Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications.
OBJECTIVE
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.


METHODS
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.
Klussmann
Jens P
JP
Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Jean-Uhrmacher Institute, University of Cologne, Cologne, Germany. peter.klussmann@uni-koeln.de
Mooren
Jeroen J
JJ
Lehnen
Martin
M
Claessen
Sandra M H
SM
Stenner
Markus
M
Huebbers
Christian U
CU
Weissenborn
Soenke J
SJ
Wedemeyer
Inga
I
Preuss
Simon F
SF
Straetmans
Jos M J A A
JM
Manni
Johannes J
JJ
Hopman
Anton H N
AH
Speel
Ernst-Jan M
EJ
D000428:Alcohol Drinking; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism* / Q000821:virology; D002869:Chromosome Aberrations; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005240:Feasibility Studies; D018628:Gene Dosage; D020869:Gene Expression Profiling; D052162:Human papillomavirus 16 / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000821:virology; D030361:Papillomavirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012307:Risk Factors; D012907:Smoking; D015996:Survival Rate
D019941:Cyclin-Dependent Kinase Inhibitor p16