232MO - Transcriptomic and tumor microenvironment landscape of EBV related nasopharyngeal carcinoma in endemic and non-endemic areas

Background

Epstein-Barr virus (EBV) related nasopharyngeal carcinoma (NPC) is an epithelial malignancy with higher incidence in Asian endemic area (EA) than in non-endemic area (NEA), where frequency is below 1/10⁵/year. The causes of such difference are unclear and might be related to viral, environmental (e.g. diet) and genomic factors. We aimed at dissecting the gene expression (GE) and microenvironment landscape in NPC leading to the identification of molecular subtypes explaining the differences between EA and NEA.

Methods

A survey on public repositories accounted for 6 GE datasets from EA (314 tumor and 35 normal specimens) was performed. Datasets were integrated following a bioinformatics meta-analysis approach. FFPE tumor tissue of 50 Italian EBV related NPC patients were collected at initial diagnosis. RNASeq was carried out by QuantSeq 3' mRNA-Seq (Lexogen). Tumor microenvironment and biological characteristics of EA and NEA cases were evaluated by xCell, and Gene Set Enrichment analyses, while the association with radiosensitivity was assessed with a specific signature.

Results

By unsupervised clustering analysis, four clusters (cl 1,2,3,4) were disclosed in EA. All clusters were predicted in NEA with the exclusion of cl4. To define cl4 identity, we analyzed the EBV-related NPC pathways among the C2 genesets. LIU_NASOPHARYNGEAL_CARCINOMA, WOOD_EBV_EBNA1 TARGETS UP AND DOWN genesets were downregulated in cl4. Cl4 and cl3 exhibited a high RSI index suggesting that patients classified in these clusters are more resistant than patients included in cl2 and cl1 (p=5.9e-05). WOOD_EBV_EBNA1 TARGETS up was upregulated in NEA cl3. The immune-score of EA patients showed a high expression of cl1 followed by normal, cl2, cl4 and cl3 (p=2.2e-16). The immune-score of NEA patients presented the same trend (p=6.4e-09).

Conclusions

To our knowledge this is the first in-deep molecular comparison between EA and NEA NPC. The presence of cl4 only in EA cases could be attributed to inactive EBV NPCs. Biological characterization of clusters already indentified in EA and NEA, validation of our data in a newly identified cohort of EBV positive NPC-EA and drug sensitivity analysis are ongoing.

Clinical trial identification

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Editorial acknowledgement

Legal entity responsible for the study

Lisa Licitra.

Funding

This study is supported by by 5 x 1000 funds - Italian Ministry of Health, financial support for healthcare research).

Disclosure

L.F. Licitra: Financial Interests, Personal, Advisory Board, for expert opinion in advisory boards: AstraZeneca, Bayer, BMS, Eisai, MSD, Merck–Serono, Boehringer Ingelheim, Hoffmann-La Roche Ltd., Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy srl, Doxa Pharma srl, Amgen, Nanobiotics e GSK.; Financial Interests, Institutional, Research Grant, Funds received by my institution for clinical studies and research activities in which I am involved: AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis, Debiopharm International SA, Hoffmann-La Roche Ltd, IRX Therapeutics, Medpace, Merck–Serono, Merck Healthcare KGaA, MSD, Novartis, Pfizer, Roche, Buran. All other authors have declared no conflicts of interest.