Abstract
Human papillomaviruses (HPV) are thought to be involved in the malignant evolution of cutaneous lesions from transplant recipients. As E6 proteins from potentially oncogenic HPV types degrade p53 tumour suppressor gene product in vitro, we analysed p53 protein status in benign, premalignant and malignant skin lesions from grafted patients, to determine whether HPV may interfere with p53 function. With immunohistochemistry, p53 protein accumulation was detected in 70% of skin lesions from grafted patients. p53 immunoreactivity was confined to basal keratinocytes in benign lesions (warts, condylomas), while suprabasal keratinocytes were also stained in premalignant and malignant skin lesions (precancerous keratoses, squamous cell carcinomas). Multiple HPV carriage was detected with in situ hybridization in benign and malignant skin lesions from transplant recipients: low risk HPV types 1, 2, 6, 11 and potentially oncogenic HPV types 5, 16, 18 were frequently found. There was no clear correlation between p53 detection and the presence of the HPV types under study. The frequent detection of p53 protein in cutaneous lesions from grafted patients is suggestive of p53 protein accumulation interfering with normal function. Our results may reflect the presence of mutated p53 proteins due to the mutagenic effect of ultra-violet (UV), or wild-type p53 protein accumulation in response to UV-induced DNA damage, or may be produced by the interaction with HPV-encoded E6 proteins.
Similar content being viewed by others
References
Arai N, Nomura D, Yokota K, Wolf D, Brill E, Shohat O, Rotter V (1986) Immunologically distinct p53 molecules generated by alternative splicing. Mol Cell Biol 6:3232–3239
Ashinoff R, Li JJ, Jacobson M, Friedman-Kien AE, Geronemus RG (1991) Detection of human papillomavirus DNA in squamous cell carcinoma of the nail bed and finger determined by polymerase chain reaction. Arch Dermatol 127:1813–1818
Barr BBB, Benton EC, McLaren K, Bunney MH, Smith IW, Blessing K, Hunter JAA (1989) Human papillomavirus infection and skin cancer in renal allograft recipients. Lancet 1:124–129
Bartek J, Bartkova J, Vojtesek B, Staskova Z, Rejthar A, Kovarik J, Lane DP (1990) Patterns of expression of p53 tumour suppressor in human breast tissues and tumours in situ and in vitro. Int J Cancer 46:839–844
Brash DE, Rudolph JA, Simon JA, Lin A, Mc Kenna GJ, Baden HP, Halperin AJ, Ponten J (1991) A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 88:10124–10128
Bruner JM, Connelly JH, Saya H (1993) p53 protein immunostaining in routinely processed paraffin-embedded sections. Mod Pathol 6:189–194
Bunney MH, Barr BB, McLaren K, Smith IW, Benton EC, Anderton JL, Hunter JAA (1987) Human papillomavirus type 5 and skin cancer in renal allograft recipients. Lancet 1:151–152
Campbell C, Quinn AG, Ro YS, Angus B, Rees JL (1993) p53 mutations are common and early events that preoede tumor invasion in squamous cell neoplasia of the skin. J Invest Dermatol 100:746–748
Caron de Fromentel C, Soussi T (1992) p53 tumor suppressor gene: a model for investigating human mutagenesis. Genes Chrom Cancer 4:1–15
Cristofolini M, Boi S, Girlando S, Zumiani G, Cristofolini P, Dalla Palma P, Doglioni C, Barbareschi M (1993) p53 protein expression in nevi and melanomas. Arch Dermatol 129:739–743
Crook T, Wrede D, Vousden KH (1991) p53 point mutation in HPV negative human cervical carcinoma cell lines. Oncogene 6:873–775
Crook T, Tidy JA, Vousden KH (1991) Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell 67:547–556
Euvrard S, Chardonnet Y, Pouteil-Noble CP, Kanitakis J, Thivolet J, Touraine JL (1993) Skin malignancies and human papillomaviruses in renal transplant recipients. Transplant Proc 25:1392–1393
Gannon JV, Greaves R, Iggo R, Lane DP (1990) Activating mutations in p53 produce a common conformational effect. A monoclonal antibody specific of the mutant form. EMBO J 9:1595–1601
Garven TC, Thelmo WL, Victor J, Pertschuk L (1991) Verrucous carcinoma of the leg positive for human papillomavirus DNA 11 and 18: a case report. Hum Pathol 22:1170–1173
Guérin-Reverchon I, Chardonnet Y, Chignol MC, Thivolet J (1990) Study of stringency conditions for human papillomavirus DNA detection on cell lines, frozen and paraffin-embedded tissue sections by in situ hybridization with biotinylated probes. Histochemistry 93:637–643
Hall PA, McKee PH, Menage H du P, Doner R, Lane DP (1993) High levels of p53 protein in UV-irradiated normal human skin. Oncogene 8:203–207
Hubbert NL, Sedman SA, Schiller JT (1992) Human papillomavirus type 16 E6 increases the degradation rate of p53 in human keratinocytes. J Virol 66:6237–6241
Iggo R, Gatter K, Bartek J, Lane D, Harris AL (1990) Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet 335:675–679
Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311
Lane D, Benchimol S (1990) p53: oncogene or anti-oncogene? Genes Dev 4:1–8
Marks JR, Davidoff AM, Kerns BJ, Humphrey PA, Pence JC, Dodge RK, Clarke-Pearson DL, Iglehart JD, Bast RC, Berchuck A (1991) Overexpression and mutation of p53 in epithelial ovarian cancer. Cancer Res 51:2979–2984
McGregor JM, Yu CCW, Dublin EA, Levison DA, McDonald DM (1992) Aberrant expression of p53 tumour suppressor protein in non-melanoma skin cancer. Br J Dermatol 127:463–469
Moles JP, Moyret C, Guillot B, Jeanteur P, Guilhou JJ, Theillet C, Basset-Seguin N (1993) p53 gene mutations in human epithelial skin cancers. Oncogene 8:583–588
Ogunbiyi OA, Scholefield JH, Smith JHF, Polacarz SV, Rogers K, Sharp F (1993) Immunohistochemical analysis of p53 expression in anal squamous neoplasia. J Clin Pathol 46:507–512
Pélisson I, Soler C, Péchoux C, Chignol MC, Viac J, Euvrard S, Chardonnet Y (1992) c-myc and c-Ha-ras cellular oncogenes and human papillomaviruses in benign and malignant cutaneous lesions. J Dermatol Sci 3:56–67
Pierceall WE, Mukhopadhyay T, Goldberg LH, Ananthaswamy HN (1991) Mutations in the p53 tumor suppressor gene in human cutaneous squamous cell carcinomas. Mol Carcinog 4:445–449
Pierceall WE, Goldberg LH, Ananthaswamy HN (1991) Presence of human papillomavirus type 16 DNA sequences in human non-melanoma skin cancers. J Invest Dermatol 97:880–884
Ro YS, Cooper PN, Lee JA, Quinn AG, Harrison D, Lane D, Horne CHW, Rees JL, Bangus B (1993) p53 protein expression in benign and malignant skin tumours. Br J Dermatol 128:237–241
Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus type 16 and 18 promotes the degradation of p53. Cell 63:1129–1136
Scheffner M, Münger K, Byrne JC, Howley PM (1991) The state of p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci USA 88:5523–5527
Shea CR, McNutt NS, Volkenandt M, Lugo J, Prioleau PG, Albino AP (1992) Overexpression of p53 protein in basal cell carcinomas of human skin. Am J Pathol 141:25–29
Sim CS, Slater S, McKee PH (1992) Mutant p53 expression in solar keratosis: an immunohistochemical study. J Cutan Pathol 19:302–308
Soler C, Chardonnet Y, Allibert P, Euvrard S, Mandrand B, Thivolet J (1992) Detection of multiple types of human papillomavirus in a giant condyloma from a grafted patient. Analysis by immunohistochemistry, in situ hybridization, Southern blot and polymerase chain reaction. Virus Res 23:193–208
Soler C, Chardonnet Y, Guérin-Reverchon I, Chignol MC, Viac J, Euvrard S, Thivolet J (1992) Influence of fixation on human papillomavirus DNA detection in frozen and embedded paraffin lesions by in situ hybridization with biotinylated probes. Pathol Res Pract 188:1018–1027
Soler C, Chardonnet Y, Euvrard S, Chignol MC, Thivolet J (1992) Evaluation of human papillomavirus type 5 on frozen sections of multiple lesions from transplant recipients with in situ hybridization and non isotopic probes. Dermatology 184:248–253
Soler C, Chardonnet Y, Allibert P, Euvrard S, Schmitt D, Mandrand B (1993) Detection of mucosal human papillomavirus types 6/11 in cutaneous lesions from transplant recipients. J Invest Dermatol 101:286–291
Srivastava S, Tong YA, Devadas K, Zou ZQ, Chen Y, Pirollo KF, Chang EH (1992) The status of the p53 gene in human papillomavirus positive or negative cervical carcinoma cell lines. Carcinogenesis 13:1273–1275
Stephenson TJ, Royds J, Silcocks PB, Bleehen SS (1992) Mutant p53 oncogene expression in keratoacanthoma and squamous cell carcinoma. Br J Dermatol 127:566–570
Thor AD, Moore DH II, Edgerton SM, Kawasaki ES, Reihsaus E, Lynch HT, Marcus JN, Schwartz L, Chen LC, Mayall BH, Smith HS (1992) Accumulation of p53 tumor suppressor gene protein: an independant marker of prognosis in breast cancer. J Natl Cancer Inst 84:845–855
Van den Berg FM, Baas IO, Polak MM, Offerhaus GJA (1993) Detection of p53 overexpression in routinely paraffin-embedded tissue of human carcinomas using a novel target-unmasking fluid. Am J Pathol 142:381–385
Van der Leest RJ, Zachow KR, Ostrow RS, Bender M, Pass F, Faras AJ (1987) Human papillomavirus heterogeneity in 36 renal transplant recipients. Arch Dermatol 123:354–357
Villiers EM de (1989) Heterogeneity of the human papillomavirus group. J Virol 63:4898–4903
Wrede D, Tidy JA, Crook T, Lane D, Vousden KH (1991) Expression of Rb and p53 proteins in HPV-positive and HPV-negative cervical carcinoma cell lines. Mol Carcinog 4:171–175
Wynford-Thomas D (1992) p53 in tumour pathology: can we trust immunocytochemistry? J Pathol 166:329–330
Ziegler AM, Leffell DJ, Kunala S, Sharma HW, Gailami M, Simon JA, Halperin AJ, Baden HP, Shapiro PE, Bale AE, Brash DE (1993) Mutation hotspots due to sunlight in the p53 gene of non-melanoma skin cancers. Proc Natl Acad Sci USA 90:4216–4220
Zur Hausen H (1989) Papillomaviruses in anogenital cancer as a model to understand the role of viruses in human cancer. Cancer Res 49:4677–4681
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Pélisson, I., Chardonnet, Y., Euvrard, S. et al. Immunohistochemical detection of p53 protein in cutaneous lesions from transplant recipients harbouring human papillomavirus DNA. Vichows Archiv A Pathol Anat 424, 623–630 (1994). https://doi.org/10.1007/BF00195776
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00195776