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Original Research

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The association between p16INK4a and prognosis in endometrial carcinoma: a meta-analysis

  • H. Cao1,†
  • S. Yang2,†
  • S. Xie3
  • M. Xi1,*,

1Department of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China

2Laboratory of Lung Development and Disease, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China

3Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu City, China

DOI: 10.12892/ejgo4535.2019 Vol.40,Issue 2,April 2019 pp.311-317

Accepted: 11 January 2018

Published: 10 April 2019

*Corresponding Author(s): M. Xi E-mail: xmrjzz1@126.com

† These authors contributed equally.

Abstract

Purpose of Investigation: P16INK4a has been suggested to be involved in the prognosis of various human malignancies. The purpose of this study was to analyze the prognostic impact of overexpressed P16INK4a in endometrial carcinoma. Materials and Methods: The PubMed, Embase, and Web of Science were searched for relevant publications in English language and the China National Knowledge Infrastructure was searched for studies in Chinese language. The pooled odds ratios (ORs) or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were used to assess the strength of association. Results: Overall, 26 studies with 1,628 patients were included. The P16 INK4a overexpression was found to correlate significantly with the lower histological grade (OR = 0.44, 95%CI: 0.25- 0.78, P = 0.005, random effect), negative lymph node metastasis (OR = 0.39, 95%CI: 0.20-0.76, P = 0.005, fixed effect) and ≤1/2 myometrial infiltration (OR = 0.63, 95% CI: 0.40-1.00, P = 0.05, fixed effect). However, no significant association was found between P16 INK4a and FIGO (International Federation of Gynecology and Obstetrics) stage (OR= 0.80, 95% CI: 0.46-1.37, P = 0.409, random effect), histological type (OR= 1.21, 95% CI: 0.40-3.61, P = 0.735, random effect) or overall survival (RR = 0.74, 95% CI: 0.20-2.72, P = 0.653, random effect). Subgroup analysis indicated that the associations might differ based on geographical location, sample size, publication year, cut-off value, and study quality. Conclusion: The P16 INK4a might be a potential biomarker for better prognosis of endometrial carcinoma.

Keywords

p16INK4a; Endometrial carcinoma; Immunohistochemistry; Prognosis


Cite and Share

H. Cao,S. Yang,S. Xie,M. Xi. The association between p16INK4a and prognosis in endometrial carcinoma: a meta-analysis. European Journal of Gynaecological Oncology. 2019. 40(2);311-317.

References

[1] Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., et al.: “Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012”. Int. J. Cancer, 2015, 136, E359.

[2] Siegel R.L., Miller K.D., Jemal A.: “Cancer statistics, 2015”. CA Cancer J. Clin.., 2015, 65, 5.

[3] Okuda T., Sekizawa A., Purwosunu Y., Nagatsuka M., Morioka M., Hayashi M., et al.: “Genetics of endometrial cancers”. Obstet. Gynecol. Int., 2010, 2010, 984013.

[4] Kamb A., Gruis N.A., Weaver-Feldhaus J., Liu Q., Harshman K., Tavtigian S.V., et al.: “A cell cycle regulator potentially involved in genesis of many tumor types”. Science, 1994, 264, 436.

[5] Ndiaye C., Mena M., Alemany L., Arbyn M., Castellsagué X., Laporte L., et al.: “HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis”. LANCET ONCOL., 2014, 15, 1319.

[6] Zhu C.Q., Shih W., Ling C.H., Tsao M.S.: “Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation”. J. Clin. Pathol., 2006, 59, 790.

[7] Lebok P., Roming M., Kluth M., Koop C., Özden C., Taskin B., et al.: “p16 overexpression and 9p21 deletion are linked to unfavorable tumor phenotype in breast cancer”. Oncotarget, 2016, 7, 81322.

[8] Rocco J.W., Sidransky D.: “p16(MTS-1/CDKN2/INK4a) in cancer progression”. Exp. Cell Res., 2001, 264, 42.

[9] Bu J., Li H., Liu L.H., Ouyang Y.R., Guo H.B., Li X.Y., et al.: “P16INK4a overexpression and survival in osteosarcoma patients: a meta analysis”. Int. J. Clin. Exp. Pathol., 2014, 7, 6091.

[10] Lin J., Albers A.E., Qin J., Kaufmann A.M.: “Prognostic significance of overexpressed p16INK4a in patients with cervical cancer: a meta-analysis”. PLoS ONE, 2014, 9, e106384.

[11] Cao H., Wang S., Zhang Z., Lou J.: “Prognostic Value of Overexpressed p16INK4a in Vulvar Cancer: A Meta-Analysis”. PLoS One, 2016, 11, e152459.

[12] Chen Y.Z., Liu D., Zhao Y.X,.Wang H.T., Gao Y., Chen Y.: “Relationships between p16 gene promoter methylation and clinicopathologic features of colorectal cancer: a meta-analysis of 27 cohort studies”. DNA Cell Biol., 2014, 33, 729.

[13] Steinbakk A., Skaland I., Gudlaugsson E., Janssen E.A., Kjellevold K.H., Klos J., et al.: “The prognostic value of molecular biomarkers in tissue removed by curettage from FIGO stage 1 and 2 endometrioid type endometrial cancer”. Am. J. Obstet. Gynecol., 2009, 200, 71.

[14] Liu H., Zhang G.N., Li J.M., Fan Y.: “Relationship between the Pathologic Expression of p16 or p53 in Curettage Specimens and the Risk Factor and Prognosis of Endometrial Carcinoma (Chinese)”. J. Pract. Obstet. Gynecol., 2010, 06, 447.

[15] Stang A.: “Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses”. Eur. J. Epidemiol., 2010, 25, 603.

[16] Ioannidis J.P., Patsopoulos N.A., Evangelou E.: “Heterogeneity in meta-analyses of genome-wide association investigations”. PLOS ONE, 2007, 2, e841.

[17] Singh M., Darcy K.M., Brady W.E., Clubwala R., Weber Z., Rittenbach J.V., et al.: “Cadherins, catenins and cell cycle regulators: impact on survival in a Gynecologic Oncology Group phase II endometrial cancer trial”. Gynecol. Oncol., 2011, 123, 320.

[18] Soslow R.A., Wethington S.L., Cesari M., Chiappetta D., Olvera N., Shia J., et al.: “Clinicopathologic analysis of matched primary and recurrent endometrial carcinoma”. Am. J. Surg. Pathol., 2012, 36, 1771.

[19] Huang D.N., Shi G.S., Huang J.F.: “The Expression and Clinical Significance of c-myc and P16 in Endometrial carcinoma (Chinese)”. Chin. J. Clin. Oncol. Rehab., 2003, 02, 27.

[20] Xiong J., Peng Z.L., Yang K.X.: “Expression of Cell Cycle Associated Proteins CyclinD1 and P16 in Endometrial Carcinoma and the Correlation between Their Expression Status (Chinese)”. Journal of West China University of Medical Sciences, 2001, 03, 365.

[21] Engelsen I.B., Stefansson I.M., Akslen L.A., Salvesen H.B.: “GATA3 expression in estrogen receptor alpha-negative endometrial carcinomas identifies aggressive tumors with high proliferation and poor patient survival”. Am. J. Obstet. Gyencol., 2008, 199, 541.

[22] Hoang L.N., McConechy M.K., Köbel M., Han G., Rouzbahman M., Davidson B., et al.: “Histotype-genotype correlation in 36 high-grade endometrial carcinomas”. Am. J. Surg. Pathol., 2013, 37, 1421.

[23] Park J.Y., Kim K.R., Nam J.H.: “Immunohistochemical analysis for therapeutic targets and prognostic markers in low-grade endometrial stromal sarcoma”. Int. J. Gynecol. Cancer, 2013, 23, 81.

[24] Salvesen H.B., Das S., Akslen L.A.: “Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis”. Clin. Cancer Res., 2000, 6, 153.

[25] Alvarez T., Miller E., Duska L., Oliva E.: “Molecular profile of grade 3 endometrioid endometrial carcinoma: is it a type I or type II endometrial carcinoma?”. Am. J. Surg. Pathol., 2012, 36, 753.

[26] Yu K.Y., Xing C.H., Liu Y.: “The Expression and Significance of P16 Protein and PCNA in the Endometrial Carcinoma (Chinese)”. ACTA Academiae Medicinae Jiangxi, 2000, 02, 79.

[27] Ignatov A., Bischoff J., Schwarzenau C., Krebs T., Kuester D., Herrmann K., et al.: “P16 alterations increase the metastatic potential of endometrial carcinoma”. Gynecol. Oncol., 2008, 111, 365.

[28] Ge W.P., Qi W.H.: “Study on the Expression of p16, p53 and rasp21 Proteins in Endometrial Carcinoma (Chinese)”. Applied Journal of General Practice, 2008, 05, 471.

[29] Semczuk A., Boltze C., Marzec B., Szczygielska A., Roessner A., Schneider-Stock R.: “p16INK4A alterations are accompanied by aberrant protein immunostaining in endometrial carcinomas”. J. Cancer Res. Clin. Oncol., 2003, 129, 589.

[30] Zhang X.Y., Cao W.H.: “A Study on The Relationship of P16 Ex- pression and Endometrial Carcinoma (Chinese)”. Hainan Medical Journal, 2005, 11, 133.

[31] Bai H., Ren C.S., Qu L.R.: “Expression and Clinical Significance of P16 Protein and CyclinD1 in Endometrial Carcinoma (Chinese)”. Maternal and Child Health Care of China, 2009, 16, 2267.

[32] Wei S.Q., Zou L.H., Sun Y.Q., Zheng J.H., Huang M.T.: “P16, CyclinD1 Expressions in Endometrial Carcinomas and Their Clinical Significance (Chinese)”. China Oncology, 2000, 06, 27.

[33] Tian D.M., Ying Y.Q., Zhang Y.Q., Huang W.B.: “Expressions of p16 and CDK4 proteins in endometrial adenocarcinomas and the clinical pathological significance (Chinese)”. Prog. Obstet. Gynecol., 2003, 03, 185.

[34] Zhang L.Z., Cui M.H., Bai F.L.: “Expressions of P16 and P15 Genes in Uterine Endometrial Carcinoma (Chinese)”. Journal of Jilin University (Medicine Edition), 2005, 01, 118.

[35] Liu D.M., He S.D., Zheng H.Y., Zhao X.Z., Chen W.M., Zhang Z.Y.: “Expression and Clinical Significance of P16 and P15 Protein in Primary Endometrial Carcinoma”. Maternal and Child Health Care of China, 2008, 25, 3583.

[36] Tsuda H., Yamamoto K., Inoue T., Uchiyama I., Umesaki N.: “The role of p16-cyclin d/CDK-pRb pathway in the tumorigenesis of endometrioid-type endometrial carcinoma”. Br. J. Cancer., 2000, 82, 675.

[37] Wang Y., Lu A.N., Liao Y.M.: “The Expressions of Cell Cycle Regulatory Proteins P14arf, P16ink4a and P53 in Human Endometrial Carcinoma (Chinese)”. Journal of Basic and Clinical Oncology, 2008, 02, 108.

[38] Zhou N., Yu P., Xu Z.X., Jiang S., Chen S.F.: “The Expression of P16 and Quantitative DNA Analysis in Endometrial Carcinoma and Its Clinical Significance (Chinese)”. Med. J. Chin. PLA., 2000, 05, 357.

[39] Li L., Chen G., Lin A.: “Expre sion of P16INK4a and CyclinD1 in endometrial carcinoma and their clinical significance (Chinese)”. F.J. Medical Journal, 2005, 02, 110.

[40] Yang S.M., Gong X.L., Shen X.D., Li J.L., Li Q.: “A Study on the Expression of P16 Protein in Endometria Cancer (Chinese)”. Journal Of Changzhi Medical College, 2000, 02, 89.

[41] Xu J.P., Zhang Y.: “Expression and clinical significance of p16 and p27kip1 in endometrial carcinoma (Chinese)”. Cancer Research and Clinic, 2006, 12, 834.

[42] Fahraeus R., Lane D.P.: “The p16(INK4a) tumour suppressor protein inhibits alphavbeta3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of alphavbeta3 to focal contacts”. EMBO J., 1999, 18, 2106.

[43] Koh J., Enders G.H., Dynlacht B.D., Harlow E.: “Tumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition”. Nature, 1995, 375, 506.

[44] Ruas M., Peters G.: “The p16INK4a/CDKN2A tumor suppressor and its relatives”. Biochim Biophys Acta., 1998, 1378, F115.

[45] Ruas M., Gregory F., Jones R., Poolman R., Starborg M., Rowe J., et al.: “CDK4 and CDK6 delay senescence by kinase-dependent and p16INK4a-independent mechanisms”. Mol. Cell. Biol., 2007, 27, 4273.

[46] Hu Z.Y., Tang L.D., Zhou Q., Xiao L., Cao Y.: “Aberrant promoter hypermethylation of p16 gene in endometrial carcinoma”. Tumour Biol., 2015, 36, 1487.

[47] Creasman W.T., Odicino F., Maisonneuve P., Quinn M.A., Beller U., Benedet J.L., et al.: “Carcinoma of the corpus uteri. FIGO 26th Annual Report on the Results of Treatment in Gynecological Cancer”. Int. J. Gynaecol. Obstet., 2006, 95, S105.

[48] Salvesen H.B., Akslen L.A.: “Molecular pathogenesis and prognostic factors in endometrial carcinoma”. APMIS, 2002, 110, 673.

[49] Grigsby P.W., Perez C.A., Kuten A., Simpson J.R., Garcia D.M., Camel H.M., et al.: “Clinical stage I endometrial cancer: prognostic factors for local control and distant metastasis and implications of the new FIGO surgical staging system”. Int. J. Radiat. Oncol. Biol. Phys., 1992, 22, 905.

[50] Ayhan A., Tuncer R., Tuncer Z.S., Yuce K., Kucukali T.: “Correlation between clinical and histopathologic risk factors and lymph node metastases in early endometrial cancer (a multivariate analysis of 183 cases)”. Int. J. Gynecol. Cancer., 1994, 4, 306.

[51] Zhao F., Chen Y., Wu Q., Wang Z., Lu J.: “Prognostic value of CD117 in cancer: a meta-analysis”. Int. J. Clin. Exp. Pathol., 2014, 7, 1012.

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