vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ20.673vavilov-2821Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSПолиморфизмы генов TP53 (rs1042522) и MDM2 (rs2279744) в раке легкого: метаанализThe cell cycle regulatory gene polymorphisms TP53 (rs1042522) and MDM2 (rs2279744) in lung cancer: a meta-analysishttps://orcid.org/0000-0003-3272-0638БулгаковаО.BulgakovaO.

Нур-Султан

Nur-Sultan

ya.summer13@yandex.kzhttps://orcid.org/0000-0002-1313-9779КусаиноваА.KussainovaA.

Нур-Султан

Nur-Sultan

https://orcid.org/0000-0002-9671-1178БерсимбаевР.BersimbaevR.

Нур-Султан

Nur-Sultan

Евразийский национальный университет им. Л.Н. Гумилева, Институт клеточной биологии и биотехнологииКазахстанL.N. Gumilyov Eurasian National University, Institute of Cell Biology and BiotechnologyKazakhstan202005122020247777784Copyright © Булгакова О., Кусаинова А., Берсимбаев Р., 20202020Булгакова О., Кусаинова А., Берсимбаев Р.Bulgakova O., Kussainova A., Bersimbaev R.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/2821

Рак легкого - один из наиболее распространенных видов рака в мире. Хотя механизм возникновения заболевания по-прежнему остается в значительной степени неизвестным, благодаря многочисленным исследованиям была выявлена связь между полиморфизмами генов и риском развития рака легкого. Решающую роль в поддержании стабильности генома и профилактике опухолей играет онкосупрессор р53. Ключевым регулятором белка р53 является MDM2. Несмотря на важность p53 сигнального пути в канцерогенезе, данные о вкладе SNP TP53 (rs1042522) и MDM2 (rs2279744) в развитие рака легкого очень противоречивы. Метаанализ, собирающий количественные данные из отдельных исследований и объединяющий их результаты, имеет преимущество, которое заключается в повышении точности, предоставлении надежных оценок и решении тех вопросов, когда исследование отдельных ассоциаций недостаточно эффективно. Целью нашей работы было изучение роли полиморфизмов ТP53 (rs1042522) и MDM2 (rs2279744) в формировании предрасположенности к раку легкого. Проведен метаанализ ассоциации полиморфизмов TP53 (rs1042522) и MDM2 (rs2279744) и рака легкого. В общей сложности рассмотрено 51 исследование типа «случай–контроль», включающее 25 366 пациентов с раком легкого и 25 239 здоровых индивидуумов. Результаты метаанализа показали отсутствие связи между раком легкого и MDM2 (rs2279744) во всех моделях. Примечательно, что ассоциация TP53 (rs1042522) с предрасположенностью к раку легкого наблюдалась в трех разных моделях (мультипликативная, аддитивная и доминантная). Стратификация по этническому признаку также указывает на связь между TP53 (rs1042522) и риском развития рака легкого как в азиатской, так и в европейской популяции. Проведенный метаанализ позволяет сделать вывод, что полиморфизм ТР53 (rs1042522), но не MDM2 (rs2279744), может обусловливать предрасположенность к раку легкого.

Lung cancer is one of the most common types of cancer in the world. Although the mechanism of lung cancer is still unknown, a large number of studies have found a link between gene polymorphisms and the risk of lung cancer. The tumor suppressor p53 plays a crucial role in maintaining genomic stability and tumor prevention. MDM2 is a critical regulator of the p53 protein. Despite the importance of p53 pathway in cancer, data on the contribution of SNPs of TP53 (rs1042522) and MDM2 (rs2279744) to the development of lung cancer are very contradictory. A metaanalysis that collects quantitative data from individual studies and combines their results has the advantage of improving accuracy, providing reliable estimates, and resolving those issues in which studies on individual associations are not effective enough. The aim of this study was to determine whether the TP53 (rs1042522) and MDM2 (rs2279744) polymorphisms confer susceptibility to lung cancer. A meta-analysis was conducted on the associations between the TP53 (rs1042522) and MDM2 (rs2279744) polymorphisms and lung cancer. A total of 51 comparison studies including 25,366 patients and 25,239 controls were considered in this meta-analysis. The meta-analysis showed no association between lung cancer and MDM2 (rs2279744) under any model. A noteworthy association of TP53 (rs1042522) with susceptibility to lung cancer in overall pooled subjects was observed under three different models (allele contrast, homozygote contrast (additive) and dominant). Stratification by ethnicity indicated an association between the TP53 (rs1042522) and lung cancer in Asians and Caucasians. This meta-analysis demonstrates that the TP53 (rs1042522), but not MDM2 (rs2279744) polymorphism may confer susceptibility to lung cancer.

полиморфизм генов TP53 (rs1042522) и MDM2 (rs2279744)рак легкогометаанализTP53 (rs1042522) and MDM2 (rs2279744) gene polymorphismlung cancermeta-analysisThis study was partially supported by the Ministry of Science and Education of the Republic of Kazakhstan (grant No. AP05135213).ReferencesBirgander R., Sjalander A., Rannug A., Alexandrie A.K., Sundberg M.I., Seidegard J. P53 polymorphisms and haplotypes in lung cancer. Carcinogenesis. 1995;16(9):2233-2236. DOI 10.1093/carcin/16.9.2233.Birgander R., Sjalander A., Rannug A., Alexandrie A.K., Sundberg M.I., Seidegard J. P53 polymorphisms and haplotypes in lung cancer. Carcinogenesis. 1995;16(9):2233-2236. DOI 10.1093/carcin/16.9.2233.Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394-424. DOI 10.3322/caac.21492.Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394-424. DOI 10.3322/caac.21492.Bulgakova O., Kussainova A., Kakabayev A., Kausbekova A., Bersimbaev R. Association of polymorphism TP53 Arg72Pro with radoninduced lung cancer in the Kazakh population. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2019;23(5):594-599. DOI 10.18699/VJ19.530.Bulgakova O., Kussainova A., Kakabayev A., Kausbekova A., Bersimbaev R. Association of polymorphism TP53 Arg72Pro with radoninduced lung cancer in the Kazakh population. Vavilovskii Zhurnal Genetiki i Selektsii = Vavilov Journal of Genetics and Breeding. 2019;23(5):594-599. DOI 10.18699/VJ19.530.Buyru N., Altinisik J., Isin M., Dalay N. p53 codon 72 polymorphism and HPV status in lung cancer. Med. Sci. Monit. 2008;14(9):CR493-497.Buyru N., Altinisik J., Isin M., Dalay N. p53 codon 72 polymorphism and HPV status in lung cancer. Med. Sci. Monit. 2008;14(9):CR493-497.Cheng H., Ma B., Jiang R., Wang W., Guo H., Shen N., Li D., Zhao Q., Wang R., Yi P., Zhao Y., Liu Z., Huang T. Individual and combined effects of MDM2 SNP309 and TP53 Arg72Pro on breast cancer risk: an updated meta-analysis. Mol. Biol. Rep. 2012;39(9):9265-9274. DOI 10.1007/s11033-012-1800-z.Cheng H., Ma B., Jiang R., Wang W., Guo H., Shen N., Li D., Zhao Q., Wang R., Yi P., Zhao Y., Liu Z., Huang T. Individual and combined effects of MDM2 SNP309 and TP53 Arg72Pro on breast cancer risk: an updated meta-analysis. Mol. Biol. Rep. 2012;39(9):9265-9274. DOI 10.1007/s11033-012-1800-z.Chowdhury M.K., Moniruzzaman M., Emran A.A., Mostafa M.G., Kuddus R.H., Uddin M.A. TP53 codon 72 polymorphisms and lung cancer risk in the Bangladeshi population. Asian Pac. J. Cancer Prev. 2015;16(8):3493-3498. DOI 10.7314/apjcp.2015.16.8.3493.Chowdhury M.K., Moniruzzaman M., Emran A.A., Mostafa M.G., Kuddus R.H., Uddin M.A. TP53 codon 72 polymorphisms and lung cancer risk in the Bangladeshi population. Asian Pac. J. Cancer Prev. 2015;16(8):3493-3498. DOI 10.7314/apjcp.2015.16.8.3493.Chua H.W., Ng D., Choo S. Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among nonsmoking Chinese women in Singapore. BMC Cancer. 2010;10:88. DOI 10.1186/1471-2407-10-88.Chua H.W., Ng D., Choo S. Effect of MDM2 SNP309 and p53 codon 72 polymorphisms on lung cancer risk and survival among nonsmoking Chinese women in Singapore. BMC Cancer. 2010;10:88. DOI 10.1186/1471-2407-10-88.Ding H., Dai Y., Ning Zh., Fan N., Wang Zh., Li P., Zhang L., Tao Y., Wang H. Murine double minute 2 SNP T309G polymorphism and urinary tract cancer risk: a meta-analysis. Medicine (Baltimore). 2016;95(12):e2941. DOI 10.1097/MD.0000000000002941.Ding H., Dai Y., Ning Zh., Fan N., Wang Zh., Li P., Zhang L., Tao Y., Wang H. Murine double minute 2 SNP T309G polymorphism and urinary tract cancer risk: a meta-analysis. Medicine (Baltimore). 2016;95(12):e2941. DOI 10.1097/MD.0000000000002941.Egger M., Smith G., Schneider M., Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634. DOI 10.1136/bmj.315.7109.629.Egger M., Smith G., Schneider M., Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634. DOI 10.1136/bmj.315.7109.629.Enokida Y., Shimizu K., Kakegawa S., Atsumi J., Takase Y., Miyamae Y., Nagashima T., Ohtaki Y., Kaira K., Sunaga N., Yanagitani N., Yoshino R., Tsunekawa K., Igai H., Kamiyoshihara M., Usui K., Lezhava A., Tomizawa Y., Ishikawa T., Murakami M., Hayashizaki Y., Takeyoshi I. Single-nucleotide polymorphism (c.309T > G) in the MDM2 gene and lung cancer risk. Biomed. Rep. 2014;2(5): 719-724. DOI 10.3892/br.2014.305.Enokida Y., Shimizu K., Kakegawa S., Atsumi J., Takase Y., Miyamae Y., Nagashima T., Ohtaki Y., Kaira K., Sunaga N., Yanagitani N., Yoshino R., Tsunekawa K., Igai H., Kamiyoshihara M., Usui K., Lezhava A., Tomizawa Y., Ishikawa T., Murakami M., Hayashizaki Y., Takeyoshi I. Single-nucleotide polymorphism (c.309T > G) in the MDM2 gene and lung cancer risk. Biomed. Rep. 2014;2(5): 719-724. DOI 10.3892/br.2014.305.Fan R., Wu M.T., Miller D., Wain J.C., Kelsey K.T., Wiencke J. The p53 codon 72 polymorphism and lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 2000;9:1037-1042.Fan R., Wu M.T., Miller D., Wain J.C., Kelsey K.T., Wiencke J. The p53 codon 72 polymorphism and lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 2000;9:1037-1042.Fernández-Rubio A., López-Cima M.F., González-Arriaga P., García-Castro L., Pascual T., Marrón M.G., Tardón A. The TP53 Arg72Pro polymorphism and lung cancer risk in a population of Northern Spain. Lung Cancer. 2008;61(3):309-316. DOI 10.1016/j.lungcan.2008.01.017.Fernández-Rubio A., López-Cima M.F., González-Arriaga P., García-Castro L., Pascual T., Marrón M.G., Tardón A. The TP53 Arg72Pro polymorphism and lung cancer risk in a population of Northern Spain. Lung Cancer. 2008;61(3):309-316. DOI 10.1016/j.lungcan.2008.01.017.Giuliani L., Jaxmar T., Casadio C., Gariglio M., Manna A., D’Antonio D. Detection of oncogenic viruses SV40, BKV, JCV, HCMV, HPV and p53 codon 72 polymorphism in lung carcinoma. Lung Cancer. 2007; 57(3):273-281. DOI 10.1016/j.lungcan.2007.02.019.Giuliani L., Jaxmar T., Casadio C., Gariglio M., Manna A., D’Antonio D. Detection of oncogenic viruses SV40, BKV, JCV, HCMV, HPV and p53 codon 72 polymorphism in lung carcinoma. Lung Cancer. 2007; 57(3):273-281. DOI 10.1016/j.lungcan.2007.02.019.Haronikova L., Olivares-Illana V., Wang L., Karakostis K., Chen S., Fåhraeus R. The p53 mRNA: an integral part of the cellular stress response. Nucleic Acids Res. 2019;47(7):3257-3271. DOI 10.1093/nar/gkz124.Haronikova L., Olivares-Illana V., Wang L., Karakostis K., Chen S., Fåhraeus R. The p53 mRNA: an integral part of the cellular stress response. Nucleic Acids Res. 2019;47(7):3257-3271. DOI 10.1093/nar/gkz124.Hiraki A., Matsuo K., Hamajima N., Ito H., Hatooka S., Suyama M., Mitsudomi T., Tajima K. Different risk relations with smoking for nonsmall-cell lung cancer: comparison of TP53 and TP73 genotypes. Asian Pac. J. Cancer Prev. 2003;4:107-112.Hiraki A., Matsuo K., Hamajima N., Ito H., Hatooka S., Suyama M., Mitsudomi T., Tajima K. Different risk relations with smoking for nonsmall-cell lung cancer: comparison of TP53 and TP73 genotypes. Asian Pac. J. Cancer Prev. 2003;4:107-112.Hu Z., Ma H., Lu D. Genetic variants in the MDM2 promoter and lung cancer risk in a Chinese population. Int. J. Cancer. 2006;118:1275-1278.Hu Z., Ma H., Lu D. Genetic variants in the MDM2 promoter and lung cancer risk in a Chinese population. Int. J. Cancer. 2006;118:1275-1278.Javid J., Mir R., Julka P.K., Ray P.C., Saxena A. Association of p53 and mdm2 in the development and progression of non-small cell lung cancer. Tumour. Biol. 2015;36(7):5425‐5432. DOI 10.1007/s13277-015-3208-6.Javid J., Mir R., Julka P.K., Ray P.C., Saxena A. Association of p53 and mdm2 in the development and progression of non-small cell lung cancer. Tumour. Biol. 2015;36(7):5425‐5432. DOI 10.1007/s13277-015-3208-6.Jiang D.K., Yao L., Wang W.Zh., Peng B., Ren W.H., Yang X.M., Yu L. TP53 Arg72Pro polymorphism is associated with esophageal cancer risk: a meta-analysis. World J. Gastroenterol. 2011;17(9):1227-1233. DOI 10.3748/wjg.v17.i9.1227.Jiang D.K., Yao L., Wang W.Zh., Peng B., Ren W.H., Yang X.M., Yu L. TP53 Arg72Pro polymorphism is associated with esophageal cancer risk: a meta-analysis. World J. Gastroenterol. 2011;17(9):1227-1233. DOI 10.3748/wjg.v17.i9.1227.Jun H.J., Park S.H., Lee W.K. Combined effects of p73 and MDM2 polymorphisms on the risk of lung cancer. Mol. Carcinog. 2007;46: 100-105. DOI 10.1002/mc.20279.Jun H.J., Park S.H., Lee W.K. Combined effects of p73 and MDM2 polymorphisms on the risk of lung cancer. Mol. Carcinog. 2007;46: 100-105. DOI 10.1002/mc.20279.Jung H.Y., Whang Y.M., Sung J.S., Shin H.D., Park B.L., Kim J.S., Shin S.W., Seo H.Y., Seo J.H., Kim Y.H. Association study of TP53 polymorphisms with lung cancer in a Korean population. J. Hum. Genet. 2008;53:508-514. DOI 10.1007/s10038-008-0278-y. Kawajiri K., Nakachi K., Imai K. Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis. 1993;14:1085-1089. DOI 10.1093/carcin/14.6.1085.Jung H.Y., Whang Y.M., Sung J.S., Shin H.D., Park B.L., Kim J.S., Shin S.W., Seo H.Y., Seo J.H., Kim Y.H. Association study of TP53 polymorphisms with lung cancer in a Korean population. J. Hum. Genet. 2008;53:508-514. DOI 10.1007/s10038-008-0278-y. Kawajiri K., Nakachi K., Imai K. Germ line polymorphisms of p53 and CYP1A1 genes involved in human lung cancer. Carcinogenesis. 1993;14:1085-1089. DOI 10.1093/carcin/14.6.1085.Kiyohara C., Horiuchi T., Miyake Y., Takayama K., Nakanishi Y. Cigarette smoking, TP53 Arg72Pro, TP53BP1 Asp353Glu and the risk of lung cancer in a Japanese population. Oncol. Rep. 2010;23(5): 1361-1368. DOI 10.3892/or_00000772.Kiyohara C., Horiuchi T., Miyake Y., Takayama K., Nakanishi Y. Cigarette smoking, TP53 Arg72Pro, TP53BP1 Asp353Glu and the risk of lung cancer in a Japanese population. Oncol. Rep. 2010;23(5): 1361-1368. DOI 10.3892/or_00000772.Kohno T., Kunitoh H., Mimaki S. Contribution of the TP53, OGG1, CHRNA3, and HLA-DQA1 genes to the risk for lung squamous cell carcinoma. J. Thorac. Oncol. 2011;6:813-817. DOI 10.1097/JTO.0b013e3181ee80ef.Kohno T., Kunitoh H., Mimaki S. Contribution of the TP53, OGG1, CHRNA3, and HLA-DQA1 genes to the risk for lung squamous cell carcinoma. J. Thorac. Oncol. 2011;6:813-817. DOI 10.1097/JTO.0b013e3181ee80ef.Lee Y.H. Meta-analysis of genetic association studies. Ann. Lab. Med. 2015;35(3):283‐287. DOI 10.3343/alm.2015.35.3.283.Lee Y.H. Meta-analysis of genetic association studies. Ann. Lab. Med. 2015;35(3):283‐287. DOI 10.3343/alm.2015.35.3.283.Li G., Zhai X., Zhang Z., Chamberlain R.M., Spitz M.R. MDM2 gene promoter polymorphisms and risk of lung cancer: a case-control analysis. Carcinogenesis. 2006;27:2028-2033. DOI 10.1093/carcin/bgl047.Li G., Zhai X., Zhang Z., Chamberlain R.M., Spitz M.R. MDM2 gene promoter polymorphisms and risk of lung cancer: a case-control analysis. Carcinogenesis. 2006;27:2028-2033. DOI 10.1093/carcin/bgl047.Li W., Wang S.S., Deng J., Tang J.X. Association of p73 gene G4C14-A4T14 polymorphism and MDM2 gene SNP309 with non-small cell lung cancer risk in a Chinese population. Oncol. Lett. 2017; 14(2):1817-1822. PMID: 28789416. PMCID: PMC5529775. DOI 10.3892/ol.2017.6327.Li W., Wang S.S., Deng J., Tang J.X. Association of p73 gene G4C14-A4T14 polymorphism and MDM2 gene SNP309 with non-small cell lung cancer risk in a Chinese population. Oncol. Lett. 2017; 14(2):1817-1822. PMID: 28789416. PMCID: PMC5529775. DOI 10.3892/ol.2017.6327.Li Y., Chang S.-C., Niu R., Li Y., Chang S.-C., Niu R., Liu L., Crabtree-Ide C.R., Zhao B., Shi J., Han X., Li J., Su J., Cai L., Yu S., Zhang Z.-F., Mu L. TP53 genetic polymorphisms, interactions with lifestyle factors and lung cancer risk: a case control study in a Chinese population. BMC Cancer. 2013;13:607. DOI 10.1186/1471-2407-13-607.Li Y., Chang S.-C., Niu R., Li Y., Chang S.-C., Niu R., Liu L., Crabtree-Ide C.R., Zhao B., Shi J., Han X., Li J., Su J., Cai L., Yu S., Zhang Z.-F., Mu L. TP53 genetic polymorphisms, interactions with lifestyle factors and lung cancer risk: a case control study in a Chinese population. BMC Cancer. 2013;13:607. DOI 10.1186/1471-2407-13-607.Lind H., Ekstrøm P.O., Ryberg D., Skaug V., Andreassen T. Frequency of TP53 mutations in relation to Arg72Pro genotypes in non-small cell lung cancer. Cancer Epidemiol. Biomarkers Prev. 2007;16(10): 2077-2081. DOI 10.1158/1055-9965.EPI-07-0153.Lind H., Ekstrøm P.O., Ryberg D., Skaug V., Andreassen T. Frequency of TP53 mutations in relation to Arg72Pro genotypes in non-small cell lung cancer. Cancer Epidemiol. Biomarkers Prev. 2007;16(10): 2077-2081. DOI 10.1158/1055-9965.EPI-07-0153.Lind H., Zienolddiny S., Ekstrom P.O., Skaug V., Haugen A. Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer. Int. J. Cancer. 2006;119: 718-721. DOI 10.1002/ijc.21872.Lind H., Zienolddiny S., Ekstrom P.O., Skaug V., Haugen A. Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer. Int. J. Cancer. 2006;119: 718-721. DOI 10.1002/ijc.21872.Liu D., Wang F., Guo X., Wang Q., Wang W., Xu H., Xu G. Association between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population. Mol. Biol. Rep. 2013; 40(1):645-649. DOI 10.1007/s11033-012-2103-0.Liu D., Wang F., Guo X., Wang Q., Wang W., Xu H., Xu G. Association between p53 codon 72 genetic polymorphisms and tobacco use and lung cancer risk in a Chinese population. Mol. Biol. Rep. 2013; 40(1):645-649. DOI 10.1007/s11033-012-2103-0.Liu G., Miller D.P., Zhou W., Thurston S.W., Fan R., Xu L.L. Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma. Cancer Res. 2001;61(24):8718-8722.Liu G., Miller D.P., Zhou W., Thurston S.W., Fan R., Xu L.L. Differential association of the codon 72 p53 and GSTM1 polymorphisms on histological subtype of non-small cell lung carcinoma. Cancer Res. 2001;61(24):8718-8722.Liu G., Wheatley-Price P., Zhou W. Genetic polymorphisms of MDM2, cumulative cigarette smoking and nonsmall cell lung cancer risk. Int. J. Cancer. 2008;122:915-918. DOI 10.1002/ijc.23178.Liu G., Wheatley-Price P., Zhou W. Genetic polymorphisms of MDM2, cumulative cigarette smoking and nonsmall cell lung cancer risk. Int. J. Cancer. 2008;122:915-918. DOI 10.1002/ijc.23178.Ma Y., Bian J., Cao H. MDM2 SNP309 rs2279744 polymorphism and gastric cancer risk: a meta-analysis. PLoS One. 2013;8(2):e56918. DOI 10.1371/journal.pone.0056918.Ma Y., Bian J., Cao H. MDM2 SNP309 rs2279744 polymorphism and gastric cancer risk: a meta-analysis. PLoS One. 2013;8(2):e56918. DOI 10.1371/journal.pone.0056918.McKay J.D., Hung R.J., Han Y., Zong X., Carreras-Torres R., Christiani D.C., Caporaso N.E., … Bossé Y., Chanock S., Brennan P., Landi M.T., Amos C.I. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat. Genet. 2017;49(7): 1126-1132. DOI 10.1038/ng.3892.McKay J.D., Hung R.J., Han Y., Zong X., Carreras-Torres R., Christiani D.C., Caporaso N.E., … Bossé Y., Chanock S., Brennan P., Landi M.T., Amos C.I. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nat. Genet. 2017;49(7): 1126-1132. DOI 10.1038/ng.3892.Mechanic L.E., Bowman E.D., Welsh J.A., Khan M.A., Hagiwara N., Enewold L. Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol. Biomarkers Prev. 2007;16(2):214-222. DOI 10.1158/1055-9965.EPI-06-0790.Mechanic L.E., Bowman E.D., Welsh J.A., Khan M.A., Hagiwara N., Enewold L. Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors. Cancer Epidemiol. Biomarkers Prev. 2007;16(2):214-222. DOI 10.1158/1055-9965.EPI-06-0790.Miller D.P., Liu G., De Vivo I., Lynch T.J., Wain J.C., Su L., Christiani D.C. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res. 2002;62:2819-2823.Miller D.P., Liu G., De Vivo I., Lynch T.J., Wain J.C., Su L., Christiani D.C. Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. Cancer Res. 2002;62:2819-2823.Mittelstrass K., Sauter W., Rosenberger A. Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene. BMC Cancer. 2008;8:113. DOI 10.1186/1471-2407-8-113.Mittelstrass K., Sauter W., Rosenberger A. Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene. BMC Cancer. 2008;8:113. DOI 10.1186/1471-2407-8-113.Mostaid M.S., Ahmed M.U., Islam M.S., Bin Sayeed M.S., Hasnat A. Lung cancer risk in relation to TP53 codon 47 and codon 72 polymorphism in Bangladeshi population. Tumour Biol. 2014;35(10): 10309-10317. DOI 10.1007/s13277-014-2285-2.Mostaid M.S., Ahmed M.U., Islam M.S., Bin Sayeed M.S., Hasnat A. Lung cancer risk in relation to TP53 codon 47 and codon 72 polymorphism in Bangladeshi population. Tumour Biol. 2014;35(10): 10309-10317. DOI 10.1007/s13277-014-2285-2.Murata M., Tagawa M., Kimura M., Kimura H., Watanabe S., Saisho H. Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history. Carcinogenesis. 1996;17(2):261-264. DOI 10.1093/carcin/17.2.261.Murata M., Tagawa M., Kimura M., Kimura H., Watanabe S., Saisho H. Analysis of a germ line polymorphism of the p53 gene in lung cancer patients: discrete results with smoking history. Carcinogenesis. 1996;17(2):261-264. DOI 10.1093/carcin/17.2.261.Nadji S.A., Mahmoodi M., Ziaee A.A., Naghshvar F., Torabizadeh J., Yahyapour Y. An increased lung cancer risk associated with codon 72 polymorphism in the TP53 gene and human papillomavirus infection in Mazandaran province, Iran. Lung Cancer. 2007;56(2): 145-151. DOI 10.1016/j.lungcan.2006.12.006.Nadji S.A., Mahmoodi M., Ziaee A.A., Naghshvar F., Torabizadeh J., Yahyapour Y. An increased lung cancer risk associated with codon 72 polymorphism in the TP53 gene and human papillomavirus infection in Mazandaran province, Iran. Lung Cancer. 2007;56(2): 145-151. DOI 10.1016/j.lungcan.2006.12.006.Nicolai S., Rossi A., Daniele N., Melino G., Annicchiarico-Petruzzelli M., Raschellà G. DNA repair and aging: the impact of the p53 family. Aging (Albany NY ). 2015;7(12):1050-1065. DOI 10.18632/aging.100858.Nicolai S., Rossi A., Daniele N., Melino G., Annicchiarico-Petruzzelli M., Raschellà G. DNA repair and aging: the impact of the p53 family. Aging (Albany NY ). 2015;7(12):1050-1065. DOI 10.18632/aging.100858.Papadakis E.D., Soulitzis N., Spandidos D.A. Association of p53 codon 72 polymorphism with advanced lung cancer: the Arg allele is preferentially retained in tumours arising in Arg/Pro germline heterozygotes. Br. J. Cancer. 2002;87(9):1013-1018. DOI 10.1038/sj.bjc.6600595.Papadakis E.D., Soulitzis N., Spandidos D.A. Association of p53 codon 72 polymorphism with advanced lung cancer: the Arg allele is preferentially retained in tumours arising in Arg/Pro germline heterozygotes. Br. J. Cancer. 2002;87(9):1013-1018. DOI 10.1038/sj.bjc.6600595.Piao J.M., Kim H.N., Song H.R., Kweon S.S., Choi J.S., Yun W.J. p53 codon 72 polymorphism and the risk of lung cancer in a Korean population. Lung Cancer. 2011;73(3):264-267. DOI 10.1016/j.lungcan.2010.12.017.Piao J.M., Kim H.N., Song H.R., Kweon S.S., Choi J.S., Yun W.J. p53 codon 72 polymorphism and the risk of lung cancer in a Korean population. Lung Cancer. 2011;73(3):264-267. DOI 10.1016/j.lungcan.2010.12.017.Pierce L.M., Sivaraman L., Chang W., Lum A., Donlon T., Seifried A. Relationships of TP53 codon 72 and HRAS1 polymorphisms with lung cancer risk in an ethnically diverse population. Cancer Epidemiol. Biomarkers Prev. 2000;9:1199-1204.Pierce L.M., Sivaraman L., Chang W., Lum A., Donlon T., Seifried A. Relationships of TP53 codon 72 and HRAS1 polymorphisms with lung cancer risk in an ethnically diverse population. Cancer Epidemiol. Biomarkers Prev. 2000;9:1199-1204.Pine S.R., Mechanic L.E., Bowman E.D., Welsh J.A., Chanock S.C., Shields P.G., Harris C.C. MDM2 SNP309 and SNP354 are not associated with lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 2006;15(8):1559-1561. DOI 10.1158/1055-9965.EPI-06-0217.Pine S.R., Mechanic L.E., Bowman E.D., Welsh J.A., Chanock S.C., Shields P.G., Harris C.C. MDM2 SNP309 and SNP354 are not associated with lung cancer risk. Cancer Epidemiol. Biomarkers Prev. 2006;15(8):1559-1561. DOI 10.1158/1055-9965.EPI-06-0217.Popanda O., Edler L., Waas P., Schattenberg T., Butkiewicz D., Muley T., Dienemann H., Risch A., Bartsch H., Schmezer P. Elevated risk of squamous-cell carcinoma of the lung in heavy smokers carrying the variant alleles of the TP53 Arg72Pro and p21 Ser31Arg polymorphisms. Lung Cancer. 2007;55(1):25-34. DOI 10.1016/j.lungcan.2006.09.006.Popanda O., Edler L., Waas P., Schattenberg T., Butkiewicz D., Muley T., Dienemann H., Risch A., Bartsch H., Schmezer P. Elevated risk of squamous-cell carcinoma of the lung in heavy smokers carrying the variant alleles of the TP53 Arg72Pro and p21 Ser31Arg polymorphisms. Lung Cancer. 2007;55(1):25-34. DOI 10.1016/j.lungcan.2006.09.006.Qin X., Peng Q., Tang W., Lao X., Chen Zh., Lai H., Deng Y., Mo C., Sui J., Wu J., Zhai L., Yang Sh., Li Sh., Zhao J. An updated metaanalysis on the association of MDM2 SNP309 polymorphism with colorectal cancer risk. PLoS One. 2013;8(9):e76031. DOI 10.1371/journal.pone.0076031.Qin X., Peng Q., Tang W., Lao X., Chen Zh., Lai H., Deng Y., Mo C., Sui J., Wu J., Zhai L., Yang Sh., Li Sh., Zhao J. An updated metaanalysis on the association of MDM2 SNP309 polymorphism with colorectal cancer risk. PLoS One. 2013;8(9):e76031. DOI 10.1371/journal.pone.0076031.Ren Y.W., Yin Zh., Wan Y., Guan P., Wu W., Li X., Zhou B. P53 Arg72Pro and MDM2 SNP309 polymorphisms cooperate to increase lung adenocarcinoma risk in Chinese female non-smokers: a case control study. Asian Pac. J. Cancer Prev. 2013;14(9):5415-5420. DOI 10.7314/apjcp.2013.14.9.5415.Ren Y.W., Yin Zh., Wan Y., Guan P., Wu W., Li X., Zhou B. P53 Arg72Pro and MDM2 SNP309 polymorphisms cooperate to increase lung adenocarcinoma risk in Chinese female non-smokers: a case control study. Asian Pac. J. Cancer Prev. 2013;14(9):5415-5420. DOI 10.7314/apjcp.2013.14.9.5415.Saikia B.J., Das M., Sharma S.K., Sekhon G.S., Zomawia E., Singh Y.M., Mahanta J., Phukan R.K. Association of a p53 codon 72 gene polymorphism with environmental factors and risk of lung cancer: a case control study in Mizoram and Manipur, a high incidence region in North East India. Asian Pac. J. Cancer Prev. 2014;15: 10653-10658. DOI 10.7314/apjcp.2014.15.24.10653.Saikia B.J., Das M., Sharma S.K., Sekhon G.S., Zomawia E., Singh Y.M., Mahanta J., Phukan R.K. Association of a p53 codon 72 gene polymorphism with environmental factors and risk of lung cancer: a case control study in Mizoram and Manipur, a high incidence region in North East India. Asian Pac. J. Cancer Prev. 2014;15: 10653-10658. DOI 10.7314/apjcp.2014.15.24.10653.Sakiyama T., Kohno T., Mimaki S., Ohta T., Yanagitani N., Sobue T., Kunitoh H., Saito R., Shimizu K., Hirama C., Kimura J., Maeno G. Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Int. J. Cancer. 2004;114:730-737. DOI 10.1002/ijc.20790.Sakiyama T., Kohno T., Mimaki S., Ohta T., Yanagitani N., Sobue T., Kunitoh H., Saito R., Shimizu K., Hirama C., Kimura J., Maeno G. Association of amino acid substitution polymorphisms in DNA repair genes TP53, POLI, REV1 and LIG4 with lung cancer risk. Int. J. Cancer. 2004;114:730-737. DOI 10.1002/ijc.20790.Sobti R.C., Kaur P., Kaur S., Janmeja A.K., Jindal S.K., Kishan J. 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. 2009;28(9):443-449. DOI 10.1089/dna.2008.0797.Sobti R.C., Kaur P., Kaur S., Janmeja A.K., Jindal S.K., Kishan J. 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. 2009;28(9):443-449. DOI 10.1089/dna.2008.0797.Souto-García A., Fernández-Somoano A., Pascual T., Álvarez-Avellón S.M., Tardón A. Association of p21 Ser31Arg and p53 Arg72Pro polymorphisms with lung cancer risk in CAPUA study. Lung Cancer (Auckl ). 2012;3:69-78. DOI 10.2147/LCTT.S35287.Souto-García A., Fernández-Somoano A., Pascual T., Álvarez-Avellón S.M., Tardón A. Association of p21 Ser31Arg and p53 Arg72Pro polymorphisms with lung cancer risk in CAPUA study. Lung Cancer (Auckl ). 2012;3:69-78. DOI 10.2147/LCTT.S35287.Sreeja L., Syamala V., Raveendran P.B., Santhi S., Madhavan J., Ankathil R. p53 Arg72Pro polymorphism predicts survival outcome in lung cancer patients in Indian population. Cancer Invest. 2009;26: 41-46. DOI 10.1080/07357900701638459.Sreeja L., Syamala V., Raveendran P.B., Santhi S., Madhavan J., Ankathil R. p53 Arg72Pro polymorphism predicts survival outcome in lung cancer patients in Indian population. Cancer Invest. 2009;26: 41-46. DOI 10.1080/07357900701638459.Su L., Sai Y., Fan R., Thurston S.W., Miller D.P., Zhou W., Wain J.C.,Su L., Sai Y., Fan R., Thurston S.W., Miller D.P., Zhou W., Wain J.C.,Lynch T.J., Liu G., Christiani D.C. P53 (codon 72) and P21 (codon 31) polymorphisms alter in vivo mRNA expression of p21. Lung Cancer. 2003;40(3):259‐266. DOI 10.1016/s0169-5002(03)00081-3. Sun Zh., Gao W., Cui G.T. Effect of TP53 rs1042522 on the susceptibility of patients to oral squamous cell carcinoma and oral leukoplakia: a meta-analysis. BMC Oral Health. 2018;18(1):143. DOI 10.1186/s12903-018-0603-6.Lynch T.J., Liu G., Christiani D.C. P53 (codon 72) and P21 (codon 31) polymorphisms alter in vivo mRNA expression of p21. Lung Cancer. 2003;40(3):259‐266. DOI 10.1016/s0169-5002(03)00081-3. Sun Zh., Gao W., Cui G.T. Effect of TP53 rs1042522 on the susceptibility of patients to oral squamous cell carcinoma and oral leukoplakia: a meta-analysis. BMC Oral Health. 2018;18(1):143. DOI 10.1186/s12903-018-0603-6.Szymanowska A., Jassem E., Dziadziuszko R., Borg A., Limon J., Kobierska-Gulida G., Rzyman W., Jassem J. Increased risk of nonsmall cell lung cancer and frequency of somatic TP53 gene mutations in Pro72 carriers of TP53 Arg72Pro polymorphism. Lung Cancer. 2006;52(1):9-14. DOI 10.1016/j.lungcan.2005.12.007.Szymanowska A., Jassem E., Dziadziuszko R., Borg A., Limon J., Kobierska-Gulida G., Rzyman W., Jassem J. Increased risk of nonsmall cell lung cancer and frequency of somatic TP53 gene mutations in Pro72 carriers of TP53 Arg72Pro polymorphism. Lung Cancer. 2006;52(1):9-14. DOI 10.1016/j.lungcan.2005.12.007.Tang T., Song X., Yang Zh., Huang L., Wang W., Tan H. Association between murine double minute 2 T309G polymorphism and risk of liver cancer. Tumour Biol. 2014;35(11):11353-11357. DOI 10.1007/s13277-014-2432-9.Tang T., Song X., Yang Zh., Huang L., Wang W., Tan H. Association between murine double minute 2 T309G polymorphism and risk of liver cancer. Tumour Biol. 2014;35(11):11353-11357. DOI 10.1007/s13277-014-2432-9.Tian X., Dai Sh., Sun J., Jiang Sh., Jiang Y. Association between TP53 Arg72Pro polymorphism and leukemia risk: a meta-analysis of 14 case-control studies. Sci. Rep. 2016;6:24097. DOI 10.1038/srep24097.Tian X., Dai Sh., Sun J., Jiang Sh., Jiang Y. Association between TP53 Arg72Pro polymorphism and leukemia risk: a meta-analysis of 14 case-control studies. Sci. Rep. 2016;6:24097. DOI 10.1038/srep24097.Tian X., Dai Sh., Sun J., Jiang Sh., Jiang Y. The association between the TP53 Arg72Pro polymorphism and colorectal cancer: an updated meta-analysis based on 32 studies. Oncotarget. 2017;8(1): 1156-1165. DOI 10.18632/oncotarget.13589.Tian X., Dai Sh., Sun J., Jiang Sh., Jiang Y. The association between the TP53 Arg72Pro polymorphism and colorectal cancer: an updated meta-analysis based on 32 studies. Oncotarget. 2017;8(1): 1156-1165. DOI 10.18632/oncotarget.13589.To-Figueras J., Gene M., Gomez-Catalan J., Galan C., Firvida J., Fuentes M. Glutathione-S-Transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility. Cancer Epidemiol. Biomarkers Prev. 1996;5(5):337-342.To-Figueras J., Gene M., Gomez-Catalan J., Galan C., Firvida J., Fuentes M. Glutathione-S-Transferase M1 and codon 72 p53 polymorphisms in a northwestern Mediterranean population and their relation to lung cancer susceptibility. Cancer Epidemiol. Biomarkers Prev. 1996;5(5):337-342.Wang X., Jin L., Cui J., Ma K., Chen X., Li W. Mouse double minute-2 homolog (MDM2)-rs2279744 polymorphism associated with lung cancer risk in a Northeastern Chinese population. Thorac. Cancer. 2015;6(1):91-96. DOI 10.1111/1759-7714.12153.Wang X., Jin L., Cui J., Ma K., Chen X., Li W. Mouse double minute-2 homolog (MDM2)-rs2279744 polymorphism associated with lung cancer risk in a Northeastern Chinese population. Thorac. Cancer. 2015;6(1):91-96. DOI 10.1111/1759-7714.12153.Wang Y.C., Chen C.Y., Chen S.K., Chang Y.Y., Lin P. p53 codon 72 polymorphism in Taiwanese lung cancer patients: association with lung cancer susceptibility and prognosis. Clin. Cancer Res. 1999;5: 129-134.Wang Y.C., Chen C.Y., Chen S.K., Chang Y.Y., Lin P. p53 codon 72 polymorphism in Taiwanese lung cancer patients: association with lung cancer susceptibility and prognosis. Clin. Cancer Res. 1999;5: 129-134.Wells G.A., Shea B., O’Connell D., Peterson J., Welch V., Losos M., Tugwell P. The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available online: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm (Accessed on 19 October 2009).Wells G.A., Shea B., O’Connell D., Peterson J., Welch V., Losos M., Tugwell P. The Newcastle–Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available online: http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm (Accessed on 19 October 2009).Wu X., Zhao H., Amos C.I., Shete S., Makan N., Hong W.K., Kadlubar F.F., Spitz M.R. p53 genotypes and haplotypes associated with lung cancer susceptibility and ethnicity. J. Natl. Cancer Inst. 2002; 94:681-690. DOI 10.1093/jnci/94.9.681.Wu X., Zhao H., Amos C.I., Shete S., Makan N., Hong W.K., Kadlubar F.F., Spitz M.R. p53 genotypes and haplotypes associated with lung cancer susceptibility and ethnicity. J. Natl. Cancer Inst. 2002; 94:681-690. DOI 10.1093/jnci/94.9.681.Xiang B., Mi Y.Y., Li T.F., Liu P.F. Updated meta-analysis of the TP53 Arg72Pro polymorphism and gastric cancer risk. Asian Pac. J. Cancer Prev. 2012;13(5):1787-1791. DOI 10.7314/apjcp.2012.13.5.1787.Xiang B., Mi Y.Y., Li T.F., Liu P.F. Updated meta-analysis of the TP53 Arg72Pro polymorphism and gastric cancer risk. Asian Pac. J. Cancer Prev. 2012;13(5):1787-1791. DOI 10.7314/apjcp.2012.13.5.1787.Xu T., Xu Z.Ch., Zou Q., Yu B., Huang X.E. P53 Arg72Pro polymorphism and bladder cancer risk – meta-analysis evidence for a link in Asians but not Caucasians. Asian Pac. J. Cancer Prev. 2012;13(5): 2349-2354. DOI 10.7314/apjcp.2012.13.5.2349.Xu T., Xu Z.Ch., Zou Q., Yu B., Huang X.E. P53 Arg72Pro polymorphism and bladder cancer risk – meta-analysis evidence for a link in Asians but not Caucasians. Asian Pac. J. Cancer Prev. 2012;13(5): 2349-2354. DOI 10.7314/apjcp.2012.13.5.2349.Zhang F., Li D., Li Y., Li H., Sun J., Li X., Li X. Quantitative assessment of the association between TP53 Arg72Pro polymorphism and risk of glioma. Tumour Biol. 2014;35(1):747-751. DOI 10.1007/s13277-013-1101-8.Zhang F., Li D., Li Y., Li H., Sun J., Li X., Li X. Quantitative assessment of the association between TP53 Arg72Pro polymorphism and risk of glioma. Tumour Biol. 2014;35(1):747-751. DOI 10.1007/s13277-013-1101-8.Zhang X., Miao M., Guo Y., Tan W., Zhou Y., Sun T., Wang Y., Lin D. Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer. Hum. Mutat. 2006;27(1):110-117. DOI 10.1002/humu.20277.Zhang X., Miao M., Guo Y., Tan W., Zhou Y., Sun T., Wang Y., Lin D. Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer. Hum. Mutat. 2006;27(1):110-117. DOI 10.1002/humu.20277.Zhuo W., Zhang L., Zhu B., Ling J., Chen Z. Association of MDM2 SNP309 variation with lung cancer risk: evidence from 7196 cases and 8456 controls. PLoS One. 2012;7:e41546. DOI 10.1371/journal.pone.0041546.Zhuo W., Zhang L., Zhu B., Ling J., Chen Z. Association of MDM2 SNP309 variation with lung cancer risk: evidence from 7196 cases and 8456 controls. PLoS One. 2012;7:e41546. DOI 10.1371/journal.pone.0041546.

The authors declare that there are no conflicts of interest present.