title: Integration of Multi-Amics approaches in Head and Neck Cancer and Their Clinical Implications.
Creators: name: Lenoci, Deborah
Publisher: name: The Open University
Year: 2025

description: Head and Neck Cancers (HNC) are the 6th most deadly tumours worldwide, with ~630.000 newly detected cases (150.000 in Europe) and ~350.000 deaths every year (~70,000 in Europe). HNC develop in the mucosal linings of the upper aerodigestive tract (oral cavity, larynx, oropharynx, hypopharynx) and over 90% are squamous cell carcinomas (head and neck squamous cell carcinoma- HNSCC). Risk factors for HNC are smoking and excessive alcohol consumption, and infection with the human papillomavirus (HPV). The majority of patients are still detected in advanced stages (III and IV). Currently, risk stratification and treatment decisions are determined based on the consensus of a multidisciplinary team using international guidelines based on the TNM staging system. Treatments include surgery or radiation alone for early-stage disease (stage I and II) and multimodal interventions, usually surgery followed by postoperative radiotherapy or definitive chemoradiation for loco-regional advanced disease (Stage III and IV). Despite improvements in diagnosis, therapy, pre-clinical and translational research efforts, the 5-year mortality rate has not changed in the past 20 years and remained roughly 50% for subjects with loco-regionally advanced disease. The recent improvements in next-generation sequencing field have enabled the whole genome/transcriptome profiling to advance our knowledge on the disease. Moreover, the role of epigenomics in cancer has still to be considered, as well as processing factors or non-coding RNAs such as miRNAs and lncRNAs. Till now, in literature is not described the biological evolution of the disease starting from early stages, through late stages until recurrent and metastatic (RM) disease. We want to disclose through the biology, if the tumour is born already in an advanced stage or it is an evolution of early stage. One of the purposes is the research of new biomarkers that could predict the evolution of the disease. Herein, we investigated the integration of gene-miRNA-lncRNA of early, late and RM. Among expressed pathways, circadian rhythm, hypoxia and senescence are the most interesting pathways due to their involvement in HNSCC progression and their gene-miRNA-lncRNA integration changed through the stages. Moreover, hypoxia was strictly linked with circadian rhythm. Circadian rhythm and senescence resulted upregulated in early stages and downregulated in RM. The circadian genes and miRNA with a prognostic value in late stages were TBL1X, hsa-miR-145-5, hsa-miR-181d-5p, hsa-miR-22-3p, hsa-miR-328-3p, hsa-miR-494-3p while for RM were NR3C1, hsa-miR-1275, hsa-miR-200c-5p, hsa-miR-29b-2-5p, hsa-miR-324-5p, hsa-miR-328-3p and hsa-miR-3974. The senescence genes and miRNA with a prognostic value were expressed only in RM and were MAPK9, STAT3, hsa-let-7e-5p, hsa-miR-1248, hsa-miR-125b-5p, hsa-miR-1301-3p, hsa-miR-205-3p, hsa-miR-29a-5p, hsa-miR-30c-1-3p, hsa-miR-30d-5p, hsa-miR-3173-5p, hsa-miR-320b, hsa-miR-320c, hsa-miR-324-5p, hsa-miR-331-5p and hsa-miR-4273. In conclusion, the current study demonstrated that HNSCC is a heterogeneous disease due to the complex interaction among genes, miRNA and lncRNA that could changed through the stages. Moreover, the tumour microenvironment was considered and we found that early stages presented the highest immunoscore while RM the lowest. Late stages showed the highest expression of pro-tumoural and immunosuppressive cells. In the future we need to consider more prognostic biomarkers that interacts each other. This PhD project gives the starting point to study HNSCC in a different way considering the global molecular vision of the disease.