P16^INK4A as a surrogate biomarker for human papillomavirus‐associated oropharyngeal carcinoma: Consideration of some aspects

Abstract

Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) frequently show different clinical and pathological features, which tend to be younger age, better performance status, less tobacco and alcohol consumption, more poorly differentiated histopathology, but usually with better treatment response and prognosis compared with HPV-negative OPSCCs. In tumor tissue, HPV infection is closely correlated with p16INK4A expression, which has been suggested to be a surrogate biomarker of HPV infection. However, there is diversity of sensitivity and specificity about p16INK4A in surrogate detection of HPV status. Herein, we summarize the current knowledge and note some aspects for consideration concerning p16INK4A as a surrogate biomarker for HPV-associated OPSCC. (Cancer Sci 2013; 104: 1553-1559 A s one of the cyclin-dependent kinase inhibitors that inhibit cyclin-dependent kinases 4 and 6, p16INK4A is encoded by the tumor suppressor gene CDKN2A. In nonhuman papillomavirus (HPV) infected carcinomas, p16 INK4A frequently showed in low levels or loss for epigenetic alteration and gene mutation.(1) However, in HPV-related cervical lesions and head and neck squamous cell carcinomas (HNSCCs), oncoprotein E7 could combine with Rb, and cause the dysfunction of Rb. The functional inactivation of Rb by E7 therefore results in the release of the transcriptional factor E2F from the Rb-E2F protein complex and the promotion of cell cycle progression, and also leads to release of the p16 INK4Agene from its transcriptional inhibition, causing p16INK4A to be expressed at a high level.(2-4) Because of this molecular event, the fact that p16INK4A turned out to be substantially overexpressed in virtually all HPV-transformed cells in cervical lesions, p16INK4A expression has been used for distinguishing high-risk from low-risk HPV infection, (5) for ancillary confirmation and grading of histological diagnosis of cervical intraepithelial neoplasia, (6) and for predicting progression or regression of low-grade cervical intraepithelial neoplasia. (7,8) Considering the etiological link with HPV in HNSCCs, p16INK4A expression has been detected in many HPV-related HNSCCs.( Human papillomavirus infection was found in 25.9% of head and neck cancers and 35.6% of oropharyngeal squamous cell carcinomas (OPSCCs).(16) Patients with HPV-associated OPS-CC are frequently of a younger age at the time of diagnosis, with better performance status, less tobacco and alcohol exposure, (17) with oral-genital sexual behavior, (18,19) poorly differentiated disease, and better prognosis than OPSCC patients without HPV infection. (13,20) We collected published reports on OPSCCs with p16 INK4A expression and simultaneous HPV DNA detection (PCR and ⁄ or in situ hybridization [ISH]) in the past 5 years in the PubMed medical literature database, (9,(21)(22)(23)(24)(25)(26)(27)(28)(29) and found that the sensitivity of p16 INK4A for HPV DNA detection varied from 46% to 98%. Although it was recognized that overexpression of p16INK4A was closel...

Sensitivity Evaluation of SYBR Green I, SYBR Safe and Calcein Dyes for Detection of Human Papillomavirus 16 by Loop-Mediated Isothermal Amplification

“…By naked eye visualization, the all three dyes demonstrated similar sensitivities, in which the detection limit was 10 3 copies/μl of HPV16. Our findings are in agreement with the previous studies, which reported no differences observed when different dyes were used for naked eye detection of LAMP products (Kwok & Kwong 2013;Wang et al 2013). Agarose gel electrophoresis and real-time analysis demonstrated the same detection limit as naked eye detection (10 3 copies/μl of HPV16).…”

Proteomic signatures reveal a dualistic and clinically relevant classification of anal canal carcinoma

“…Although excellent concordance between HPV DNA status and p16 ink4 immunoreactivity was observed, three out of 11 HPV-negative cases (27%) strongly expressed this surrogate biomarker for HPV infection. This phenomenon of false-positive results with the use of p16 ink4 immunostaining has been extensively reported in the context of head and neck cancers [38]. Although less frequently detected, similar data were also recently pointed out in anal SCC [9,10].…”

Molecular characterization of human papillomavirus in head and neck tumors.

“…INK4a is inexpensive, highly sensitive and can be performed in virtually any histology laboratory with very quick turnaround (34,46).…”

“…INK4a is often used as a surrogate marker of HPV infection in oropharyngeal cancers, while its use in oral cavity cancers is not well established, even though both are subgroups of HNC (46,47). Current studies show that other non-viral mechanism can also increase p16 INK4a expression, making it a non-specific marker for HPV infection, Figure 5 (18,46,48).…”

“…Current studies show that other non-viral mechanism can also increase p16 INK4a expression, making it a non-specific marker for HPV infection, Figure 5 (18,46,48). This warrants the need for reliable and appropriate biomarkers to precisely diagnose HPV status in head and neck tumors or to determine HPV-associated cancer progression.…”