Patients with oral cavity squamous cell carcinomas without traditional head and neck cancer risk factors such as smoking history, alcohol use, or human papillomavirus infections demonstrated distinct mutational and molecular profiles compared with tobacco-associated head and neck cancers. Researchers identified two subtypes with no-identified risk factor.
In a study, the researchers analyzed publicly available multi-omics data, including whole-exome sequenced, methylome, and transcriptomic data sets from 347 human papillomavirus (HPV)-unrelated head and neck squamous cell carcinomas. The cohort included 253 oral cavity squamous cell carcinomas and 94 laryngeal cancers used as tobacco-related controls. Mutational-signature extraction identified four clusters dominated by SBS1, SBS1/APOBEC, SBS16, or SBS4/SBS92 mutational processes.
The SBS1 and SBS1/APOBEC clusters accounted for 94% of tumors among patients classified as having no identified risk factors, including patients who were nonsmokers, nondrinkers, and HPV negative. Specifically, 60% of tumors with no-identified risk factors were clustered in the SBS1 group and 34% clustered in the SBS1/APOBEC group. The SBS1 cluster showed elevated clock-like endogenous mutagenesis, whereas the SBS1/APOBEC cluster demonstrated increased apolipoprotein B mRNA–editing enzyme catalytic polypeptide-like–associated mutagenesis and higher mutation burden.
Tumor distribution differed across mutational groups. Oral tongue squamous cell carcinomas were concentrated primarily in the SBS1 cluster, whereas floor-of-mouth tumors were most commonly observed in the SBS16 cluster. Laryngeal tumors predominated in the SBS4/SBS92 cluster. Further, the researchers noted that younger patients were overrepresented in the SBS1 cluster, while older patients were more frequently distributed between the SBS1 and SBS1/APOBEC groups.
Smoking-associated mutational signatures also varied by anatomic site. SBS4 and SBS92, both associated with tobacco exposure, were detected almost exclusively in the highly mutated SBS4/SBS92 larynx-enriched cluster, whereas SBS16 was observed primarily in oral cavity squamous cell carcinoms from smokers and smokers who also consumed alcohol. None of the oral cavity tumors from nonsmoking drinkers carried SBS16. The researchers stated that the findings suggested “distinct mutational processes occurring in the laryngeal tissues of smokers [...] and in oral cavity tissues.”
Genomic and transcriptomic analyses identified additional biologic differences between no-identified-risk-factor and tobacco-associated cancers. Mutations affecting antigen-presentation and immune-response genes, including HLA-A, HLA-B, B2M, and CASP8, were enriched in the SBS1 and SBS1/APOBEC clusters that were specific to cancers with no-identified risk factors. Differential gene-expression analyses also demonstrated increased antimicrobial-response and keratinization pathways in those clusters, including upregulation of S100A7, KLK7, CXCL11, CST9, WFDC12, and DEFB4A. The SBS1/APOBEC subgroup additionally showed elevated APOBEC3A expression and enrichment of pathways associated with bacterial immune responses, cytokine signaling, and T-cell activation.
The study was observational and did not identify a specific environmental or infectious cause for these tumors. The researchers noted that lower mutation counts in some tumors may complicate mutational-signature assignment and increase the risk of overfitting. Validation experiments were limited to two oral tongue squamous cell carcinoma samples. The cohort was derived primarily from US public sequencing data sets, which may have limited generalizability.
“Our study represents the first molecular and genomic characterization of [no-identified risk factor oral cavity sqmaous cell carcinomas], revealing distinct molecular programs of this emerging pathological entity with increasing global incidence,” wrote lead study author Sophie Deneuve, of the Department of Otolaryngology-Head and Neck Surgery at Rouen University Hospital in France, and colleagues.
The study authors reported no competing interests.
