Re: Ashley M. Hopkins, Ganessan Kichenadasse, Christos S. Karapetis, et al. Concomitant Proton Pump Inhibitor Use and Survival in Urothelial Carcinoma Treated with Atezolizumab. Clin Cancer Res. In press. https://doi.org/10.1158/1078-0432.CCR-20-1876

Vollständiger Abstract

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<h4>Purpose</h4>A subset of patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma develops disease recurrence despite generally favorable outcomes. Reliable biomarkers for risk stratification remain lacking. We investigated whether comprehensive viral genomic profiling refines prognostic classification.<h4>Experimental design</h4>Tumor samples from 100 patients with p16-positive and human papillomavirus DNA-positive oropharyngeal squamous cell carcinoma enrolled in two independent cohorts were analyzed using targeted viral capture sequencing. Viral genotype, sublineage, single-nucleotide variation, viral-host integration sites, viral structural variants, clonality, and viral copy number were characterized. Associations with cumulative incidence of progression, progression-free survival and overall survival were assessed at 60 months.<h4>Results</h4>Human papillomavirus 16 was detected in 94 tumors, of which 83 belonged to the HPV16_A1 sublineage. Within this sublineage, 20 tumors harbored strictly episomal viral genomes, whereas 63 exhibited integration and/or viral structural variants. No progression events occurred in the strictly episomal HPV16_A1 subgroup, while 12 occurred among tumors HPV16_A1 with integration and/or structural variant. At 60 months, no progression events were observed in strictly episomal HPV16_A1 tumors, compared with a 23.1% cumulative incidence of progression in HPV16_A1 tumors with integration and/or structural variant. Previously reported high-risk single-nucleotide variants and a novel upstream regulatory region variant were associated with worse progression-free survival. Integration sites were enriched in open chromatin and promoter regions and clustered within viral E2 and E4 genes.<h4>Conclusions</h4>Within human papillomavirus 16 A1 tumors, viral genomic architecture defines clinically distinct subgroups. Strictly episomal (WT) genomes identify a low-risk population, whereas integration and structural variants characterize higher-risk disease.

Abstract: PubMed · Datensatz