p53, p16 and cyclin D1: Molecular determinants of radiotherapy treatment response in oral carcinoma

Abstract

Management of oral cancer by radiotherapy has witnessed promising advances in the past few years, with patient-tailored radio fractionation regimens. Different fractionation schedules, conventional and altered regimes, have been used in curative radiotherapy. Although contribution of biological markers on radio response has been evaluated, its unique influence on various radio fractionation schemes has not been accounted so far. Our study analyses a set of proteins that previously demonstrated radio response influence for their possible prognostic value in decision-making process between the respective fractionation schemes. Expression patterns of regulatory proteins such as p53, cyclin D1, p16, Cdk4, p21, Rb, bcl-2 and PCNA were determined by immunohistochemistry utilizing monoclonal antibodies in 125 patients who received curative radiotherapy dose. Among these 125 patients, 90 (72%) received altered fractionation, whereas 35 (28%) received conventional fractionation. p53 over-expression correlated with local treatment failure among the patients treated with conventional fractionation whereas cyclin D1 over-expression and p16 underexpression were associated with local treatment failure as well as overall survival in altered fractionation treated cases. Our findings suggest that wild-type p53 status may be an important parameter for achieving high local control in those patients undergoing conventional fractionation, where as intact p16 and cyclin D1 status may be beneficial for effective local control in patients who are treated with altered fractionation. Furthermore, it can be assumed that conventional fractionation employs p53-mediated apoptosis, whereas altered fractionation activates the functional G1 cell-cycle checkpoint for tumor growth suppression.

Phenotypic alterations in Rb pathway have more prognostic influence than p53 pathway proteins in oral carcinoma

“…22 Our previous report also demonstrated that p16 and cyclin D1 were significant biological markers to assess the radioresponse in oral cancer patients. 9 Cyclin D1 and p16 predicted the survival of the patients comparatively stronger than any of the conventional clinicopathological prognostic markers examined. Therefore, subgrouping the patients based on the molecular phenotype of cyclin D1 and p16, we could identify groups of patients with bad prognosis, and this might be of clinical utility in designing treatment modalities.…”

“…We had reported earlier that p53 overexpression detected by mutant-specific Pab240 can independently predict the local treatment failure in conventional fractionation of radiotherapy protocol and not in altered fractionation schedule. 9 Conventional fractionation is expected to activate selectively p53-mediated apoptotic pathway in the tumour cell. Hence, patients with mutant-specific p53 overexpression should be considered for other treatment modalities.…”

“…9 Briefly, 5-mm-thick tissue sections were cut from buffered formalin-fixed, paraffin-embedded tissues. Sections were deparaffinized in xylene and rehydrated.…”

Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality?

“…Similar results were published by others. 25,37 Jayasurya et al further differentiated oral squamous cell carcinoma treated by normal from altered fractionation. Loss of p16 expression combined with cyclin D1 overexpression correlated to worse prognosis in the 90 tumors treated by altered fractionation only.…”

“…Nevertheless, we can compare the influence of p16 expression on overall survival in both treatment groups. Reports on prognosis of HPV induced p16 positive OPSCC including tumor collectives treated by different treatment modalities such as surgery, 26,37 RT, 37 RCT 25,40 or OPSCC treated by various, but summarized modalities. 15,20,21,24,34,35,38,39 In addition, our single-institutional study requires validation in large prospective trials prior to implementation of p16 as a potential prognostic marker in OPSCC.…”