further clinical validation is warranted. This study was registered at the Chinese Clinical Trial Registry (https://www.chictr.org.cn; registration number: ChiCTR1900022193; registration date: 2019/03/30).Observational Study.