Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis

Paul M. Weinberger, Ziwei Yu, Bruce Haffty, Diane Kowalski, Malini Harigopal, Janet Brandsma, Clarence Sasaki, John Joe, Robert L. Camp, David L. Rimm, Amanda Psyrri

Research output: Contribution to journalArticle

573 Citations (Scopus)

Abstract

Purpose: We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Methods: Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Results: Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Conclusion: Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.

Original languageEnglish (US)
Pages (from-to)736-747
Number of pages12
JournalJournal of Clinical Oncology
Volume24
Issue number5
DOIs
StatePublished - Feb 10 2006
Externally publishedYes

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Oropharyngeal Neoplasms
Retinoblastoma
Squamous Cell Carcinoma
Recurrence
Survival
Survival Analysis
Viral Load
Disease-Free Survival
Real-Time Polymerase Chain Reaction
Neoplasms
Up-Regulation
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Weinberger, Paul M. ; Yu, Ziwei ; Haffty, Bruce ; Kowalski, Diane ; Harigopal, Malini ; Brandsma, Janet ; Sasaki, Clarence ; Joe, John ; Camp, Robert L. ; Rimm, David L. ; Psyrri, Amanda. / Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis. In: Journal of Clinical Oncology. 2006 ; Vol. 24, No. 5. pp. 736-747.
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title = "Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis",
abstract = "Purpose: We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Methods: Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Results: Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79{\%}) compared with the other two classes (20{\%} and 18{\%}; P = .0095). Disease-free survival for the same class was 75{\%} versus 15{\%} and 13{\%} (P = .0025). The 5-year local recurrence was 14{\%} in class III versus 45{\%} and 74{\%} (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Conclusion: Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.",
author = "Weinberger, {Paul M.} and Ziwei Yu and Bruce Haffty and Diane Kowalski and Malini Harigopal and Janet Brandsma and Clarence Sasaki and John Joe and Camp, {Robert L.} and Rimm, {David L.} and Amanda Psyrri",
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Weinberger, PM, Yu, Z, Haffty, B, Kowalski, D, Harigopal, M, Brandsma, J, Sasaki, C, Joe, J, Camp, RL, Rimm, DL & Psyrri, A 2006, 'Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis', Journal of Clinical Oncology, vol. 24, no. 5, pp. 736-747. https://doi.org/10.1200/JCO.2004.00.3335

Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis. / Weinberger, Paul M.; Yu, Ziwei; Haffty, Bruce; Kowalski, Diane; Harigopal, Malini; Brandsma, Janet; Sasaki, Clarence; Joe, John; Camp, Robert L.; Rimm, David L.; Psyrri, Amanda.

In: Journal of Clinical Oncology, Vol. 24, No. 5, 10.02.2006, p. 736-747.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular classification identifies a subset of human papillomavirus- associated oropharyngeal cancers with favorable prognosis

AU - Weinberger, Paul M.

AU - Yu, Ziwei

AU - Haffty, Bruce

AU - Kowalski, Diane

AU - Harigopal, Malini

AU - Brandsma, Janet

AU - Sasaki, Clarence

AU - Joe, John

AU - Camp, Robert L.

AU - Rimm, David L.

AU - Psyrri, Amanda

PY - 2006/2/10

Y1 - 2006/2/10

N2 - Purpose: We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Methods: Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Results: Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Conclusion: Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.

AB - Purpose: We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Methods: Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Results: Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Conclusion: Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.

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