Genetic polymorphisms as predictors of the response of hepatocellular carcinoma patients to doxorubicin chemotherapy: a genome-wide association study

Abstract

Background: Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is commonly treated with doxorubicin (DOX). However, its effectiveness varies significantly among patients.

Aim: The present study aimed to identify potential genetic variants affecting the response of HCC patients to DOX.

Methods: 78 patients with HCC who received DOX via transarterial chemoembolization (TACE) technology were selected. DNA was extracted from blood for genome-wide genotyping using the Applied Biosystems™ Axiom™ Precision Medicine Diversity Research™ Array. Genetic data were analysed using Axiom™ Analysis Suite software v5.2.

Results: Six hits in five genes [AK3 (rs378117), TRPM3 (rs1329774 and rs4745058), CDH4 (rs2427043), LINC00504 (rs76228864), and GRIN2D (rs76754767)] were associated with a risk of tumour progression, whereas variants in HPGD (rs45593131) and RC3H2 (rs2792999) were suggested as protective factors. rs8038528 in the PCSK6 gene was categorized as a low-response variant associated with an unsatisfactory reduction in α-fetoprotein (AFP) levels after DOX chemotherapy (P = 6.82 × 10^-5). In contrast, three SNPs (rs1998853, rs12440990, and rs4774596) located within two genes (NPAS3 and DMXL2) were identified as predictors of good response rates to the treatment, as AFP levels were reduced by ≥ 20%. Death incidents showed associations with five SNPs that reached p ≤ 5.0 × 10^-8; four of these are located within the DENND1B, LOC107986086, TMEM169, and RNF152 genes.

Conclusion: These findings support the incorporation of pharmacogenomic testing into clinical practice for HCC therapy, paving the way for customized treatment methods that may improve therapeutic efficacy and patient outcomes. Future research is needed to replicate these genetic connections.

Keywords: array genotyping; doxorubicin; genome-wide association study; hepatocellular carcinoma; transarterial chemoembolization.

FIGURE 1

Manhattan plot of tumour progression markers in HCC patients receiving DOX chemotherapy. The plot shows the statistical association between each genomic variant and the outcome. The dots on the plot represent the chromosomal location on the x-axis and their statistical significance with respect to the phenotype of interest according to the logarithmic P value (-log10) on the y-axis. Each dot on the plot represents a single genomic variant. Variants that exceed the threshold line are statistically significant and are worth investigating. The–log10 P values of the detected SNPs were plotted across the 23 chromosomes. None of the SNPs met the genome-wide significance threshold (P < 5 × 10⁻⁸), as indicated by the red dashed line. Only the top markers of interest were annotated; the rs ID numbers of some SNPs above and below the blue dashed line (P < 9 × 10⁻⁶) are shown.

FIGURE 2

Manhattan plot of markers associated with the biological response (defined by the percentage of AFP reduction) in HCC patients receiving DOX chemotherapy. The–log10 P values of the detected SNPs were plotted across the 23 chromosomes. None of the SNPs met the genome-wide significance threshold (P < 5 × 10⁻⁸), as indicated by the red dashed line. Only four markers of interest were annotated; their rs ID numbers are shown below the blue dashed line (P < 9 × 10⁻⁶).

FIGURE 3

Manhattan plot of death markers in HCC patients receiving DOX chemotherapy. The–log10 P values of the detected SNPs were plotted across the 23 chromosomes. Five SNPs that met the genome-wide significance threshold (P < 5 × 10⁻⁸) are shown above the red dashed line. Other markers of interest were also annotated; their rs ID numbers are shown above the blue dashed line (P < 9 × 10⁻⁶).