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Int J Cancer. 2019 May 16. doi: 10.1002/ijc.32412. [Epub ahead of print]

Identification of prognostic molecular biomarkers in 157 HPV-positive and HPV-negative squamous cell carcinomas of the oropharynx.

Author information

1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
2
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
3
Department of Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY.
4
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.

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-IMPACTâ„¢ 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.

KEYWORDS:

NOTCH1; SOX2; HPV; oropharynx; squamous cell carcinoma

PMID:
31093971
DOI:
10.1002/ijc.32412

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