Abstract 3095: Aneuploidy profiles in hepatocellular carcinoma and their impact on tumor progression and immune features

Introduction: Aneuploidy is a cancer hallmark that includes broad somatic copy-number alterations (SCNAs), being whole chromosome- or arm-level events, or smaller focal SCNAs. Pan-cancer studies suggest that tumor broad and focal SCNAs are linked to distinctive molecular/clinical traits, and broad SCNAs may potentially interfere with tumor immune infiltrates. However, the impact of SCNA genomic loads in hepatocellular carcinoma (HCC) is still unresolved. Here we have assessed broad and focal SCNA burdens in HCC to unveil associations with clinic-molecular characteristics and immune cell profiles. Method: The study includes 520 paired tumor/adjacent surgically resected HCC samples: 150 of a training cohort (HEPTROMIC) and 370 of a validation cohort (TCGA). Tumor ploidy and SCNA segments were extracted from SNP array data using ASCAT and SAASCNV. We applied the CNApp tool (bioinfo.ciberehd.org/CNApp) to extract a Broad SCNA Score (BCS) and Focal SCNA Score (FCS) to assess broad and focal SCNA loads of each sample. Broad and focal alterations were defined as those spanning ≥50% and <50% of a chromosome arm, respectively. Subsequently, the scores were integrated with a) gene expression data, b) clinic-pathological data, and c) the composition of the tumor immune infiltrate, determined using the Immunophenoscore. Results: HCC tumors characterized by a low BCS (25% of Heptromic, 15% of TCGA) were associated with the HCC Immune class and up-regulation of genes related to inflammation, active infiltrate signaling, antigen presentation and cytolytic activity (FDR<0.1, p<0.05). Conversely, tumors with high BCS (25% in Heptromic, 45% in TCGA) were linked to polyploidy and TP53 loss of function, were enriched in proliferation and DNA repair gene signatures and presented up-regulation of genes from immune suppressor cells and cytokines. On the other hand, while tumors with high FCS (25% in Heptromic, 49% in TCGA) were associated with TP53 loss of function, up-regulation of genes related to proliferation and progenitor cells and gene expression signatures suggesting increased tumor aggressiveness. Conversely, low-intermediate FCS tumors displayed higher β-catenin pathway activity, with enrichment in CTNNB1 mutations. FSS was not associated with immunity. Conclusions: Broad are more informative than focal SCNA burdens in terms of molecular features and immune status of HCC tumors. Those tumors characterized by chromosomal stability (low broad SCNAs loads) are enriched in antitumor immune response and antigenicity traits and therefore might correspond to those tumors responding to checkpoint inhibitors. Citation Format: Roger Esteban-Fabró, Laia Bassaganyas, Sara Torrecilla, Agrin Moeini, Sebastià Franch-Expósito, Maria Vila-Casadesús, Ferran Nadeu, Daniela Sia, Itziar Salaverria, Laia Cabellos, Roser Pinyol, Jordi Camps, Vicenzo Mazzaferro, Vicenzo Mazzaferro, Josep M Llovet. Aneuploidy profiles in hepatocellular carcinoma and their impact on tumor progression and immune features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3095.