High frequency of RB1 mutations p16 positive early stage oropharyngeal carcinoma: A genomic and transcriptomic analysis

Background: The genomic landscape of p16 + oropharyngeal cancer (OPX), particularly in early-stage disease, remains limited. Better understandings of the differences between early and late-stage disease may improve elucidation of risk factors that warrant de-escalation. This analysis aims to substantially contribute to existing knowledge of the genomic landscape in an exclusively stage group I/II cohort. Materials and methods: Next-generation sequencing (NGS) DNA mutational profiling (648-gene panel) was performed on 37 samples of p16 + OPX (24 stage I, 13 stage II). Somatic nonsynonymous pathogenic mutations were identified using Mutect2 and the ClinVAR database. Fisher’s exact test compared mutation frequencies with a 107-patient cohort from the literature of largely advanced-stage and metastatic p16 + OPX. Results: Median age was 64; most were male, white, T2-3 node-positive disease. 582 nonsynonymous somatic mutations (median 12/sample) were identified. The median tumor mutation burden per sample was 5 mutations/Mb. 37 pathogenic/likely pathogenic somatic mutations were annotated using the ClinVar database which includes 33 SNPs and 8 INDELs. The top10 pathogenic/likely pathogenic mutated genes were PIK3CA, RB1, FBXW7, FGFR3, TP53, CYLD, B2M, FLCN, FGF23, and ERBB2. Compared to reported rates in predominantly advanced/metastatic stages [1–3], there were high nonsynonymous mutations in KMT2D, 29.7% v. 8.41% [OR4.55 (1.5–13.9) p < 0.01], RB1, 16.2% v. 3.7% [OR4.9 (1.09–25.2) p = 0.02], and FANCA, 13.5% v. 2.8% [OR5.3(1–36) p = 0.03] in our cohort. Conclusions: In this study, the genomic landscape of early-stage p16 + OPX shows comparable mutational frequencies of known genes in advanced/metastatic stages, including PIK3CA, FGFR3, and FBXW7. This early-stage cohort contained higher-than-expected RB1 and KMT2D mutations.