Genetic Mutations Associated with Inflammatory Response Caused by HPV Integration in Oropharyngeal Squamous Cell Carcinoma

Abstract

(1) Background: Head and neck cancer (HNC) ranks as the sixth most prevalent cancer in the world. In addition to the traditional risk factors such as alcohol and tobacco consumption, the implication of the human papillomavirus (HPV) is becoming increasingly significant, particularly in oropharyngeal cancer (OPC). (2) Methods: This study is based on a review analysis of different articles and repositories investigating the mutation profile of HPV-related OPC and its impact on patient outcomes. (3) Results: By compiling data from 38 datasets involving 8311 patients from 12 countries, we identified 330 genes that were further analyzed. These genes were enriched for regulation of the inflammatory response (RB1, JAK2, FANCA, CYLD, SYK, ABCC1, SYK, BCL6, CEBPA, SRC, BAP1, FOXP1, FGR, BCR, LRRK2, RICTOR, IGF1, and ATM), among other biological processes. Hierarchical cluster analysis showed the most relevant biological processes were linked with the regulation of mast cell cytokine production, neutrophil activation and degranulation, and leukocyte activation (FDR < 0.001; p-value < 0.05), suggesting that neutrophils may be involved in the development and progression of HPV-related OPC. (4) Conclusions: The neutrophil infiltration and HPV status emerge as a potential prognostic factor for OPC. HPV-infected HNC cells could potentially lead to a decrease in neutrophil infiltration. By gaining a better molecular understanding of HPV-mediated neutrophil immunosuppression activity, it is possible to identify a meaningful target to boost antitumor immune response in HNC and hence to improve the survival of patients with HNC.

Therapeutic Advances and Challenges for the Management of HPV-Associated Oropharyngeal Cancer

“…Currently, clinical data that support the use of alternative drugs for the treatment of the 10 most mutated genes (TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A [15]) in HPV-positive HNC are limited. Despite showing potential as novel HNC targets, few registered ongoing clinical trials are investigating drugs that may target these genes (Table 1).…”

“…These studies spanned 8311 patients across 12 countries. The mutated genes identified most often in these 38 studies included TP53 (n = 22), PIK3CA (n = 20), PTEN (n =16), NOTCH1 (n = 14), RB1 (n = 13), FAT1 (n = 13), FBXW7 (n = 12), HRAS (n = 10), KRAS (n = 10), and CDKN2A (n = 10) [15]. TP53 was the most cited mutated gene among the studies reviewed.…”

“…Due to the distinct genetic landscape and etiology of HPV-positive HNC, it is increasingly recognized as a unique HNC subtype, with its genetic and mutational profile offering new targets for de-escalated drug therapies. Recently, our group identified, based on public data repository, the genes that are commonly mutated in HPV-positive HNC, including TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A [15]. These genes were involved in proliferative and apoptotic mechanisms, supporting cancer cell growth when dysregulated [15].…”

“…Recently, our group identified, based on public data repository, the genes that are commonly mutated in HPV-positive HNC, including TP53, PIK3CA, PTEN, NOTCH1, RB1, FAT1, FBXW7, HRAS, KRAS, and CDKN2A [15]. These genes were involved in proliferative and apoptotic mechanisms, supporting cancer cell growth when dysregulated [15]. As such, drugs that target these genes and their signaling pathways could provide alternative de-intensified treatment strategies for HPV-positive HNC (Figure 5).…”

“…Currently, eight semi-synthetic or synthetic agents have been approved for use against all HNC subtypes, including bleomycin sulfate, cetuximab (Erbitux), docetaxel (Taxotere), hydroxyurea (Hydrea), pembrolizumab (Keytruda), loqtorzi (Toripalimab-tpzi), methotrexate sodium (Trexall), and nivolumab (Opdivo) [14]. Furthermore, based on a systematic data collection from the literature, our team has recently identified commonly mutated genes in HPV-positive OPC, which may provide avenues for novel therapeutic target selection and drug development [15]. This comprehensive review explored the status of approved therapies (chemotherapy, immunotherapy, and target therapy), therapies that are currently under investigation, and potential investigational drugs and treatment strategies that can be further studied in the context of head and neck cancer research.…”