Cold Tumour Phenotype Explained Through Whole Genome Sequencing in Clinical Nasopharyngeal Cancer: A Preliminary Study

Abstract

Handoko,1– 3,* Marlinda Adham,2,4,* Lisnawati Rachmadi,2,5,* Heri Wibowo,6,* Soehartati A Gondhowiardjo1,2,* 1Department of Radiation Oncology, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia; 2Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 3Doctoral Program in Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 4Department of Otorhinolaryngology - Head and Neck Surgery Department, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia; 5Department of Anatomical Pathology, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia; 6Integrated Laboratory, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia*These authors contributed equally to this workCorrespondence: Soehartati A Gondhowiardjo, Faculty of Medicine, Universitas Indonesia, Jl. Salemba Raya No. 6, Jakarta, 10430, Indonesia, Email [email protected]; [email protected]: Nasopharyngeal cancer (NPC) is a complex cancer due to its unique genomic features and association with the Epstein–Barr virus (EBV). Despite therapeutic advancements, NPC prognosis remains poor, necessitating a deeper understanding of its genomics. Here, we present a comprehensive whole genome sequencing (WGS) view of NPC genomics and its correlation with the phenotype.Methods: This study involved WGS of a clinical NPC biopsy specimen. Sequencing was carried out using a long read sequencer from Oxford Nanopore. Analysis of the variants involved correlation with the phenotype of NPC.Results: A loss of genes within chromosome 6 from copy number variation (CNV) was found. The lost genes included HLA-A, HLA-B, and HLA-C, which work in the antigen presentation process. This loss of the major histocompatibility complex (MHC) apparatus resulted in the tumour’s ability to evade immune recognition. The tumour exhibited an immunologically “cold” phenotype, with mild tumour-infiltrating lymphocytes, supporting the possible etiology of loss of antigen presentation capability. Furthermore, the driver mutation PIK3CA gene was identified along with various other gene variants affecting numerous signaling pathways.Discussion: Comprehensive WGS was able to detect various mutations and genomic losses, which could explain tumour progression and immune evasion ability. Furthermore, the study identified the loss of other genes related to cancer and immune pathways, emphasizing the complexity of NPC genomics. In conclusion, this study underscores the significance of MHC class I gene loss and its probable correlation with the cold tumour phenotype observed in NPC.Keywords: nasopharyngeal cancer, genomic, MHC class I, antigen processing and presentation, copy number variation, deletion

Keywords

• nasopharyngeal cancer
• genomic
• mhc class i
• antigen processing and presentation
• copy number variation
• deletion