Upregulation of telomerase-independent apoptosis characterizes cutaneous malignancies in older patients
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Background: There are controversial results on the influence of age on malignancy prognosis, being the patient age used as staging criteria (e.g., thyroid neoplasms). To test biologic features that can explain differences in tumors by age, the skin model was selected for two main reasons: tumors tend to be detected relatively early due to their easy access and a whole variety of common neoplasms (carcinomas, melanomas, sarcomas and lymphomas) can be analyzed.
Design: We selected 50 cases of nodular basal cell carcinomas, well-differentiated squamous cell carcinoma, superficial spreading malignant melanoma, dermatofibrosarcoma protuberans, and patch stage mycosis fungoides that have appropriate archival material. Representative samples were evaluated by standard immunohistochemistry for Ki67, telomerase, mlh1, msh2, In situ end labeling of DNA fragments (TUNNEL for apoptosis detection), and FISH-PNA of telomere. The tests were assessed in the whole lesion and the positive cells expressed as percentage of tumor cells. Appropriate controls were run in each sample. Cases were stratified according to patient’s age in <50 years (group A, 10 cases), 50-70 years (group B, 30 cases) and >70 years (group C, 10 cases). The results were statistically compared using analysis of variance and Student t-test, and considered significant if P<0.05.
Results: The average age in each group was 34 (group A), 59 (group B) and 78 years (group C). All neoplasms were revealed positive for mlh1 and msh2, regardless of the age group. Proliferation and the percentage of FISH-detectable telomere revealed and inverse correlation, being proliferation significantly higher in group A than in group C; telomere revealed the opposite pattern. Apoptosis and the global kinetic index Ki67×Telomere/ TUNNEL (%) were significantly higher in group C as compared with A and B (P=0.0003 and P=0.0006). Group B was heterogeneous, cases being able to stratified by group A and C patterns.
Group A/ Group B/ Group C
<50/ 50-70/ >70
Ki67/ 19.74/ 16.75/ 15.40
Telomere FISH/ 41.66/ 53.97/ 53.25
Ki67×Telomere (%)/ 3.42/ 7.35/ 7.56
TUNNEL / 0.50/ 2.82/ 10.17
Ki67×Telomere/TUNNEL (%) / 31.64/ 26.49/ 43.94
Conclusion: In the absence of mismatch repair abnormalities, malignancies in older patients are defined by significantly increased apoptosis, related with a telomere-independent accumulation of genetic alteration that is facilitated by lower cellular turnover.
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