Genomic characterization of rare molecular subclasses of hepatocellular carcinoma

Abstract

Primary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy.

DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

“…Although several studies have identified important molecular classes in HCC, uncertainty remains regarding their associations with outcomes and their complex interaction with liver regenerative processes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Recently, our lab defined three distinct molecular-based subpopulations of HCC tumors, namely HCC, Blast-Like, and CCA-like, based on gene expression similarity to cholangiocarcinomas and hepatoblast cells [ 14 ]. The HCC class has prototypical HCC tumor characteristics.…”

Expanded detection and impact ofBAP1alterations in cancer

“…Annotations of tumor molecular subtyping from Damrauer et al revealed that this altered subset was enriched for blast-like and cholangiocarcinoma-like LIHC samples. 14 These two molecular subtypes were also observed among the unaltered samples (77/330, 23.3%). Blast-like and cholangiocarcinoma-like tumors also have BAP1 alteration signature scores higher than the other LIHC tumors (Figures 4A-B and Supplemental Table S3B, pairwise two-sided Mann-Whitney U test with continuity correction and Bonferroni adjusted p=3.96e-7 and p=5.54e-15 respectively).…”

“…This work led to further investigations into the role of BAP1 mutations in promoting the development of cancer across multiple tissue types as well as the relation of BAP1 loss to differential survival outcomes. [11][12][13][14] BAP1 mutations are most prevalent in uveal melanoma, mesothelioma, and renal cell carcinoma. 1,15 Mutations occur very infrequently in other cancer types, often leading to exclusion from consideration due to underpowered analyses.…”

“…This work led to further investigations into the role of BAP1 mutations in promoting the development of cancer across multiple tissue types as well as the relation of BAP1 loss to differential survival outcomes. 11–14…”

Hepatitis B virus pathogenesis relevant immunosignals uncovering amino acids utilization related risk factors guide artificial intelligence-based precision medicine

“…SPP1(the CD44 ligand) derived from activated hepatic stellate cells (HSC) serves as a stimulator for KLRG1+ NK cells that can mediate liver scarring limitation in CHB pathogenesis (Wijaya et al, 2019) and has predictive value in the prognosis of HCC (Shang et al, 2012;da Costa et al, 2015). SOX9, which can be directly induced in HBV-infected human hepatoma cells (Yang et al, 2020) has been identified as a risk factor for cirrhosis and HCC (Chen et al, 2021;Damrauer et al, 2021). However, these previous studies are performed just through flow cytometry (FCM), immune fluorescence (IF), and immunohistochemistry (IHC) with limited subpopulations of liver-infiltrating lymphocytes (LILs) and a small samples size; the orchestra of multiple chemokines and ECM related genes with a variety of LILs during HBV pathogenesis are not globally indicated.…”