Skip to main content
Top
Published in: BMC Cancer 1/2013

Open Access 01-12-2013 | Research article

Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignant and malignant lesions of the cervix

Authors: Gang Chen, Cheng He, Ling Li, An Lin, Xiongwei Zheng, Ellen He, Sven Skog

Published in: BMC Cancer | Issue 1/2013

Login to get access

Abstract

Background

Thymidine kinase 1 (TK1) is a proliferation biomarker that has been found useful for prognostication in cancer patients. Here we investigate for the first time the use of TK1 expression as a prognostic factor for patients with premalignant and malignant lesions of the uterine cervix.

Methods

TK1 expression was determined by immunohistochemistry in cervical lesions (cervical intraepithelial neoplasia (CIN), n = 216; invasive cervical carcinoma, n = 84). TK1 and Ki-67 expressions and pathological/FIGO stages and age were correlated with 5-year survival by Kaplan-Meier, log rank and COX hazard uni- and multivariate analyses.

Results

TK1 labeling index (LI) was significantly correlated with CIN grades and invasive cervical carcinoma stages, while TK1 labeling intensity was only correlated to CIN grades. TK1 LI was significantly higher compared with Ki-67 LI. TK1 LI correlated significantly to 5-year survival in patients with invasive cervical carcinoma, particularly nuclear TK1 LI. In a multivariate analysis, nuclear TK1 expression was independent prognostic factor in patients with in situ/invasive cervical carcinoma or in invasive cervical carcinoma alone. Interestingly, in invasive cervical carcinoma patients with advanced tumors, nuclear TK1 expression could identify patients with significantly better survival rates (80%), while Ki-67 could not.

Conclusions

Nuclear TK1 expression in early grade CIN predicts risk for progression to malignancy. Nuclear TK1 expression is also a prognostic factor for treatment outcome, particularly in patients with advanced cervical carcinomas. Nuclear TK1 expression is more useful than Ki-67 and pathological/FIGO stages.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference Cheung FY, Mang OW, Law SC: A population-based analysis of incidence, mortality, and stage-specific survival of cervical cancer patients in Hong Kong 1997–2006. Hong Kong Med J. 2011, 17: 89-95.CrossRefPubMed Cheung FY, Mang OW, Law SC: A population-based analysis of incidence, mortality, and stage-specific survival of cervical cancer patients in Hong Kong 1997–2006. Hong Kong Med J. 2011, 17: 89-95.CrossRefPubMed
3.
go back to reference Underwood JCE: General and systematic pathology. 2005, London: Churchill Livingstone Underwood JCE: General and systematic pathology. 2005, London: Churchill Livingstone
4.
go back to reference Kovács K, Varnai AD, Bollmann M, Bankfalvi A, Szendy M, Speich N, Schmitt C, Pajor L, Bollmann R, Hildenbrand R: A 7.5-year prospective study of longer than 18 months type-specific human papillomavirus persistence in a routine cytology-based cervical screening population of about 31,000 women in West Germany. Eur J Cancer Prev. 2009, 18: 307-315. 10.1097/CEJ.0b013e328324061a.CrossRefPubMed Kovács K, Varnai AD, Bollmann M, Bankfalvi A, Szendy M, Speich N, Schmitt C, Pajor L, Bollmann R, Hildenbrand R: A 7.5-year prospective study of longer than 18 months type-specific human papillomavirus persistence in a routine cytology-based cervical screening population of about 31,000 women in West Germany. Eur J Cancer Prev. 2009, 18: 307-315. 10.1097/CEJ.0b013e328324061a.CrossRefPubMed
5.
go back to reference Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NW, Heideman DA, Kenter GG, Cuzick J, Snijders PJ, Meijer CJ: Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012, 13: 78-88. 10.1016/S1470-2045(11)70296-0.CrossRefPubMed Rijkaart DC, Berkhof J, Rozendaal L, van Kemenade FJ, Bulkmans NW, Heideman DA, Kenter GG, Cuzick J, Snijders PJ, Meijer CJ: Human papillomavirus testing for the detection of high-grade cervical intraepithelial neoplasia and cancer: final results of the POBASCAM randomised controlled trial. Lancet Oncol. 2012, 13: 78-88. 10.1016/S1470-2045(11)70296-0.CrossRefPubMed
6.
go back to reference Isacson C, Kessis TD, Hedrick L, Cho KR: Both cell proliferation and apoptosis increase with lesion grade in cervical neoplasia but do not correlate with human papillomavirus type. Cancer Res. 1996, 56: 669-674.PubMed Isacson C, Kessis TD, Hedrick L, Cho KR: Both cell proliferation and apoptosis increase with lesion grade in cervical neoplasia but do not correlate with human papillomavirus type. Cancer Res. 1996, 56: 669-674.PubMed
7.
go back to reference Kruse AJ, Baak JP, Janssen EA, Kjellevold KH, Fiane B, Lovslett K, Bergh J, Robboy S: Ki67 predicts progression in early CIN: validation of a multivariate progression-risk model. Cell Oncol. 2004, 26: 13-20.PubMedPubMedCentral Kruse AJ, Baak JP, Janssen EA, Kjellevold KH, Fiane B, Lovslett K, Bergh J, Robboy S: Ki67 predicts progression in early CIN: validation of a multivariate progression-risk model. Cell Oncol. 2004, 26: 13-20.PubMedPubMedCentral
8.
go back to reference Queiroz C, Silva TC, Alves VA, Villa LL, Costa MC, Travassos AG, Filho JB, Studart E, Cheto T, de Freitas LA: Comparative study of the expression of cellular cycle proteins in cervical intraepithelial lesions. Pathol Res Pract. 2006, 202: 731-737. 10.1016/j.prp.2006.07.003.CrossRefPubMed Queiroz C, Silva TC, Alves VA, Villa LL, Costa MC, Travassos AG, Filho JB, Studart E, Cheto T, de Freitas LA: Comparative study of the expression of cellular cycle proteins in cervical intraepithelial lesions. Pathol Res Pract. 2006, 202: 731-737. 10.1016/j.prp.2006.07.003.CrossRefPubMed
9.
go back to reference Nam EJ, Kim JW, Hong JW, Jang HS, Lee SY, Jang SY, Lee DW, Kim SW, Kim JH, Kim YT, Kim S, Kim JW: Expression of the p16 and Ki-67 in relation to the grade of cervical intraepithelial neoplasia and high-risk human papillomavirus infection. J Gynecol Oncol. 2008, 19: 162-168. 10.3802/jgo.2008.19.3.162.CrossRefPubMedPubMedCentral Nam EJ, Kim JW, Hong JW, Jang HS, Lee SY, Jang SY, Lee DW, Kim SW, Kim JH, Kim YT, Kim S, Kim JW: Expression of the p16 and Ki-67 in relation to the grade of cervical intraepithelial neoplasia and high-risk human papillomavirus infection. J Gynecol Oncol. 2008, 19: 162-168. 10.3802/jgo.2008.19.3.162.CrossRefPubMedPubMedCentral
10.
go back to reference Gertych A, Joseph AO, Walts AE, Bose S: Automated detection of dual p16/Ki67 nuclear immunoreactivity in liquid-based pap tests for improved cervical cancer risk stratification. Ann Biomed Eng. 2012, 40: 1192-1204. 10.1007/s10439-011-0498-8.CrossRefPubMedPubMedCentral Gertych A, Joseph AO, Walts AE, Bose S: Automated detection of dual p16/Ki67 nuclear immunoreactivity in liquid-based pap tests for improved cervical cancer risk stratification. Ann Biomed Eng. 2012, 40: 1192-1204. 10.1007/s10439-011-0498-8.CrossRefPubMedPubMedCentral
11.
go back to reference Gasparri F, Wang N, Skog S, Galvani A, Eriksson S: Thymidine kinase 1 expression defines an activated G1 state of the cell cycle as revealed with site-specific antibodies and ArrayScan assays. Eur J Cell Biol. 2009, 88: 779-785. 10.1016/j.ejcb.2009.06.005.CrossRefPubMed Gasparri F, Wang N, Skog S, Galvani A, Eriksson S: Thymidine kinase 1 expression defines an activated G1 state of the cell cycle as revealed with site-specific antibodies and ArrayScan assays. Eur J Cell Biol. 2009, 88: 779-785. 10.1016/j.ejcb.2009.06.005.CrossRefPubMed
12.
go back to reference Guan H, Sun Y, Zan Q, Xu M, Li Y, Zhou J, He E, Eriksson S, Wen W, Skog S: Thymidine kinase 1 expression is significantly different in breast benign (UDH), and in pre-malignant (ADH), primary tumour in situ (DCIS) and invasive ductal (IDC) of breast carcinoma. Mol Med Rep. 2009, 2: 923-929.PubMed Guan H, Sun Y, Zan Q, Xu M, Li Y, Zhou J, He E, Eriksson S, Wen W, Skog S: Thymidine kinase 1 expression is significantly different in breast benign (UDH), and in pre-malignant (ADH), primary tumour in situ (DCIS) and invasive ductal (IDC) of breast carcinoma. Mol Med Rep. 2009, 2: 923-929.PubMed
13.
go back to reference Ye FP, Xie QL, Liu XL, Zeng JH, Nan JL, Yu M: Expression of TK1 and Ki67 in prostate diseases. J Clin Exp Pathol. 2008, 24: 644-667. Ye FP, Xie QL, Liu XL, Zeng JH, Nan JL, Yu M: Expression of TK1 and Ki67 in prostate diseases. J Clin Exp Pathol. 2008, 24: 644-667.
14.
go back to reference Aufderklamm S, Hennenlotter J, Todenhoefer T, Gakis G, Schilling D, Vogel U, Kuehs U, Dlugosch J, Knapp J, Merseburger A, Gerber V, Ordelheide A, Hevler J, Stenzl A, Schwentner C: XPA-210: a new proliferation marker determines locally dvanced prostate cancer and is a predictor of biochemical recurrence. World J Urol. 2011, 4: 21969130-PMID Aufderklamm S, Hennenlotter J, Todenhoefer T, Gakis G, Schilling D, Vogel U, Kuehs U, Dlugosch J, Knapp J, Merseburger A, Gerber V, Ordelheide A, Hevler J, Stenzl A, Schwentner C: XPA-210: a new proliferation marker determines locally dvanced prostate cancer and is a predictor of biochemical recurrence. World J Urol. 2011, 4: 21969130-PMID
15.
go back to reference Liu C, Gao Q, Shi QL, Yu B, Ma HH, Eriksson S, He E, Skog S: Significance of TK1 and Ki-67 expression in ovarian serous adenocarcinoma. J Clin Exp Pathol. 2011, 27: 1289-1293. Liu C, Gao Q, Shi QL, Yu B, Ma HH, Eriksson S, He E, Skog S: Significance of TK1 and Ki-67 expression in ovarian serous adenocarcinoma. J Clin Exp Pathol. 2011, 27: 1289-1293.
16.
go back to reference Kruck S, Hennenlotter J, Vogel U, Schilling D, Gakis G, Hevler J, Kuehs U, Stenzl A, Schwentner C: Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: clinical utility and biological implications. BJU Int. 2012, 109: 634-638. 10.1111/j.1464-410X.2011.10392.x.CrossRefPubMed Kruck S, Hennenlotter J, Vogel U, Schilling D, Gakis G, Hevler J, Kuehs U, Stenzl A, Schwentner C: Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: clinical utility and biological implications. BJU Int. 2012, 109: 634-638. 10.1111/j.1464-410X.2011.10392.x.CrossRefPubMed
17.
go back to reference Xu Y, Shi QL, Ma H, Zhou H, Lu Z, Yu B, Zhou X, Eriksson S, He E, Skog S: High thymidine kinase 1 (TK1) expression is a predictor of poor survival in patients with pT1 of lung adenocarcinoma. Tumor Biol. 2012, 33: 475-483. 10.1007/s13277-011-0276-0.CrossRef Xu Y, Shi QL, Ma H, Zhou H, Lu Z, Yu B, Zhou X, Eriksson S, He E, Skog S: High thymidine kinase 1 (TK1) expression is a predictor of poor survival in patients with pT1 of lung adenocarcinoma. Tumor Biol. 2012, 33: 475-483. 10.1007/s13277-011-0276-0.CrossRef
18.
go back to reference Gakis G, Hennenlotter J, Scharpf M, Hevler J, Schilling D, Kuehs U, Stenzl A, Schwentner C: XPA-210: a new proliferation marker to characterize tumor biology and progression of renal cell carcinoma. World J Urol. 2011, 29: 801-806. 10.1007/s00345-010-0621-8.CrossRefPubMed Gakis G, Hennenlotter J, Scharpf M, Hevler J, Schilling D, Kuehs U, Stenzl A, Schwentner C: XPA-210: a new proliferation marker to characterize tumor biology and progression of renal cell carcinoma. World J Urol. 2011, 29: 801-806. 10.1007/s00345-010-0621-8.CrossRefPubMed
19.
go back to reference Aufderklamm S, Todenhöfer T, Gakis G, Kruck S, Hennenlotter J, Stenzl A, Schwentner C: Thymidine kinase and cancer monitoring. Cancer Lett. 2012, 6: 6-10.CrossRef Aufderklamm S, Todenhöfer T, Gakis G, Kruck S, Hennenlotter J, Stenzl A, Schwentner C: Thymidine kinase and cancer monitoring. Cancer Lett. 2012, 6: 6-10.CrossRef
20.
go back to reference Topolcan O, Holubec L: The role of thymidine kinase in cancer diseases. Expert Opin Med Diagn. 2008, 2: 129-141. 10.1517/17530059.2.2.129.CrossRefPubMed Topolcan O, Holubec L: The role of thymidine kinase in cancer diseases. Expert Opin Med Diagn. 2008, 2: 129-141. 10.1517/17530059.2.2.129.CrossRefPubMed
21.
go back to reference He E, Xu XH, Guan H, Chen Y, Chen ZH, Pan ZL, Tang LL, Hu GZ, Li Y, Zhang M, Zhou J, Eriksson S, Fornander T, Skog S: Thymidine kinase 1 is a potential marker for prognosis and monitoring the response to treatment of patients with breast, lung, and esophageal cancer and non-Hodgkin's lymphoma. Nucleosides Nucleotides Nucleic Acids. 2010, 29: 352-358. 10.1080/15257771003738535.CrossRefPubMed He E, Xu XH, Guan H, Chen Y, Chen ZH, Pan ZL, Tang LL, Hu GZ, Li Y, Zhang M, Zhou J, Eriksson S, Fornander T, Skog S: Thymidine kinase 1 is a potential marker for prognosis and monitoring the response to treatment of patients with breast, lung, and esophageal cancer and non-Hodgkin's lymphoma. Nucleosides Nucleotides Nucleic Acids. 2010, 29: 352-358. 10.1080/15257771003738535.CrossRefPubMed
22.
go back to reference Benedet JL, Bender H, Jones H, Ngan HY, Pecorelli S: FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. Int J Gynaecol Obstet. 2000, 70: 209-262.CrossRefPubMed Benedet JL, Bender H, Jones H, Ngan HY, Pecorelli S: FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. Int J Gynaecol Obstet. 2000, 70: 209-262.CrossRefPubMed
23.
go back to reference Sobin LH, Wittekind C: International Union against Cancer (UICC) TNM Classification of Malignant Tumours 6th edition. 2002, New Jersey: John Wiley & Sons Sobin LH, Wittekind C: International Union against Cancer (UICC) TNM Classification of Malignant Tumours 6th edition. 2002, New Jersey: John Wiley & Sons
24.
go back to reference He Q, Wang N, Skog S, Ericsson S, Tribukait B: Characterization of a peptide antibody against a C-terminal part of human and mouse cytosolic thymidine kinase, which is a marker for cell proliferation. Europ J Cell Biol. 1996, 70: 117-124.PubMed He Q, Wang N, Skog S, Ericsson S, Tribukait B: Characterization of a peptide antibody against a C-terminal part of human and mouse cytosolic thymidine kinase, which is a marker for cell proliferation. Europ J Cell Biol. 1996, 70: 117-124.PubMed
25.
go back to reference Chen YL, Eriksson S, Chang ZF: Regulation and functional contribution thymidine kinase 1 in repair of DNA damage. J Biol Chem. 2010, 285: 27327-27335. 10.1074/jbc.M110.137042.CrossRefPubMedPubMedCentral Chen YL, Eriksson S, Chang ZF: Regulation and functional contribution thymidine kinase 1 in repair of DNA damage. J Biol Chem. 2010, 285: 27327-27335. 10.1074/jbc.M110.137042.CrossRefPubMedPubMedCentral
Metadata
Title
Nuclear TK1 expression is an independent prognostic factor for survival in pre-malignant and malignant lesions of the cervix
Authors
Gang Chen
Cheng He
Ling Li
An Lin
Xiongwei Zheng
Ellen He
Sven Skog
Publication date
01-12-2013
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2013
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-13-249

Other articles of this Issue 1/2013

BMC Cancer 1/2013 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine