Genetic Characterization of Hepatoid Tumors from Different Organs: Context Matters

Abstract

Background: Hepatoid tumors (HT) are a rare group of cancers resembling morphologically hepatocellular carcinoma, which arise in different organs other than liver. A comprehensive molecular profile of this group of neoplasms is still lacking. Design: A genetic characterization of 20 HT from different organs was performed using three different multigene next-generation sequencing panels. Results: TP53 was the only mutated gene occurring in HT of different sites (8/20 cases), while the vast majority of alterations were clustered according to the tissue of origin. The most relevant findings were: i) colorectal HT: microsatellite instability, high tumor mutation burden, mutations in ARID1A/B and KMT2D genes, and NCOA4-RET gene fusion (2/3 cases); ii) gastric HT: TP53 mutations (2/4); iii) pancreatico-biliary: loss of CDKN2A and loss of chromosome 18 (3/5); iv) genital HT: gain of chromosome 12 (3/6); v) lung HT: STK11 somatic mutations (2/2). Conclusions: The analysis of a heterogeneous cohort of HT from different organs did not reveal a common molecular hallmark that could explain the peculiar hepatoid morphology. Most genetic alterations were clearly clustered by site, highlighting that context matters: the tissue of origin emerged as the most important factor in influencing HT molecular landscape.