Oral oncology · 2026
High frequency of RB1 mutations p16 positive early stage oropharyngeal carcinoma: A genomic and transcriptomic analysis.
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Brown Matthew H, Mendes William S, Song Yang, Shetty Amol C, Witek Matthew E, Mehra Ranee, Hatten Kyle M, Taylor Rodney J, Moyer Kelly F, Wolf Jeffrey S, Tyer Tiffani N, Steacy Katarina J, Eggleston Caitlin, Datnow Claudia, Gaykalova Daria A, Regine William F, Ren Lei, Tran Phuoc T, Ferris Matthew J, Molitoris Jason K
Аннотация
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.
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.