Genomic landscape of lymphoepithelioma‐like hepatocellular carcinoma

Abstract

Lymphoepithelioma‐like hepatocellular carcinoma (LEL‐HCC) is a distinct variant of HCC that is characterized by dense tumor‐infiltrating lymphocytes (TILs). Patients with LEL‐HCC also show better clinical outcomes compared to conventional HCC (c‐HCC), which is commonly presented with low TIL. Emerging evidence has begun to highlight tumor‐intrinsic genetic abnormalities in the tumor–host immune interfaces. However, genome‐wide characterization of LEL‐HCC remains largely unexplored. Here, we defined the genomic landscape of 12 LEL‐HCC using whole‐exome sequencing, and further underpinned those genetic alterations related to an immune active microenvironment by comparing findings to 15 c‐HCC that were sequenced in parallel. Overall, the mutational load between LEL‐HCC and c‐HCC was similar. Interestingly, SNV incidences of specific genes (CTNNB1, AXIN1, NOTCH1, and NOTCH2) were significantly higher in c‐HCC than LEL‐HCC, suggesting a plausible link between activated Wnt/β‐catenin and Notch signaling pathways and immune avoidance. Marked focal amplification of chromosome 11q13.3 was prevalent in LEL‐HCC. Using The Cancer Genome Atlas dataset, we further established oncogenes expressed from chromosome 11q13.3 (CCND1, FGF19, and FGF4) to be strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Our results have illustrated for the first time the somatic landscape of LEL‐HCC, and highlighted molecular alterations that could be exploited in combinatory therapy with checkpoint inhibitors in targeting HCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

High expression of EMP1 predicts a poor prognosis and correlates with immune infiltrates in bladder urothelial carcinoma

“…Checkpoint inhibitors are monoclonal antibodies that block inhibitory checkpoint antigens and repress the stimulation of T cells, exhibiting anticancer effects (75,76). Upon chronic stimulation by tumor antigens, tumor-infiltrating T cells lose their effector functions and their ability to kill tumor cells, accompanied by a progressive increase in the diversity and number of inhibitory receptors expressed on them, including CD274, PDCD1LG2, HAVCR2, CTLA4, LAG3, PDCD1 and TIGIT (75)(76)(77)(78)(79)(80)(81)(82). Therefore, genes that were associated with immune checkpoints were selected for analysis in the present study.…”

Pathomolecular characterization of HCC in non-cirrhotic livers

“…Lymphocyte-rich HCCs are characterized by an immune rich stroma and have been demonstrated to have cirrhosis in only 46% of cases in a recent comprehensive review [104] . Molecular studies have revealed that mutations of CTNNB1, AXIN1, APC, NOTCH1 and NOTCH2 were less frequently observed in lymphocyte-rich HCCs than conventional HCCs [105] , suggesting a relation between these pathways and immune exclusion. In lymphoepithelioma-like HCC, oncogenes expressed from chromosome 11q13.3 (CCND1FGF19, and FGF4) are strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3).…”

“…In lymphoepithelioma-like HCC, oncogenes expressed from chromosome 11q13.3 (CCND1FGF19, and FGF4) are strongly associated with the immune checkpoint signature (CD274, PDCD1, BTLA, CTLA4, HAVCR2, IDO1, and LAG3). Such differences in genetic aberrations from classical HCCs provide insight into the need for therapeutic strategies that evade immune surveillance seen in classical HCCs [105,106] . Scirrhous HCC is another variant, which is less often associated with liver cirrhosis when compared with conventional HCC [55] .…”

An update on the histological subtypes of hepatocellular carcinoma

“…While a few studies demonstrated a trend of better survival with this subtype [19][20][21]28] , the prognostic significance of this subtype remains to be clarified due to its rarity. The genomic landscape of 12 lymphocyte-rich HCC was determined by whole-exome sequencing in a recent report [32] . Mutations of CTNNB1, AXIN1, APC, NOTCH1 and NOTCH2 were less frequently observed in lymphocyte-rich HCC than conventional HCC.…”