Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma

Abstract

Background and Aims: Chromosomal instability is a hallmark of cancer that results in broad and focal copy number alterations (CNAs), two events associated with distinct molecular, immunological and clinical features. In hepatocellular carcinoma (HCC) the CNAs role has not been thoroughly assessed. Thus, we dissected the impact of CNA burdens on HCC molecular and immune features. Methods: We analyzed SNP-array data from 452 paired tumor/adjacent resected HCCs and 25 dysplastic nodules. For each sample, broad and focal CNA burdens were quantified using CNApp, and the resulting broad scores (BS) and focal scores (FS) were correlated with transcriptomic, mutational and methylation profiles, tumor immune composition, and with clinico-pathological data. Results: HCCs with low broad CNA burdens (defined as BS≤4; 17%) presented high inflammation, active infiltrate signalling, high cytolytic activity, and enrichment of the 'HCC-Immune-Class' and gene signatures related to antigen presentation. Conversely, tumors with chromosomal instability (high broad CNA loads, BS≥11; 40%), displayed immune excluded traits and were linked to proliferation, TP53 dysfunction, and DNA repair. Candidate determinants of the low cytotoxicity and immune exclusion features of high-BS tumors included alterations in antigen presenting machinery (i.e. HLA), widespread hypomethylation and decreased rates of observed/expected neoantigenic mutations. High focal scores were independent of tumor immune features, but were related to proliferation, TP53 dysfunction and progenitor cell traits. Research.

Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

“…In addition, we further investigated the molecular features of tumors with low and high CNV risk scores, and the results showed that tumors with high CNV risk scores were characterized as highly malignant, as reflected by the TMB, MMB and CNI score. A recent study reported that HCC with high broad CNV score showed high mutational burdens, 35 which was similar to our study. In addition, this study indicated that patients with HCC with high broad CNV scores had lower ratio of observed/expected neo-antigens.…”

“…[31][32][33][34] A recent study found that HCC tumors with a low burden of broad copy number chromosomal alterations display higher immune infiltration and have a better response rate to anti-PD-1 inhibitors than those with a median/high broad copy number. 35 Moreover, Davoli et al 31 found that a higher CNV burden in tumor tissue correlated with immune escape and poorer survival in patients with metastatic melanoma treated with immunotherapy. Regarding liquid biopsy, Weiss et al 36 constructed a CNI scoring system based on plasma cfDNA and found that the CNI score could be used as an early indicator of the response Open access to immunotherapy for diverse advanced cancers.…”

“…It suggested that the accumulation of CNV may be associated with an enhanced editing of non-antigenic mutations, regardless of overall mutation burdens. 35 These findings may explain the poor clinical outcome of patients with tumors with high CNV risk scores treated with ICI-based therapy.…”

Are Molecular Alterations Linked to Genetic Instability Worth to Be Included as Biomarkers for Directing or Excluding Melanoma Patients to Immunotherapy?

“…Moreover, tumor aneuploidy is likely to increase intratumor heterogeneity, which may inhibit tumor immunity ( 63 ). Many solid cancers presenting with a high somatic copy alteration burden exhibit features of immune exclusion, whereas tumors displaying low rates of aneuploidy present an immune active profile ( 26 , 27 , 64 ). High-level SCNAs are classified through bioinformatic approaches as events where focal copy number gain (or loss) are higher (or lower) than the maximum (or minimum) median arm-level copy number gain (or loss), hence avoiding artifacts or false positives after comparison with low-level SCNAs linked to the ploidy of tumor samples and thus obtaining more reliable thresholds ( 65 , 66 ).…”

Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics

“…Aneuploidy, the harboring of an abnormal number of chromosomes, in several tumors has been reported as a predictive biomarker for efficacy of immune checkpoint inhibitor (78). A recently conducted study on the relationship between copy number alterations (CNAs) and immune profiles of HCC, found that higher levels of broad CNAs resulting from aneuploidy show less immune-cell infiltration and are regarded as the primary reason for resistance to immune therapy (79). This CNAs and immune-phenotype relationship was seen in dysplastic nodules and early HCC.…”