Identification of prognostic molecular biomarkers in 157 HPV-positive and HPV-negative squamous cell carcinomas of the oropharynx Journal Article
| Authors: | Dogan, S.; Xu, B.; Middha, S.; Vanderbilt, C. M.; Bowman, A. S.; Migliacci, J.; Morris, L. G. T.; Seshan, V. E.; Ganly, I. |
| Article Title: | Identification of prognostic molecular biomarkers in 157 HPV-positive and HPV-negative squamous cell carcinomas of the oropharynx |
| Abstract: | The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing due to high-risk HPV infection. We explored the significance of genetic alterations in HPV-positive (HPV-P) and HPV-negative (HPV-N) OPSCC patients on long-term outcome. A total of 157 cases of primary resected OPSCC diagnosed from 1978 to 2005 were subjected to a targeted exome sequencing by MSK-IMPACTTM interrogating somatic mutations in 410 cancer-related genes. Mutational profiles were correlated to recurrence and survival outcomes. OPSCC included 47% HPV-positive (HPV-P) and 53% HPV-negative (HPV-N) tumors arising in the base of tongue (BOT, 43%), palatine tonsil (30%) and soft palate (SP, 27%). HPV negative status, SP location and smoking were associated with poorer outcome. Poorer overall survival was found in NOTCH1-mutated HPV-P (p = 0.039), and in SOX2-amplified HPV-N cases (p = 0.036). Chromosomal arm gains in 8p and 8q, and 16q loss were more common in HPV-P (p = 0.005, 0.04 and 0.01, respectively), while 9p, 18q and 21q losses were more frequent in HPV-N OPSCC (p = 0.006, 0.002 and 0.01, respectively). Novel, potentially functional JAK3, MYC and EP300 intragenic deletions were found in HPV-P, and FOXP1, CDKN2A, CCND1 and RUNX1 intragenic deletions and one FGFR3 inversion were detected in HPV-N tumors. HPV-N/TP53-wild-type OPSCC harbored recurrent mutations in NOTCH1/3/4 (39%), PIK3CA, FAT1 and TERT. In comparison to their oral and laryngeal counterparts, HPV-N OPSCC were genetically distinct. In OPSCC, HPV status, tumor subsite and smoking determine outcome. Risk-stratification can be further refined based on the mutational signature, namely, NOTCH1 and SOX2 mutation status. © 2019 UICC |
| Keywords: | adult; controlled study; aged; major clinical study; overall survival; somatic mutation; squamous cell carcinoma; gene; progression free survival; chromosome 9p; smoking; fibroblast growth factor receptor 3; protein p53; tumor suppressor gene; tumor recurrence; cyclin dependent kinase inhibitor 2a; chromosome 8p; tongue; pik3ca gene; sox2; transcription factor sox2; oncogene myc; chromosome 16q; notch1 receptor; chromosome 8q; oropharynx; notch3 receptor; notch4 receptor; transcription factor runx1; copy number variation; e1a associated p300 protein; chromosome 18q; papillomavirus infection; hpv; janus kinase 3; notch1; cdkn2a gene; soft palate; cancer prognosis; sox2 gene; ep300 gene; fgfr3 gene; tert gene; ccnd1 gene; human; male; female; priority journal; article; chromosome 21q; runx1 gene; whole exome sequencing; oropharynx squamous cell carcinoma; notch1 gene; foxp1 gene; fat1 gene; jak3 gene; notch3 gene; notch4 gene; palatine tonsil |
| Journal Title: | International Journal of Cancer |
| Volume: | 145 |
| Issue: | 11 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2019-12-01 |
| Start Page: | 3152 |
| End Page: | 3162 |
| Language: | English |
| DOI: | 10.1002/ijc.32412 |
| PUBMED: | 31093971 |
| PROVIDER: | scopus |
| PMCID: | PMC7595146 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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