Download This Paper
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
A Novel Medication Decision Gene Signature Predicts Response to Individualized Therapy and Prognosis Outcomes in Hepatocellular Carcinoma Patients
47 Pages Posted: 21 Jun 2022
More...Abstract
Background: Molecular targeted therapy has shown potential in hepatocellular carcinoma (HCC) patients, and immunotherapy applications are developing rapidly. However, clinical guidance for making individualized therapy decisions for HCC patients remains lacking.
Methods: Transcriptomic analysis of multikinase inhibitor (TKI)-resistant HCC models screened MDH (medicationdecision in HCC) gene signatures. Unsupervised cluster analysis defined HCC subtypes based on MDH gene signatures. Principal component analysis established the MDH score, and the TIDE algorithm predicted HCC patient immunotherapy responses. Iteration LASSO Cox regression constructed a nomogram predicting HCC prognosis.
Findings: MDH gene signatures comprising 70 genes were screened using transcriptomic data from TKI-resistant HCC cells and HCC PDX models. Four MDH subtypes with distinct biological and clinical characteristics were defined by unsupervised cluster analysis of HCC data from the TCGA database. To facilitate individualized and reasonable clinical guidance for each HCC patient, we constructed the MDH score. Comprehensive analysis suggested high MDH scores were associated with TKI resistance, a high proportion of stromal cell infiltration and poor survival outcomes. We recommend concomitant stromal activity intervention and immunotherapy for this type of HCC. Moreover, low MDH scores indicate TKI sensitivity, and a combination of targeted and immunotherapy is recommended. The nomogram constructed by iteration LASSO Cox regression analysis successfully predicted 3- or 5-year survival outcomes and mortality risks of HCC patients.
Interpretation: TKI resistance model-based MDH gene signatures provide novel insight into potential mechanisms of drug resistance and heterogeneity in HCC. Integrative analysis plus a simplified decision model may aid personalized treatment and prognostic assessment among HCC patients.
Funding Information: This work was supported by grants from the National Natural Science Foundation of China (no. 82070674), the Sichuan Province Science and Technology Department Project (no. 2019YFG0036), the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (no. ZY2017308).
Declaration of Interests: The authors have declared that no competing interest exists.
Ethics Approval Statement: Human samples were obtained patient consent and approval from the institutional review board, conforming to the ethical guidelines of the 1975 Declaration of Helsinki. Animals received humane care, and the Institutional Animal Care and Use Committee (IACUC) approved all animal experiments. Subsequently, tumour samples were collected by GeneChem Co., Ltd. (Shanghai, China) for transcriptome sequencing and subsequent data analysis. This clinical sample study was approved by the Ethics Committee on Biomedical Research, West China Hospital of Sichuan University. Informed consent was obtained from all patients or their relatives.
Keywords: hepatocellular carcinoma, immunotherapy, multikinase inhibitor, individualized therapy, prognostic model
Suggested Citation: Suggested Citation