P16/Rb Pathway in Oropharyngeal Squamous Cell Carcinoma
Madalina Tuluc, Voichita Bar-Ad, David Cognetti. Jefferson University Hospital, Philadelphia, PA
Background: HPV oncoproteins E6 and E7 interfere with crucial cellular mechanisms such as cell regulation and apoptosis. E6 disrupts the p53 pathway while E7 inactivates Rb.
P16 activates Rb-dependent cell cycle arrest; in cells with functional Rb, elevated p16 is a potent inhibitor of cellular proliferation. HPV positive tumors which are characterized by loss of Rb function secondary to E7 oncoprotein activity, have high levels of p16. In consequence, HPV positive oropharyngeal squamous cell carcinoma (OSCC) is characterized by overexpression of p16 and low Rb.
However, in many patients with OSCC, HPV is not the only carcinogen and superimposed chemical/toxin carcinogens (smoking and alcohol) often play an important role in tumor initiation and progression.
The objective of this study is to explore the p16/Rb pathway in patients with p16 positive and p16 negative OSCC.
Design: Rb and p16 expression was evaluated by immunohistochemistry in 66 cases of p16 positive and 36 cases of p16 negative OSCC. Smoking history was available in all cases.
Rb expression was assessed as low if 20% or less of tumor cells showed nuclear staining and high if nuclear staining was present in more than 20% of tumor cells.
p16 was considered positive if more than 50% of the tumor cells demonstrated cytoplasmic and nuclear staining.
Results: More than 50% of the 66 patients with p16 positive OSCC showed low Rb (59% in nonsmokers, 73% in remote smokers and 62% in smokers). The remaining p16 positive patients had high Rb expression.
Among the 36 cases of p16 negative OSCC, 100% of smokers had high Rb expression, while in the nonsmoker and remote smoker groups only 20% of patients showed high Rb expression.
Conclusions: Low Rb expression in p16 positive OSCC is in agreement with the effect of HPV E7 oncoprotein on the p16/Rb axis. However, approximately 30% of p16 positive patients had high Rb expression, irrespective of their smoking history. This may be due to differences in the degree of Rb inhibition by E7 oncoprotein, making the HPV action on the host cell more important than patients' smoking history.
High Rb expression in p16 negative OSCC supports the hypothesis that cell proliferation in HPV negative tumors may involve loss or silencing of the p16 tumor suppressor via a pathway independent of Rb activity.
Category: Head & Neck
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 181, Wednesday Morning