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Association of p53 codon 72 polymorphism and survival of North Indian lung cancer patients treated with platinum-based chemotherapy

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Abstract

p53 helps in maintaining genomic stability by undergoing cellular arrest, DNA repair or cellular apoptosis during DNA damage. So, as to find the association of p53Arg 72 Pro towards lung carcinogenesis and overall survival of North Indian lung cancer patients, single nucleotide polymorphic variant (rs1042522) was analyzed. 840 subjects including 420 cases and 420 controls were recruited and genotyped using PCR-RFLP technique for p53Arg 72 Pro polymorphic site. Association was analyzed using adjusted odds ratio along with its confidence intervals (95 % CI) and p value predicted from logistic regression whereas overall survival for lung cancer patients was obtained using Kaplan–Meir and Cox regression model for different parameters to obtain hazard ratio and survival time with statistical significance (log-rank p value). None of the variant genotypes for p53Arg 72 Pro showed any association towards lung cancer risk or any specific histological subtype. Lung cancer subjects with Pro/Pro genotype had better median survival time as compared to Arg/Pro genotype (10 months; HR = 0.65; 95 % CI = 0.45–0.95; p = 0.03). Furthermore, female lung cancer patients with Arg/Pro (HR = 0.08; 95 % CI = 0.02–0.34; p = 0.0005) and Pro/Pro (HR = 0.21; 95 % CI = 0.06–0.67; p = 0.008) genotypes showed a better overall survival and hence a better prognosis as compared to males. Our data also reveals that lung cancer patients with ECOG scores between 0 and 1 and carrying the Pro/Pro had better chances of survival. p53 codon 72 polymorphism could play a role as a prognostic marker in lung cancer patients.

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Abbreviations

MDM2:

Mouse double minute 2

BAX:

Bcl2-Associated X protein

PCR:

Polymerase chain reaction

RFLP:

Restriction fragment length polymorphism

BSA:

Bovine serum albumin

OR:

Odds ratio

CI:

Confidence interval

KPS:

Karnofsky performance status

ECOG:

Eastern Cooperative Oncology Group

OS:

Overall survival

CR:

Complete response

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

SQCC:

Squamous cell carcinoma

ADCC:

Adenocarcinoma

SCLC:

Small cell lung cancer

NSCLC:

Non-small cell lung cancer

References

  1. Behra D, Balamughesh T (2004) Lung Cancer in India. Indian J Chest Allied Sci 46:269–281

    Google Scholar 

  2. George P (2011) p53 How crucial its role in Cancer. Int J Curr Pharm Res 2:19–25

    Google Scholar 

  3. Sakiyama T, Kohno J, Mimaki S, Onta T, Yanagitani N, Sobou T, Kunitoh H, Saito R, Shimizu K, Himara C, Kimura J, Maeno G, Hirose H, Eguchi T, Saito D, Ohki M, Yokota J (2005) Association of amino acid substitution polymorphism in DNA repair genes TP53, POLI, REVI and LIGG with Lung cancer risk. Int J Cancer 114:730–737

    Article  CAS  PubMed  Google Scholar 

  4. Ozaki T and Nakagawara A (2011) Role of p53 in cell Death and Human Cancers. Cancers 3:994–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Han JY, Lee GK, Jang DH, Lee SY (2008) Association of p53 codon 72 polymorphism and MDM2 SNP309 with clinical outcome of advanced non-small cell lung cancer. Cancers 113:799–807

    Article  CAS  Google Scholar 

  6. Haupt S, Berger M, Goldberg Z, Haupt Y (2003) Apoptosis- the p53 network. JCS 116:4077–4085

    Article  CAS  Google Scholar 

  7. Vijayaraman KP, Veluchamy M, Murugesan P, Shanmugiah KP, Kasi PD (2012) p53 Exon 4 (codon 72) polymorphism and exon 7 (codon 249) mutation in breast cancer patients in Southern Region (Madurai) of Tamil Nadu. Asian Pacific J Cancer Prev 13:511–516

    Article  Google Scholar 

  8. Katkoori VR, Jia X, Shanmugam C, Wan W, Meleth S, Bumpers H, Grizzle WE, Manne U (2009) Prognostic significance of p53 codon 72 polymorphism differs with race in Colorectal Adenocarcinoma. Clin Cancers Res 15:2406–2416

    Article  CAS  Google Scholar 

  9. Fan R, Wu MT, Miller D, Wain JC, Kelsey JK, Christiani DC (2000) The p53 codon 72 polymorphism and lung cancer Risk. Cancer Epidemiol Biomarkers Prev 9:1037–1042

    CAS  PubMed  Google Scholar 

  10. Yu D, Berlin JA, Penning TM, Field J (2002) Reactive oxygen species generated by PAH o-Quinines cause change-in-function mutations in p53. Chem Res Toxicol 15:832–842

    Article  CAS  PubMed  Google Scholar 

  11. Shen YM, Troxel AB, Vendantam S, Penning M, Field J (2006) Comparison of p53 Mutations Induced by PAH o-Quinones with those caused by anti-Benzo[a] pyrene diol epioxide in vitro: role of reactive oxygen and biological selection. Chem Res Toxicol 19:1441–1450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Figueras JT, Gene M, Catalan JG, Galan C, Firvida J, Fuentes M, Rodamilans M, Huguet E, Estape J, Corbelle J (1996) Glutathione-S-transferase M1 and codon 72 p53 polymorphism in a Northwestern Mediterrenean population and their relation to lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev 5:337–348

    Google Scholar 

  13. Ozeki C, Sawai Y, Shibata T, Kohna T, Okamoto K, Yokota J, Tashiro F, Tanuma S, Sakai R, Kowase T, Kitabayashi I, Taya Y (2000) Cancer susceptibility polymorphism of p53 at codon 72 Affects phosphorylation and degradation of p53 Protein. Int. J Biol Chem 286:18251–18260

    Article  CAS  Google Scholar 

  14. Dumont P, Leu JI, Pietra D, Murphy M (2003) The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nat Genet 33:357–365

    Article  CAS  PubMed  Google Scholar 

  15. Tilak AR, Kumar S, Pant MC, Mathur V, Kumar A (2003) Polymorphism Arg72Pro of p53 confers susceptibility to Squamous cell carcinoma of lungs in a North Indian Population. DNA Cell Biol 32:66–72

    Article  CAS  Google Scholar 

  16. Sreeja L, Syamala V, Ravendran PB, Santhi S, Madhavan J, Ankathil R (2008) p53Arg72Pro polymorphism predicts survival outcomes in Lung cancer pateints in Indian population. Cancer Invest 26:41–46

    Article  CAS  PubMed  Google Scholar 

  17. Sobti RC, Kaur P, Kaur S, Janmeja AK, Jindal SK, Kishan J, Raimondi S (2009) Impact of interaction of polymorphic forms of p53 codon 72 and N-acetylation gene (NAT2) on the risk of lung cancer in the North Indian population. DNA Cell Biol 28:443–449

    Article  CAS  PubMed  Google Scholar 

  18. Popanda O, Elder L, Waas P, Schattenberg T, Butkiewicz D, Muley T, Dienemann H, Risch A, Bartsch H, Schmezer P (2007) Elevated risk of Squamous cell carcinoma of the lung in heavy smokers carrying the variant alleles of TP53 Arg72Pro and p21Ser31Arg polymorphisms. Lung Cancers 55:25–34

    Article  Google Scholar 

  19. Murata M, Tagawa M, Kimura H, Watanabe S, Saisho H (1996) Analysis of germ line polymorphism of p53 gene in lung cancer patients; discrete results with smoking history. Carcinogenesis 17:261–264

    Article  CAS  PubMed  Google Scholar 

  20. Wang YC, Chen CY, Chen SK, Chang YY, Lin P (1999) p53 codon 72 polymorphism in Taiwanese lung cancer patients: association with lung cancer susceptibility and prognosis. Clin Cancer Res 5:129–134

    CAS  PubMed  Google Scholar 

  21. Hiraki A, Matsuo K, Hamajima N, Ito H, Hatroka S, Suyama M, Mitsudomi T, Tajima K (2003) Different risk relations with smoking for non-small cell lung cancer: comparison of TP53 and TP73 genotypes. Asian Pac J Cancer Prev 4:107–112

    PubMed  Google Scholar 

  22. Zhang X, Miao X, Guo Y, Tan W, Zhou Y, Sun T, Wang Y, Lin D (2006) Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer. Hum Mutat 27:110–117

    Article  CAS  PubMed  Google Scholar 

  23. Jung HY, Whang YM, Sung JS, Shin HD, Park B, Kim JS, Shin SW, Seo HY, Seo JH, Kim YH (2008) Association study of TP53 polymorphisms with lung cancer in a Korean population. J Hum Genet 53:508–514

    Article  CAS  PubMed  Google Scholar 

  24. Chua HW, Ng D, Choo S, Lum SS, Li H, Soh LY (2010) Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among non-smoking Chinese women in Singapore. BMC Cancer 10:1471–2407

    Article  CAS  Google Scholar 

  25. Pierce LM, Sivaramah L, Chang W, Lum A, Donlon T, Seifried A, Wilkens LR, Lan AF, Marchand L (2000) Relationships of Tp53 codon 72 and HRAS1 polymorphisms with lung cancer risk in an ethnically diverse population. Cancer Epidemiol Biomarkers Prev 9:1199–1204

    CAS  PubMed  Google Scholar 

  26. Piao JM, Kim HN, Song HR, Kweon SS, Choi JS, Yun WJ, Kim YC, Oh IJ, Kim KS, Shin MH (2011) p53 codon 72 polymorphism and the risk of lung cancer in Korean population. Lung Cancer 73:264–267

    Article  PubMed  Google Scholar 

  27. Liu D, Wang F, Guo X, Wang Q, Wang W, Huo X, Guangquan X (2013) Association between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in Chinese population. Mol Biol Rep 40:645–649

    Article  CAS  PubMed  Google Scholar 

  28. Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP (2001) 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 18:705–719

    Article  CAS  PubMed  Google Scholar 

  29. Ryo JS, Hong YC, Han HS, Lee JE, Kim S, Park YM, Kim YC, Hwang TS (2004) Association between polymorphisms of ERCC1 and XPD and survival in non-small-cell lung cancer patients treated with cisplatin combination chemotherapy. Lung Cancer 44:311–316

    Article  Google Scholar 

  30. Mitsudomi T, Hamajima M, Ogawa M, Takahashi T (2000) Prognostic significance of p53 alteration in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res 6:4055–4063

    CAS  PubMed  Google Scholar 

  31. Mahesh PA, Archana S, Jayaraj BS, Patil S, Chaya SK, Sashidhar HP, Sunitha BS, Prabhakar AK (2012) Factors affecting 30-month survival in lung cancer patients. Indian J Med Res 136:614–621

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Tagawa M, Murata M, Kimura H (1998) Prognostic value of mutations and a germ line polymorphism of the p53 gene in non-small cell lung carcinoma: association with clinic-pathological features. Cancer Lett 128:93–99

    Article  CAS  PubMed  Google Scholar 

  33. Hu Y, McDermott MP, Ahrendt SA (2005) The p53 codon 72 proline allele is associated with p53 gene mutations in non-small cell lung cancer. Clin Cancer Res 11:2502–2509

    Article  CAS  PubMed  Google Scholar 

  34. Matakidou A, Galta R, Webb EL, Rudd MF, Bridle H, Eisen T (2007) Lack of evidence that p53Arg72Pro influences lung cancer prognosis: an analysis of survival in 619 female patients. Lung Cancer 57:207–212

    Article  PubMed  Google Scholar 

  35. Sodhi KK, Bahl C, Singh N, Behera D, Sharma S (2015) Functional genetic variants in pre-miR-146a and 196a2 genes are associated with risk of lung cancer in North Indians. Future Oncol 11:2159–2173

    Article  CAS  PubMed  Google Scholar 

  36. Addala L, Kalyan K, Mohan R, Anjaneyulu V, Sadanani MD (2012) p53 codon 72 gene polymorphism and risk of oral Squamous cell carcinoma in South Indian Population: a case-control study. J Cancer Sci Ther 4:188–192

    Article  CAS  Google Scholar 

  37. Li J, Chen Y, Moz, Li L (2015) TP53 Arg72Pro polymorphism and risk of endometriosis among Asian and Caucasian population. Eur J Obsetet Gynecol Reprod Biol 189:73–78

    Article  CAS  Google Scholar 

  38. Gharesouran J, Ghojazadeh M, Montazeri V, Mosaddes Ardebili SM (2015) Lack of influence of TP53 Arg72Pro and 16 bp duplication polymorphisms on risk of breast cancer in Iran. Asian Pac J Cancer Prev 16:2971–2974

    Article  PubMed  Google Scholar 

  39. Chikako N, Yasuo M, Jetsuya J, Makhiro T and Shinzaburo (2004) Association of p53 genetic polymorphism (Arg72Pro) with estrogen receptor positive breast cancer risk in Japanese women. Cancer Lett 210:197–203

    Article  CAS  Google Scholar 

  40. Dastjerdi M, Mansoor S, Roza Mohajeri M, Ferestitch M, Sadeghi HM, Ebrahim E (2008) Evidence for an association of TP53 codon72 polymorphism with sporadic colorectal cancer risk in Isfahan. JRMS 13:317–323

    CAS  Google Scholar 

  41. Jira C, Theamboonters A, Pairoj J, Sukumarn S, Anant K, Teeraporn C, Yong P (2013) Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQ01 (rs1800566) genes in Thai Cervical cancer patients with HPV16 Infection. APJCP 14:341–346

    Google Scholar 

  42. Wu B, Guo D, Guo Y (2014) Association between p53Arg72Pro polymorphisms and thyroid cancer risk: a meta-analysis. Tumor Biol 35:561–565

    Article  CAS  Google Scholar 

  43. Helen N, Eduaro M, Mauricio W, Perroud J, Aristoteles S, Ivan FC, Daniel B, Carmen SP, Lair Z (2007) Influence of p53 codon 72 exon 4, GSTM1.GSTT1 and GSTP1*B polymorphisms in lung cancer risk in a Brazilian population. Lung Cancer 61:152–162

    Google Scholar 

  44. Amelia S, Ewa J, Rafal D, Borg A, Limon J, Kobierska G, Rzyman W, Jaseem J (2006) Increased risk of non-small cell lung cancer an frequency of somatic TP53 gene mutation in Pro72 carriers of TP53 Arg72Pro polymorphism. Lung Cancer 52:9–14

    Article  Google Scholar 

  45. Wang S, Lan X, Tan S, Wang S (2013) p53 codon72 Arg/Pro polymorphism and lung cancer risk in Asians: an updated meta-analysis. Tumor Biol 34:2511–2521

    Article  CAS  Google Scholar 

  46. Rubio A, Felicitas M, Gonzalez P, Laura G, Teresa P, Manuel G, Adonina T (2008) The TP53 Arg72Pro polymorphism and lung cancer risk in population of Northern Spain. Lung Cancer 62:309–316

    Article  Google Scholar 

  47. Liu G, David P, Zhou W, Rong F, Li X, Thomas J, John C, Li S, David C (2001) Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung Carcinoma. Cancer Res 61:8718–8722

    CAS  PubMed  Google Scholar 

  48. Dante D, Luis A, Jane C, Leonel D, Carlos E (2009) Association between p53 codon 72 genetic polymorphism and tobacco use and lung cancer risk. Lung 187:110–115

    Article  CAS  Google Scholar 

  49. Orested DD, Bojesen SE, Hansen AT, Nordestgaard BG (2007) Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population. JEM 204:1295–1301

    Article  CAS  Google Scholar 

  50. Mitsudomi T, Oyama T, Kusano T, Osaki T, Nakanishi R, Shirakusa T (1993) Mutations of the p53 gene as a predictor of poor prognosis in patients with non small-cell lung cancer. JNCI 85:2018–2023

    Article  CAS  PubMed  Google Scholar 

  51. Wang YC, Lee HS, Chang YY, Chen CY (1999) Prognostic significance of p53 codon 72 polymorphism in lung cancer carcinomas. Eur J Cancer 35:226–230

    Article  CAS  PubMed  Google Scholar 

  52. Lin HY, Huang CH, Wu WJ, Chang LC, Lung FW (2008) TP53 codon 72 gene polymorphism paradox in associated with various carcinoma incidences, invasiveness and chemotherapy response. IJBS 4:248–254

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We would like to express our gratitude to all the subjects who participated in this current study. This work was supported by grant from the Indian Council of Medical Research, New Delhi, India (Grant No. 5/13/126/2011/NCD-III).

Funding

This work was supported by grant from the Indian Council of Medical Research, New Delhi, India (Grant No. 5/13/126/2011/NCD-III).

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Authors and Affiliations

  1. Department of Biotechnology, Thapar University, Patiala, Punjab, 147002, India

    Ankita Kumari, Charu Bahl & Siddharth Sharma

  2. Department of Pulmonary Medicine, Post Graduate Institute of Education and Medical Research (PGIMER), Sector 14, Chandigarh, India

    Navneet Singh & Digambar Behera

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  1. Ankita Kumari
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  2. Charu Bahl
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Correspondence to Siddharth Sharma.

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Kumari, A., Bahl, C., Singh, N. et al. Association of p53 codon 72 polymorphism and survival of North Indian lung cancer patients treated with platinum-based chemotherapy. Mol Biol Rep 43, 1383–1394 (2016). https://doi.org/10.1007/s11033-016-4072-1

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