Clinical implications of cytosine deletion of exon 5 of P53 gene in non small cell lung cancer patients

Abstract

Aim: Lung cancer is considered to be the most common cancer in the world. In humans, about 50% or more cancers have a mutated tumor suppressor p53 gene thereby resulting in accumulation of p53 protein and losing its function to activate the target genes that regulate the cell cycle and apoptosis. Extensive research conducted in murine cancer models with activated p53, loss of p53, or p53 missense mutations have facilitated researchers to understand the role of this key protein. Our study was aimed to evaluate the frequency of cytosine deletion in nonsmall cell lung cancer (NSCLC) patients. Methods: One hundred NSCLC patients were genotyped for P53 (exon5, codon168) cytosine deletion leading to loss of its function and activate the target genes by allele-specific polymerase chain reaction. The P53 cytosine deletion was correlated with all the clinicopathological parameters of the patients. Results and Analysis: 59% cases were carrying P53 cytosine deletion. Similarly, the significantly higher incidence of cytosine deletion was reported in current smokers (75%) in comparison to exsmoker and nonsmoker. Significantly higher frequency of cytosine deletion was reported in adenocarcinoma (68.08%) than squamous cell carcinoma (52.83%). Also, a significant difference was reported between p53 cytosine deletion and metastasis (64.28%). Further, the majority of the cases assessed for response carrying P53 cytosine deletion were found to show faster disease progression. Conclusion: The data suggests that there is a significant association of the P53 exon 5 deletion of cytosine in codon 168 with metastasis and staging of the disease.

Key words

Nonsmall cell lung cancer - adeno-carcinoma - squamous cell carcinoma - allele specific oligonucleotide - P53 (exon5,codon168) cytosine deletion

Publication History

Article published online:
30 December 2020

• References

• 1 Chang F, Syrjänen S, Syrjänen K. Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 1995;13:1009-22.
• 2 Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106-30.
• 3 Mowat MR. p53 in tumor progression: Life, death, and everything. Adv Cancer Res 1998;74:25-48.
• 4 Steele RJ, Thompson AM, Hall PA, Lane DP. The p53 tumour suppressor gene. Br J Surg 1998;85:1460-7.
• 5 Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis. Cancer Res 1994;54:4855-78.
• 6 Soussi T, Dehouche K, Béroud C. p53 website and analysis of p53 gene mutations in human cancer: Forging a link between epidemiology and carcinogenesis. Hum Mutat 2000;15:105-13.
• 7 Starzynska T, Bromley M, Ghosh A, Stern PL. Prognostic significance of p53 overexpression in gastric and colorectal carcinoma. Br J Cancer 1992;66:558-62.
• 8 Moch H, Sauter G, Gasser TC, Buchholz N, Bubendorf L, Richter J, et al. p53 protein expression but not mdm-2 protein expression is associated with rapid tumor cell proliferation and prognosis in renal cell carcinoma. Urol Res 1997;25 Suppl 1:S25-30.
• 9 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1:27-31.
• 10 Dameron KM, Volpert OV, Tainsky MA, Bouck N. Control of angiogenesis in fibroblasts by p53 regulation of thrombospondin-1. Science 1994;265:1582-4.
• 11 Van Meir EG, Polverini PJ, Chazin VR, Su Huang HJ, de Tribolet N, Cavenee WK. Release of an inhibitor of angiogenesis upon induction of wild type p53 expression in glioblastoma cells. Nat Genet 1994;8:171-6.
• 12 Lung ML, Wong MP, Skaanild MT, Fok CL, Lam WK, Yew WW. p53 mutations in non-small cell lung carcinomas in Hong Kong. Chest 1996;109:718-26.
• 13 Suzuki H, Takahashi T, Kuroishi T, Suyama M, Ariyoshi Y, Takahashi T, et al. p53 mutations in non-small cell lung cancer in Japan: Association between mutations and smoking. Cancer Res 1992;52:734-6.
• 14 Takeshima Y, Inai K, Bennett WP, Metcalf RA, Welsh JA, Yonehara S, et al. p53 mutations in lung cancers from Japanese mustard gas workers. Carcinogenesis 1994;15:2075-9.
• 15 Vähäkangas KH, Samet JM, Metcalf RA, Welsh JA, Bennett WP, Lane DP, et al. Mutations of p53 and ras genes in radon-associated lung cancer from uranium miners. Lancet 1992;339:576-80.
• 16 Sozzi G, Miozzo M, Donghi R, Pilotti S, Cariani CT, Pastorino U, et al. Deletions of 17p and p53 mutations in preneoplastic lesions of the lung. Cancer Res 1992;52:6079-82.
• 17 Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, et al. Role of p53 as a prognostic factor for survival in lung cancer: A systematic review of the literature with a meta-analysis. Eur Respir J 2001;18:705-19.
• 18 El-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, et al. WAF1, a potential mediator of p53 tumor suppression. Cell 1993;75:817-25.
• 19 Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991;253:49-53.
• 20 Sundaresan V, Ganly P, Hasleton P, Rudd R, Sinha G, Bleehen NM, et al. p53 and chromosome 3 abnormalities, characteristic of malignant lung tumours, are detectable in preinvasive lesions of the bronchus. Oncogene 1992;7:1989-97.
• 21 Baumann M, Zips D, Appold S. Radiotherapy of lung cancer: Technology meets biology meets multidisciplinarity. Radiother Oncol 2009;91:279-81.
• 22 Stoehr R, Knuechel R, Boecker J, Blaszyk H, Schmitt R, Filbeck T, et al. Histologic-genetic mapping by allele-specific PCR reveals intraurothelial spread of p53 mutant tumor clones. Lab Invest 2002;82:1553-61.
• 23 Levine AJ, Perry ME, Chang A, Silver A, Dittmer D, Wu M, et al. The 1993 Walter Hubert Lecture: The role of the p53 tumour-suppressor gene in tumorigenesis. Br J Cancer 1994;69:409-16.
• 24 Vogelstein B. Cancer. A deadly inheritance. Nature 1990;348:681-2.
• 25 Hainaut P, Soussi T, Shomer B, Hollstein M, Greenblatt M, Hovig E, et al. Database of p53 gene somatic mutations in human tumors and cell lines: Updated compilation and future prospects. Nucleic Acids Res 1997;25:151-7.
• 26 Bennett WP, Colby TV, Travis WD, Borkowski A, Jones RT, Lane DP, et al. p53 protein accumulates frequently in early bronchial neoplasia. Cancer Res 1993;53:4817-22.
• 27 Sozzi G, Miozzo M, Pastorino U, Pilotti S, Donghi R, Giarola M, et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res 1995;55:135-40.