Sinonasal squamous cell carcinomas are extremely rare malignancies, occurring at an incidence rate of roughly three cases per million annually. Despite their scarcity, SNSCCs are clinically significant because their anatomical origins near sensitive structures such as the eyes and nasal passages allow tumors ample space to grow unnoticed, often leading to diagnosis at advanced stages. The overall five-year survival rate for SNSCC remains dismally around 50%, underscoring the urgent need for insights into tumor biology and potential intervention strategies.

HPV’s involvement in head and neck cancers has been well documented, particularly in oropharyngeal squamous cell carcinoma, where it is a major oncogenic driver. However, its role in SNSCC has been under debate, with some researchers postulating that HPV presence was incidental, a passive inhabitant rather than an active disease instigator. The Johns Hopkins investigation, led by associate professor Nyall London Jr., M.D., Ph.D., employed whole-genome sequencing to conduct the first comprehensive comparison between HPV-associated and HPV-independent SNSCCs, definitively demonstrating that HPV actively drives tumor biology in many SNSCC cases.

The research team analyzed tumor specimens from fifty-six patients diagnosed with SNSCC arising from the sinonasal cavity or the nasolacrimal duct, including matched normal DNA to identify somatic mutations. Thirty-seven of these samples exhibited HPV association, primarily localized to tumors originating in the nasal cavity, whereas HPV-independent tumors predominantly arose in the maxillary sinus. An interesting clinical observation was that patients with HPV-associated tumors tended to present with disease at a younger average age of approximately sixty years compared to sixty-six years for those with HPV-negative cancers.

Genomic profiling revealed starkly divergent mutational landscapes between HPV-associated and HPV-independent SNSCCs. The HPV-negative tumors commonly harbored mutations in classic oncogenic drivers such as TP53, NOTCH1, and KRAS, as well as alterations in CDKN2A and other genes implicating cell cycle regulation and structural integrity. Conversely, HPV-associated tumors frequently mutated genes involved in chromatin remodeling and epigenetic regulation, including KMT2D, FGFR3, KMT2C, GOLGA5, TET1, and ARID1B, highlighting a distinct oncogenomic pathway underpinning viral-driven carcinogenesis in the sinonasal tract.

The presence of hotspot mutations—those occurring at high frequency and conferring selective advantage—was confirmed chiefly in HPV-related SNSCCs. In particular, missense mutations like E542K and E545K in the PIK3CA gene were prominent, as were S249C mutations in FGFR3. These alterations lead to aberrant activation of the PI3K signaling pathway, a critical mediator of cell proliferation and survival. Notably, none of these hotspot mutations were detected in the HPV-independent cohort, further delineating the molecular divide between the two tumor types. Additionally, recurrent mutations not previously associated with other cancer types, such as KMT2C N729D and AP3S1 P158L, were identified exclusively in HPV-driven SNSCCs, suggesting unique mutational fingerprints.

Clinically relevant correlations emerged from the mutational analysis—mutations in TP53 among HPV-negative tumors predicted poorer overall survival, paralleling trends observed in other head and neck squamous cell carcinomas. Within the HPV-positive group, mutations in KMT2D and FGFR3 were similarly associated with worsened prognosis, emphasizing the clinical impact of these genetic aberrations. The study also reinforced the presence of a characteristic APOBEC mutational signature in HPV-driven SNSCCs, indicative of the action of specific cytidine deaminases that create a fingerprint unique to virally induced malignancies.

In addition to identifying genetic mutations, the researchers explored the functional pathways altered in these cancers. HPV-associated SNSCCs demonstrated heightened activity in both the PI3K and YAP/TAZ signaling pathways, which regulate cellular growth, survival, and mechanotransduction. HPV-independent tumors showed increased engagement of PI3K, as well as RAS and MYC pathways, underscoring differential oncogenic mechanisms. This dichotomy opens windows for targeted therapeutics tailored to tumor etiology.

Capitalizing on these insights, the team successfully established a novel cell line derived from a patient with HPV-associated SNSCC. They probed the therapeutic potential of pathway-specific inhibitors by administering alpelisib, a PI3K pathway blocker, alongside verteporfin, which inhibits the YAP/TAZ pathway. The combinatorial treatment produced a synergistic effect, markedly inhibiting tumor cell proliferation in vitro, highlighting promising avenues for dual-targeted therapy in HPV-driven sinonasal cancers.

The study’s authors caution that while the findings are compelling, validation in larger patient cohorts is necessary to fully comprehend the biological and clinical significance of the newly identified recurrent mutations. Nonetheless, the revelation of five previously undescribed mutations exclusive to HPV-associated SNSCC is a remarkable advance that could redefine molecular classification and treatment paradigms for these malignancies. Ongoing research efforts are aimed at elucidating the mechanistic roles and therapeutic exploitable vulnerabilities linked to these alterations.

Parallel investigations are underway to examine behavioral and epidemiological factors influencing HPV presence in sinonasal tumors, potentially offering preventive insights. As the molecular taxonomy of SNSCC becomes clearer, the integration of genomic data with epidemiology and clinical characteristics promises to refine diagnosis, prognosis, and personalized treatment strategies for this rare but formidable cancer subclass.

This study received funding from the NIH’s Intramural Research Program, the Center for Cancer Research and National Cancer Institute, and Merck Sharp & Dohme LLC. It represents a collaborative effort involving researchers from Johns Hopkins University, the National Cancer Institute, University of California San Diego Health, and Harvard Medical School, jointly propelling our understanding of HPV’s oncogenic role beyond the oropharynx and into the sinonasal milieu.

Subject of Research: Sinonasal squamous cell carcinomas (SNSCCs) and the oncogenic role of human papillomavirus (HPV)

Article Title: Human papillomavirus drives tumor development in rare sinonasal squamous cell carcinomas: Comprehensive genomic characterization reveals distinct mutational landscapes and therapeutic targets

News Publication Date: June 11, 2025

Web References:

• Johns Hopkins University School of Medicine: https://www.hopkinsmedicine.org/som/
• Johns Hopkins Kimmel Cancer Center: https://www.hopkinsmedicine.org/kimmel-cancer-center
• Nature Communications article: https://www.nature.com/articles/s41467-025-59409-7

References:

• Prior HPV association study: https://pmc.ncbi.nlm.nih.gov/articles/PMC7286346/
• SNSCC incidence study: https://onlinelibrary.wiley.com/doi/10.1002/lary.24264

Image Credits: Johns Hopkins Medicine

Keywords: Cancer cells, Cancer research, Cancer treatments, Human papillomavirus, Sinonasal squamous cell carcinoma, Genomic characterization, Oncogenic mutations, PI3K pathway, YAP/TAZ pathway, Targeted therapy

A recent study published in Science China Life Sciences brought to light a novel circular RNA named circTP63-N that emerges during the splicing of the TP63 gene, noteworthy for its implications in NPC. The TP63 gene, an essential member of the TP53 family, is predominantly involved in cellular processes such as proliferation and differentiation. The study’s lead figures, Professors Zhaoyang Zeng and Can Guo, along with Researcher Wenjia Guo, spotlight the diminished levels of circTP63-N in clinical NPC samples, just as they underscore its substantial presence in healthy nasopharyngeal epithelium. Their findings indicated that restoring circTP63-N expression notably inhibits NPC cell proliferation and metastasis, stirring interest in its potential as a therapeutic target.

Delving deeper into the molecular landscape of the TP63 gene reveals its complex structure and varied splicing possibilities. This gene possesses two independent promoters: one situated upstream of exon 1, driving the transcription of TAp63, and the other located within intron 3, responsible for the transcription of ΔNp63. Collectively, these promoters give rise to distinct isoforms that undergo further processing to produce numerous variants, including α, β, and γ transcripts. While studies have identified other circular RNAs, such as circTP63, implicated in oncogenic processes, the exploration of circTP63-N’s role is unprecedented, marking a significant contribution to understanding NPC biology.

It is particularly intriguing that the research team noted a stark contrast between the expression levels of circTP63 and circTP63-N in NPC. Although circTP63 has been characterized in various malignancies as an oncomir, their analysis revealed that the expression of circTP63 was either greatly reduced or entirely absent in both NPC cell lines and biopsy specimens. Conversely, circTP63-N displayed a unique expression pattern, characterized by its abundance in non-cancerous nasopharyngeal tissues and significant downregulation in cancerous samples—a finding that could hold critical implications for diagnostic and therapeutic strategies.

In terms of functionality, the study meticulously demonstrated that circTP63-N interacts directly with HSP90AB1, a protein that has garnered attention for its involvement in several tumorigenic processes. By binding to HSP90AB1, circTP63-N facilitates the recruitment of LATS1/2 and YAP1 proteins. This recruitment orchestrates a cascade of molecular events leading to the phosphorylation and subsequent degradation of YAP1 through ubiquitin-mediated mechanisms. As YAP1 is pivotal for the transcriptional activation of genes associated with invasion and proliferation, including those related to the extracellular matrix and the cell cycle, the implications of circTP63-N in hindering NPC progression are profound.

The study’s innovative approach combined in vitro and in vivo experiments to validate the inhibitory effects of circTP63-N on NPC cells. Results revealed that enforced expression of this circular RNA not only curtailed the proliferation of NPC cells but also effectively diminished their invasive and migratory capabilities. Such insights not only augment our understanding of the regulatory networks governed by the TP63 gene but also emphasize circTP63-N as a novel player with significant regulatory potential in cancer biology.

Furthermore, the authors acknowledged the contribution of various collaborators in the study, including Professors Guiyuan Li, Wei Xiong, and Bo Xiang. Their collective efforts highlight the importance of interdisciplinary research in unraveling the complexities of cancer biology, particularly in niche areas such as circRNA function and gene regulation. The study presents promising avenues for research into therapeutic interventions that could potentially augment the current arsenal against NPC.

Emerging research into circRNA such as circTP63-N may reshape therapeutic strategies for malignancies like NPC. As the understanding of these molecules deepens, it opens the door for innovative treatments that leverage the unique properties of circRNAs to modulate tumor behavior. The potential for circRNAs to act as biomarkers for diagnosis or therapeutic targets can revolutionize traditional approaches to cancer treatment.

The implications of this research resonate beyond nasopharyngeal carcinoma, as they touch upon larger themes within cancer biology relating to gene regulation and the multifaceted roles of non-coding RNAs. As the landscape of cancer research continues to evolve, studies like this pave the way for breakthroughs that could lead to more effective, targeted treatment options and improve patient outcomes for those battling malignancies.

In conclusion, the recent study exploring circTP63-N’s role in nasopharyngeal carcinoma sheds light on new molecular mechanisms underlying tumor behavior. While much is yet to be uncovered, the initial findings pave the way for future explorations that could not only provide clarity regarding NPC but also enhance our understanding of circular RNAs in cancer and their therapeutic potential. The spotlight on circTP63-N underlines the importance of ongoing research endeavors aimed at unlocking the complex dance between genes, their transcripts, and their roles in cancer.

Subject of Research: Nasopharyngeal carcinoma and circular RNA
Article Title: CircTP63-N suppresses the proliferation and metastasis of nasopharyngeal carcinoma via engaging with HSP90AB1 to modulate the YAP1/Hippo signaling pathway
News Publication Date: October 2023
Web References: 10.1007/s11427-023-2737-2
References: Science China Life Sciences, October 2023
Image Credits: ©Science China Press

Keywords: Nasopharyngeal carcinoma, circular RNA, circTP63-N, TP63 gene, HSP90AB1, YAP1, Hippo signaling pathway, tumor biology, cancer research.