Hepatocellular Carcinoma With JAK1 Mutations Harbors Distinct Histologic Features and Specific Mutational Hotspots in an Asian Cohort

The pathogenesis and clinicopathological features of hepatocellular carcinoma (HCC) harboring JAK1 mutation have not been reported. Sixty inflammatory hepatocellular adenoma-like HCCs (IHA-like HCCs) and 16 IHAs were analyzed using targeted next-generation sequencing. Nearly all IHA-like HCCs (n=59, 98%) showed positive SAA/CRP expression. Genetic alterations of the JAK/STAT pathway were detected in 35 (58%) IHA-like HCCs, encompassing mutations in JAK1 (n=22), STAT3 (n=8), and IL6ST (n=5). Nine (56%) IHAs harbored mutations in STAT3 (n=3), IL6ST (n=4), GNAS (n=1), and FRK (n=1). All the mutations occurred in a mutually exclusive manner. JAK1 mutations were frequent (22/60, 37%) in IHA-like HCCs. JAK1-mutated IHA-like HCCs displayed distinctive cytologic characteristics, including abundant eosinophilic cytoplasm, vesicular chromatin, and prominent central nucleoli. Recurrent hotspot JAK1 mutations were identified at S703, S729, and L910. Surveillance for JAK1 mutations in the HCC genomics of other cohorts also revealed recurrent mutations at S703, S729, and L910. In particular, the S703 and S729 mutations were strongly associated with the features of Asian ethnicity, presence of chronic viral hepatitis, and hepatic fibrosis/cirrhosis. In conclusion, JAK1 mutations were frequent in HCC with IHA-like morphology in an Asian cohort. JAK1 mutation exhibited recurrent and specific hotspot mutations at S703, S729, and L910 in HCC. Patients diagnosed with JAK1-mutated HCC may be eligible for JAK-targeted molecular therapy.