The transcriptomic G1–G6 signature of hepatocellular carcinoma in an Asian population: Association of G3 with microvascular invasion

In this study, a transcriptomic group classification based on a European population is tested on a Singapore cohort. The results highlight the genotype/phenotype correlation in a Southeast Asian population. The G1–G6 transcriptomic classification derived from hepatocellular carcinoma (HCC) resected from European patients, robustly reflected group-specific clinical/pathological features. We investigated the application of this molecular classification in Southeast Asian HCC patients. Gene expression analysis was carried out on HCC surgically resected in Singapore patients who were grouped into G1–G6 transcriptomic categories according to expression of 16 predictor genes (illustrated in Supplementary Table 1 and Supplementary Fig. 1) using quantitative reverse transcription polymerase chain reaction (RT-PCR). Univariate and multivariate polytomous logistic regression was used to investigate association between clinical variables and pooled transcriptomic classes G12, G3, and G456. HCC from Singapore (n = 82) were distributed (%) into G1 (13.4), G2 (24.4), G3 (15.9), G4 (24.4), G5 (14.6), and G6 (7.3) subgroups. Compared to the European data, the Singapore samples were relatively enriched in G1–G3 versus G4–G6 tumors (53.7% vs 46.3%) reflecting the higher proportion of hepatitis B virus (HBV) patients in Singapore versus Europe samples (43% vs 30%). Pooled classes were defined as G12, G3, and G456. G12 was associated with higher alpha-fetoprotein (AFP) concentrations (OR = 1.69, 95% CI: 1.30–2.20; P < 0.0001) and G3 with microvascular invasion (OR = 4.91, 95% CI: 1.06–24.8; P = 0.047). The European and Singapore cohorts were generally similar relative to associations between transcriptomic groups and clinical features. This lends credence to the G1–G6 transcriptomic classifications being applicable regardless of the ethnic origin of HCC patients. The G3 group was associated with microvascular invasion and holds potential for investigation into the underlying mechanisms and selection for therapeutic clinical trials.