Genetic Signatures of HPV-related and Unrelated Oropharyngeal Carcinoma and Their Prognostic Implications

Abstract

Purpose: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer. Experimental Design: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16 INK4A immunostaining. The results were correlated with HPV status and clinical data from patients. Results: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P = 0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P = 0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P = 0.002, 0.03; <0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P = 0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P = 0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P = 0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P = 0.008; disease-free survival, P = 0.01) and none of these patients had a tumor recurrence. Conclusions: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.

Chromosome stability in tonsillar squamous cell carcinoma is associated with HPV16 integration and indicates a favorable prognosis

“…As stated above, chromosome instability was particularly observed in HPV-negative TSCC from heavy smokers. More likely factors for malignant progression in the Cancer Genetics HPV-positive group include the accumulation of confined chromosomal alterations, such as extra copies of chromosome 3q found in HPV-positive uterine cervical cancers and TSCC, [39][40][41] deletion of 16q, 40,41 and/or modification of the methylation status of the host cell DNA. 42,43 In addition, molecular alterations underlying lymphangiogenesis and epithelial mesenchymal transition might contribute to malignant tumor progression in these cases.…”

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

“…A mutually exclusive association between 11q13.3 amplification, smoking history and HPV/p16 has been widely reported across many populations (Smeets et al, 2006;Ragin et al, 2006;Klussmann et al, 2009;Lechner et al, 2013;Seiwert et al, 2015). Our findings are consistent with this model, observing again an inverse relationship between HPV/p16 status and the presence of CCND1 and ANO1 copy number gains.…”

p16INK4a overexpression predicts translational active human papillomavirus infection in tonsillar cancer

“…22,23 Based on these observations, several studies propose p16 INK4a determined by immunohistochemistry in tumor tissue-derived material to be a useful surrogate marker for HPV-associated disease in HNSCC. 24,25 Exclusively, those HNSCCs being positive for both HPV DNA and p16 INK4a staining are expected to show the typical clinical HPV-related behavior, as mentioned earlier.…”