Recent and Projected Trends in Oral Tongue Cancer in the United States: A Demographic Shift in Case Burden as Early Onset Increases Among Females Subside.

Background: Oral tongue cancer (OTC) incidence has increased rapidly among young (< 50 years) non-Hispanic White (NHW) individuals in the United States (U.S.) over the last two decades; however, it is unknown if age-associated trajectories have persisted. Furthermore, incidence trends for all 50 U.S. states and the District of Columbia have never been investigated. Materials and methods: Using U.S. Cancer Statistics data, we investigated incidence trends from 2001-2019, overall and according to age, sex, race/ethnicity, and state of residence. We used age-period-cohort analysis to explore temporal patterns among birth cohorts and to project future trends and case counts. Results: OTC incidence increased across all age, sex, and racial/ethnic groups, with marked increases observed among the NHWs (2.9%/year; 95%CI, 2.2%-3.7%). Incidence among NHWs increased in most U.S. states, particularly in the Southeast. Increases were significantly greater among NHW females compared to males (3.6%/year vs 2.6%/year; P = 0.022). Increases among females aged 50-59 years were most notable and significantly outpaced increases among younger females (4.8%/year [95% CI, 4.1%-5.4%] vs. 3.3%/year [95% CI, 2.7%-3.8%]; P < .001). While both NHW male and female birth cohorts from 1925 to 1980 saw sustained increases, rates stabilized among females born after 1980. Should trends continue, the burden of new OTC cases among NHWs in the U.S. is projected to shift to older individuals (33.1% versus 49.3% aged ≥ 70) and females (86% case increase versus 62% among males). Conclusion: The period of rapidly increasing OTC incidence among younger NHW females in the U.S. is tempering and giving way to greater increases among older females, suggesting that a birth cohort effect may have influenced previously observed trends. Recent increases among NHWs aged ≥ 50 of both sexes have matched or outpaced younger age groups. Continuing increases among older individuals, particularly females, will lead to a shift in the OTC patient profile over time.

APOBEC Mutagenesis Is Concordant between Tumor and Viral Genomes in HPV-Positive Head and Neck Squamous Cell Carcinoma.

APOBEC is a mutagenic source in human papillomavirus (HPV)-mediated malignancies, including HPV+ oropharyngeal squamous cell carcinoma (HPV + OPSCC), and in HPV genomes. It is unknown why APOBEC mutations predominate in HPV + OPSCC, or if the APOBEC-induced mutations observed in both human cancers and HPV genomes are directly linked. We performed sequencing of host somatic exomes, transcriptomes, and HPV16 genomes from 79 HPV + OPSCC samples, quantifying APOBEC mutational burden and activity in both host and virus. APOBEC was the dominant mutational signature in somatic exomes. In viral genomes, there was a mean of five (range 0-29) mutations per genome. The mean of APOBEC mutations in viral genomes was one (range 0-5). Viral APOBEC mutations, compared to non-APOBEC mutations, were more likely to be low-variant allele fraction mutations, suggesting that APOBEC mutagenesis actively occurrs in viral genomes during infection. HPV16 APOBEC-induced mutation patterns in OPSCC were similar to those previously observed in cervical samples. Paired host and viral analyses revealed that APOBEC-enriched tumor samples had higher viral APOBEC mutation rates (p = 0.028), and APOBEC-associated RNA editing (p = 0.008), supporting the concept that APOBEC mutagenesis in host and viral genomes is directly linked and occurrs during infection. Using paired sequencing of host somatic exomes, transcriptomes, and viral genomes, we demonstrated for the first-time definitive evidence of concordance between tumor and viral APOBEC mutagenesis. This finding provides a missing link connecting APOBEC mutagenesis in host and virus and supports a common mechanism driving APOBEC dysregulation.

A prognostic gene expression signature for oropharyngeal squamous cell carcinoma.

BACKGROUND: Robust prognostic stratification of patients with oropharyngeal squamous cell carcinoma (OPSCC) is important for developing individualized treatment plans. This study was conducted to develop and validate a clinically feasible prognostic classifier based on transcriptome-wide gene expression profiles. METHODS: Tumor tissues were collected from 208 OPSCC patients treated at Washington University in St. Louis and 130 OPSCC patients treated at Vanderbilt University, used for model training and validation, respectively. OPSCC patients (n = 70) from the TCGA cohort were also included for independent validation. Based on RNA-seq profiling data, Cox proportional hazards regression analysis was performed to identify genes associated with disease outcomes. Then, Lasso-penalized multivariate survival models were constructed to identify biomarker genes for developing a prognostic gene signature. FINDINGS: A 60-gene signature was identified by RNA-seq profiling analysis. Computed risk score of the gene signature was significantly predictive of 5-year overall survival of the training cohort (Hazard ratio (HR) 28·32, P = 4·3E-41). Subgroup analysis stratified by HPV status revealed that the signature was prognostic in HPV-positive OPSCC patients (HR 30·55, P = 7·0E-37) and was independent of clinical features. Importantly, the gene signature was validated in two independent patient cohorts, including the TCGA cohort (HR 3·94, P = 0·0018) and the Vanderbilt cohort (HR 8·50, P = 5·7E-09) for overall survival. INTERPRETATION: The prognostic gene signature is a robust tool for risk stratification of OPSCC patients. The signature remains prognostic among HPV-positive OPSCC patients. FUNDING: National Institutes of Health.

HPV16 E6 seropositivity among cancer-free men with oral, anal or genital HPV16 infection.

Antibodies against the Human papillomavirus 16 (HPV16) E6 oncoprotein appear years prior to clinical diagnosis of anal and oropharyngeal cancer, but whether they develop around the time of HPV infection is unclear. Serum samples from 173 cancer-free men from the Human Papillomavirus Infection in Men (HIM) Study were tested for HPV antibodies and DNA. HPV16 E6 seropositivity was low among men with oral HPV16-infection (1/28; 3.6%, 95%CI=0.0%-18.4%), anal HPV16-infection (1/61; 1.6%, 95%CI=0.0%-8.8%), and 24-month persistent genital HPV16-infection (1/84; 1.2%, 0.0-6.5%). This suggests E6 seroconversion may not occur around the time of oral, anal, or genital HPV16 acquisition.

Structure-activity relationships and molecular modeling of the N-(3-pivaloyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl] thiourea template for TRPV1 antagonism.

The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino)benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor.