Nuclear expression of human apurinic/apyrimidinic endonuclease (HAP1/REF-1) in head-and-neck cancer is associated with resistance to chemoradiotherapy and poor outcome

Purpose: HAP1/Ref-1 endonuclease is involved in the repair of DNA strand br eaks and in the activation of DNA binding of several transcription factors. HAP1 is also a potent activator of wild type p53, It therefore has multipl e possible roles in the response of human cancer to radiotherapy and chemot herapy. Methods and Materials: The nuclear expression of HAP1 and p53 proteins was studied by immunohistochemistry in paraffin-embedded material from 95 patie nts with locally advanced squamous cell head-and-neck cancer (HNC) treated with radical radiotherapy (38 cases with induction platinum-based chemother apy and 57 with concurrent platinum chemoradiotherapy), Results: HAP1 was present in the nuclei of normal epithelium and stromal ce lls. Loss of HAP1 nuclear expression was frequently noted in cancer cells. Tumors with high HAP1 nuclear expression (% of positive cells > mean; mean = 11%) were of good differentiation (p = 0.06) and presented frequently wit h advanced nodal disease (p 0.01). High nuclear HAP1 expression was signifi cantly associated with poor complete response rate (p = 0.00001), shorter l ocal relapse-free interval (p < 0.0001), and poorer survival (p < 0.0008), HAP1 nuclear reactivity was inversely associated with p53 nuclear accumulat ion (p = 0.003). The inverse correlation between HAP1 expression and progno sis was independent of p53 status. Conclusion: HAP1 nuclear expression in HNC is inversely associated with p53 nuclear accumulation and directly related to resistance to chemoradiothera py and poor survival. Further clinical investigation is required to confirm these findings. (C) 2001 Elsevier Science Inc.