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STUDIES
Year : 2005  |  Volume : 50  |  Issue : 3  |  Page : 133-135
The evaluaton of prevalence rate of p53 antigen expression in cutaneous malignant melanoma and it's relation to tumor thickness


Department of Dermatology and Pathology, Skin research center, Isfahan University School of Medicine, Iran

Correspondence Address:
Gita Faghihi
Department of Dermatology and Pathology, Skin research center, Isfahan University School of Medicine
Iran
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Source of Support: None, Conflict of Interest: None


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   Abstract 

P53 tumor suppressor gene mutation is one of the most common genetic alteration in human malignancies. This study was done to determine the prevalence of the P53 antigen expression by sex, age, type of melanoma, thickness of the lesion and site of the antigen expression either cytoplasmic or nuclear. Paraffin embeded block of 50 patients (45 primary and metastatic)with documented diagnosis of melanoma deparaffinized and immuno stained with DO-7 monoclonal antibody. The lesions were divided depending on the degree of the staining as follow: 1. no staining, 2. mild (less than 10%), 3. moderate (10%-50% staining), 4. severe (more than 50%). Fifty four percent of evaluated patients were female and 46% were male. Forty percent of lesions were graded as no staining, 36% of lesions showed mild staining, 14% moderate and 10% severe staining site of expression was excusively in the cytoplasm. There was no meaningful statistical deference between severity of staining and the age group, sex, type and thickness of melanoma. (p value was 0.532, 0.488, 0.626, 0.954 respectively).


Keywords: Melanoma, P53 antigen


How to cite this article:
Faghihi G, Radan M, Ghanei N, Rajabi P, Taheri D. The evaluaton of prevalence rate of p53 antigen expression in cutaneous malignant melanoma and it's relation to tumor thickness. Indian J Dermatol 2005;50:133-5

How to cite this URL:
Faghihi G, Radan M, Ghanei N, Rajabi P, Taheri D. The evaluaton of prevalence rate of p53 antigen expression in cutaneous malignant melanoma and it's relation to tumor thickness. Indian J Dermatol [serial online] 2005 [cited 2019 Jul 21];50:133-5. Available from: http://www.e-ijd.org/text.asp?2005/50/3/133/18925



   Introduction Top


P53 is a known tumor-suppressing gene located on 17PB-1 chromosome. A little more than 50% of human cancers contain such gene mutations.[1] P53 protein is highly active with a low physiologic concentration in cells.[2] According to a short half life (about 20 minutes) of the protein, its detection in normal tissues is a difficult task. In mutated form, increase in persistence of the protein causes higher expression and concentration in tissues.[3] In cases of DNA damage due to UV radiation or chemical mutagens, P53 is being expressed as immediate suppressor. A rapid increase in P53 activity and the following transcription of several P53 mediating genes lead to stop in cell cycle and apoptosis phenomenon. In homozygote gene loss, the damaged cellular DNA persists unchanged so, the cell progresses towards malignant transformation.[1]

The P53 gene mutant plays a role in melanoma resistance to chemotherapy.[4] Recently a synthetic product (CP-31398) stabilizes the DNA binding site of innate P53, causes the inhibition of cancerous cell growth in rat model.[5] With the advent of new biotechnological progress, we can use such gene product in treatment of squamous cell carcinomas, by substituting the innate gene with the mutant form.

Several investigations about P53 antigenic expression rate had been performed, and the results showed significant variation (3-97%).[6],[7] Some investigators found significant difference between P53 expression in primary and metastatic melanomas, the others showed the contrary correlation.[8]-[10]

Controversies about the prognostic value of P53 positivity also, evolved.[11] We conducted this study in order to evaluate the prevalence rate of P53 antigen expression in cutaneus malignant melanoma and its relation to patient's age, sex, histologic subtype, site of expression in histological specimens and especially to tumor thickness.


   Materials and Methods Top


This cross-sectional study was conducted on 50 melanoma biopsy specimens reserved in Isfahan St-zahra histo-pathology laboratory. After deparaffinization and rehydration process and stabilization of molecular structure of the antigen, the specimens were incubated in the presence of - strength of 1/50 D0-7 monoclonal antibody (DAKO-Company, Denmark). In the second stage, Link­Ab (antibody against the previous Ab) was added in order to increase the sensitivity of the interpretation. Finally after adding chromogens, background staining with hematoxyline and mounting process were taken, sequentially.

The histopathological evaluation on the prepared specimens was performed by two separate pathologists and staining intensity grading was scored[13] as follows:

No staining

Weakly positive stain: A positive staining in less than 10% of specimens.

Moderate positive stain: A positive staining in 10-50% of specimens.

High positive stain: A positive staining in more than 50% of specimens.


   Results Top


Of 50 cutaneus melanoma specimens, 27 and 23 belonged to female and male patients, respectively. On the whole, 20 specimens (40%) were reported as negative. From 30 positive specimens, 18(36%)with weak positive staining, 7 (14%) with moderate positive staining and 5(10%) with high positive staining were detected. There was not any significant difference between the prevalence of P53 expression in different age groups or sexes. Meanwhile, all the specimens studied belonged to above 30years of age group.

The site of P53 antigen expression was the nucleus in all the tissue specimens and no staining occurred in the cytoplasm. According to the H&E staining results, from 50 specimens studied, 5 (10%) were nodular, 20(40%) acral lentiginous, 7(14%) lentigo maligna, 13(26%) superficial spreading and 5(10%) were defined as metastatic.

The correlation between thickness of melanoma and P53 expression rate had also been investigated, according to Breslow index from 45 primary melanoma specimens. Ten (10) had been measured as thin (<1mm), and 35 as thick (>1mm), though, there were no significant differences between P53 expression rate and melanoma thickness measurement.


   Discussion Top


Our findings of 60% total P53 antigen reactivity and the majority (36%) with weakly positive staining of which were consistent with the study of Mc Gregor et al ,[14] which was performed on 24 cutaneus melanoma specimens.[14]

It seems that the cause of wide variations between several previous investigations can be related to some factors, [6],[7] pre-dominent by the difference between positivity threshold and its impact on interpretation process.[2],[11] Some researchers considered either the amount of nuclear staining or (6) both nuclear and cytoplasmic staining as the cause of difference.[2],[6],[7],[11] The other explanations for the variability of results can be related to different laboratory methods of tissue preparations, for example, using paraffinized tissue specimens which were incubated in microwave device compared to using protease exposed materials.[2] The variability in the sensitivity of anti- P53 monoclonal antibodies, like CMI, P240, DO-7, DO-2, DO-I, can also influence on the final results. DO-7 antibody in our research is able to detect both wild and mutant types and is specified to paraffinized blocks. The absence of correlation between prevalence of P53 expression and sex or age groups is similar to Straume's study. In spite of Weiss's research which showed that the majority of antigen expression was in the cytoplasm, in our study the major site of P53 expression was in the nucleus.

Weiss et al speculated that complex binding of P53 with other cellular proteins might explain the accumulation of it in cytoplasm.[2]

In some studies, they obtained a significant difference in rate of expression in primary or metastatic subtypes of melanoma,[8] and concluded that P53 gene has a role in the metastatic phenotype of tumor, Barinhil et al, like ours got the contrary results and interpreted that P53 mutation has little role in progression of tumor.[9] Zhangh, et al , found no role for P53 in progression of melanoma from primary to metastatic phenotype.[14] Some previous studies believed in a direct relationship between tumor Breslow thickness and the rate of P53 expression. The same happens with colonic carcinoma and some other internal malignancies.[15]-[18]

In our study, however, we found no direct correlation between antigenic expression and Breslow thickness and concluded that the presence of such antigen may be only a primary event in the pathogenesis of melanoma, and this finding is similar to that of animal models found by in previous researches.[9],[19]

Finally, one should consider the role of, P53 antigen expression in tumor genesis and its resistance to chemotherapy, although the highly positive P53 staining is not common in cutaneous melanomas.


   Acknowledgments Top


We are very grateful to Dr. M. Mohajeri, Mrs. F. Mahmoodi and all the staff of St-Zahra Department of histopathologic tissue processing.



 
   References Top

1.Cotron, Kumar, Collins, Robbins. Pathologic basis of disease. Philadelphia: Saunders company, 1999: 290-2.  Back to cited text no. 1    
2.Weiss J, Heine. M, Korner. B, Pilch. H, Jung. EG. Expression of P53 protein in malignant melanoma: Clinicopathological and prognostic implication. Br J Dermatol 1995; 133: 23-31.  Back to cited text no. 2    
3.Nylander K, Dabel steen E, Hall P A. The P53 molecule and its prgnostic role in squamous cell carcinoma of the head and neck. J oral path Med 2000; 4 13-25.  Back to cited text no. 3    
4.Gang Li, Jason AB, Vincent C. P53- dependent apoptosis in melanoma cells after treatment with camptothecin. J Inves Dermatol 2000; 114: 5 14-9.  Back to cited text no. 4    
5.Yvonne Luu, Gang Li. The P53- stabilizing compound CP-3 1398 enhances ultraviolet- B- induced apoptosis in a human melanoma cell line MMRU. J Invest Dermatol 2002; 119:1207-9.  Back to cited text no. 5    
6.Ro Ys, Cooper PN, Lee JA, et al. P53 protein expression in benign and malignant skin tumours. Br J Dermatol. 1993; 129: 739-43.  Back to cited text no. 6    
7.Akslen LA, Morkve O. Expression of P53 protein in cutaneous melanoma. Int J cancer 1992;52: 13-6.  Back to cited text no. 7    
8.Stretch JR. Gatter KC, Ralfkiaer E, et al. Expression of mutant P53 in melanoma. Cancer Res 1991; 51(2): 5976-9.  Back to cited text no. 8    
9.Barnhill RL, Castresana JS, Rubio MP, et al. P53 expression in cutaneous malignant melanoma: an immunohistochemical study of 87 cases of primary, recurrent and Metastatic melanoma. Mod pathm 1997; 7(5):533-5.   Back to cited text no. 9    
10. RhimKJ, Hong SI, HongWS, et al. Aberrant expression of P53 gene product in malignant melanoma. J Korean Med Sci. 1994; 9(5): 376-81.  Back to cited text no. 10    
11.Loggini B, Rinaldi I, Pingitore R, et al. Immuno histochemical study of 49 cutaneous melanoma: P53, PCNA, Bcl.2 expression and multidrug resistance. Tumori 2001; 87(3): 179-86.  Back to cited text no. 11    
12.Straume O, Akslen LA. Alteration and prognostic significance of P16 and P53 protein expression in subgroups of cutaneous melanoma. Int J cancer 1997; 74: 535-9.  Back to cited text no. 12    
13.McGregor JM, Yu ccw, Dublin EA, et al. P53 immunoreactivity in human malignant melanoma and dysplastic nevi. Br J Dermatol 1993; 128: 606-11.  Back to cited text no. 13    
14.Zhang H, Schneider J, Rosdahl I. Expression of P16 P27. P53, P73 and N4P88 proteins in matched primary and metastatic melanoma cells. In J oncol 2002; 21(1): 43-8.  Back to cited text no. 14    
15.Stretch JR, Gatter K C, RaIf kiaer E, et al. Expression of mutant P53 in melanoma. Cancer Res 1991; 51: 5976-9.  Back to cited text no. 15    
16.Lassan NJ, From L, Kahn HJ. Over expression of P53 is a late event in the development of malignant melanoma. Cancer Res 1993; 53: 2235-8.  Back to cited text no. 16    
17.Sun X F, Carstensen JM, Zhang H, et al. Prognostic significance of cytoplasmic P53 oncoprotein in colorectal adenocarcinoma. Lancet 1992; 340:1369-73.  Back to cited text no. 17    
18.Scott N, Sagar P. Stewart J, et al . P53 in colorectal cancer: Clinicopathological correlation and prognostic significance. Br J cancer 1991; 63: 3 17-9.  Back to cited text no. 18    
19.Frances P, Noonan, Dudek J, et al. Animal models of melanoma: An HGF SF transgenic mouse model may facilitate experimental acces to UV initiating events. Pigment cell Res 2003; 16: 16-25.  Back to cited text no. 19    




 

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    Abstract
    Introduction
    Materials and Me...
    Results
    Discussion
    Acknowledgments
    References

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