Association between telomere length and survival in cancer patients: a meta-analysis and review of literature

Abstract

The relationship between telomere length and cancer survival has been widely studied. To gain a deeper insight, we reviewed the published studies. A total of 29 studies evaluated telomere length in the peripheral blood; 22 studies evaluated telomere length in the tumor tissue. First, in the peripheral blood studies, for solid tumor patients with shortened telomere length, the combined hazard ratios (HRs) for mortality and tumor progression were 1.21 (95%CI, 1.10–1.32) and 1.71 (95%CI, 1.37–2.13), respectively. Meanwhile, in hematology malignancy, the combined HRs for mortality and tumor progression were 2.83 (95%CI, 2.14–3.74) and 2.65 (95%CI, 2.18–3.22), respectively. Second, in the studies that use tumor tissue, for patients with shortened telomeres, the combined HRs for mortality and tumor progression were 1.26 (95%CI, 0.95–1.66) and 1.65 (95%CI, 1.26–2.15), respectively. In the studies that calculate the telomere length ratios of tumor tissue to adjacent normal mucosa, for patients with lower telomere length ratios, the combined HRs were 0.66 (95%CI, 0.53–0.83) and 0.74 (95%CI, 0.41–1.32) for mortality and tumor progression, respectively. In conclusion, shortened telomere in peripheral blood and tumor tissue might indicate poor survival for cancer patients. However, by calculating the telomere length ratios of tumor tissue to adjacent normal mucosa, the lower ratio might indicate better survival.

Keywords

telomere / survival / cancer / meta-analysis

References

[1] Blackburn EH. Switching and signaling at the telomere. Cell 2001; 106(6): 661–673

[2] Mathon NF, Lloyd AC. Cell senescence and cancer. Nat Rev Cancer 2001; 1(3): 203–213

[3] Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266(5193): 2011–2015

[4] Gertler R, Rosenberg R, Stricker D, Friederichs J, Hoos A, Werner M, Ulm K, Holzmann B, Nekarda H, Siewert JR. Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma. J Clin Oncol 2004; 22(10): 1807–1814

[5] Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 2000; 406(6796): 641–645

[6] Rudolph KL, Millard M, Bosenberg MW, DePinho RA. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans. Nat Genet 2001; 28(2): 155–159

[7] Ma H, Zhou Z, Wei S, Liu Z, Pooley KA, Dunning AM, Svenson U, Roos G, Hosgood HD 3rd, Shen M, Wei Q. Shortened telomere length is associated with increased risk of cancer: a meta-analysis. PLoS ONE 2011; 6(6): e20466

[8] McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM; the Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 2005; 93(4): 387–391

[9] Hayes DF, Ethier S, Lippman ME. New guidelines for reporting of tumor marker studies in breast cancer research and treatment: REMARK. Breast Cancer Res Treat 2006; 100(2): 237–238

[10] McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM; Statistics Subcommittee of NCI-EORTC Working Group on Cancer Diagnostics. REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 2006; 100(2): 229–235

[11] Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8(1): 16

[12] Ohyashiki JH, Ohyashiki K, Fujimura T, Kawakubo K, Shimamoto T, Iwabuchi A, Toyama K. Telomere shortening associated with disease evolution patterns in myelodysplastic syndromes. Cancer Res 1994; 54(13): 3557–3560

[13] Donaldson L, Fordyce C, Gilliland F, Smith A, Feddersen R, Joste N, Moyzis R, Griffith J. Association between outcome and telomere DNA content in prostate cancer. J Urol 1999; 162(5): 1788–1792

[14] Martinez-Delgado B, Gallardo M, Tanic M, Yanowsky K, Inglada-Perez L, Barroso A, Rodriguez-Pinilla M, Cañamero M, Blasco MA, Benitez J. Short telomeres are frequent in hereditary breast tumors and are associated with high tumor grade. Breast Cancer Res Treat 2013; 141(2): 231–242

[15] Heaphy CM, Yoon GS, Peskoe SB, Joshu CE, Lee TK, Giovannucci E, Mucci LA, Kenfield SA, Stampfer MJ, Hicks JL, De Marzo AM, Platz EA, Meeker AK. Prostate cancer cell telomere length variability and stromal cell telomere length as prognostic markers for metastasis and death. Cancer Discov 2013; 3(10): 1130–1141

[16] La Torre D, Aguennouz M, Conti A, Giusa M, Raffa G, Abbritti RV, Germano’ A, Angileri FF. Potential clinical role of telomere length in human glioblastoma. Transl Med UniSa 2011; 1: 243–270

[17] Damle RN, Batliwalla FM, Ghiotto F, Valetto A, Albesiano E, Sison C, Allen SL, Kolitz J, Vinciguerra VP, Kudalkar P, Wasil T, Rai KR, Ferrarini M, Gregersen PK, Chiorazzi N. Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations. Blood 2004; 103(2): 375–382

[18] Yoon SY, Sung HJ, Park KH, Choi IK, Kim SJ, Oh SC, Seo JH, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS. Telomere length shortening of peripheral blood mononuclear cells in solid-cancer patients undergoing standard-dose chemotherapy might be correlated with good treatment response and neutropenia severity. Acta Haematol 2007; 118(1): 30–37

[19] Kubuki Y, Suzuki M, Sasaki H, Toyama T, Yamashita K, Maeda K, Ido A, Matsuoka H, Okayama A, Nakanishi T, Tsubouchi H. Telomerase activity and telomere length as prognostic factors of adult T-cell leukemia. Leuk Lymphoma 2005; 46(3): 393–399

[20] Sieglová Z, Zilovcová S, Cermák J, Ríhová H, Brezinová D, Dvoráková R, Marková M, Maaloufová J, Sajdová J, Brezinová J, Zemanová Z, Michalová K. Dynamics of telomere erosion and its association with genome instability in myelodysplastic syndromes (MDS) and acute myelogenous leukemia arising from MDS: a marker of disease prognosis? Leuk Res 2004; 28(10): 1013–1021

[21] Wu KD, Orme LM, Shaughnessy J Jr, Jacobson J, Barlogie B, Moore MA. Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival. Blood 2003; 101(12): 4982–4989

[22] Brümmendorf TH, Holyoake TL, Rufer N, Barnett MJ, Schulzer M, Eaves CJ, Eaves AC, Lansdorp PM. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood 2000; 95(6): 1883–1890

[23] Oh BK, Kim H, Park YN, Yoo JE, Choi J, Kim KS, Lee JJ, Park C. High telomerase activity and long telomeres in advanced hepatocellular carcinomas with poor prognosis. Lab Invest 2008; 88(2): 144–152

[24] Rosenberg R, Gertler R, Stricker D, Lassmann S, Werner M, Nekarda H, Siewert JR. Telomere length and hTERT expression in patients with colorectal carcinoma. Recent Results Cancer Res 2003; 162: 177–181

[25] Hirashima T, Komiya T, Nitta T, Takada Y, Kobayashi M, Masuda N, Matui K, Takada M, Kikui M, Yasumitu T, Ohno A, Nakagawa K, Fukuoka M, Kawase I. Prognostic significance of telomeric repeat length alterations in pathological stage I-IIIA non-small cell lung cancer. Anticancer Res 2000; 20(3B): 2181–2187

[26] Yan S, Han B, Wu Y, Zhou D, Zhao Y. Telomerase gene mutation screening and telomere overhang detection in Chinese patients with acute myeloid leukemia. Leuk Lymphoma 2013; 54(7): 1437–1441

[27] Boscolo-Rizzo P, Rampazzo E, Perissinotto E, Piano MA, Giunco S, Baboci L, Spinato G, Spinato R, Tirelli G, Da Mosto MC, Del Mistro A, De Rossi A. Telomere shortening in mucosa surrounding the tumor: biosensor of field cancerization and prognostic marker of mucosal failure in head and neck squamous cell carcinoma. Oral Oncol 2015; 51(5): 500–507

[28] Willeit P, Willeit J, Kloss-Brandstätter A, Kronenberg F, Kiechl S. Fifteen-year follow-up of association between telomere length and incident cancer and cancer mortality. JAMA 2011; 306(1): 42–44

[29] Kotsopoulos J, Prescott J, De Vivo I, Fan I, Mclaughlin J, Rosen B, Risch H, Sun P, Narod SA. Telomere length and mortality following a diagnosis of ovarian cancer. Cancer Epidemiol Biomarkers Prev 2014; 23(11): 2603–2606

[30] Duggan C, Risques R, Alfano C, Prunkard D, Imayama I, Holte S, Baumgartner K, Baumgartner R, Bernstein L, Ballard-Barbash R, Rabinovitch P, McTiernan A. Change in peripheral blood leukocyte telomere length and mortality in breast cancer survivors. J Natl Cancer Inst 2014; 106(4): dju035

[31] Chen Y, Qu F, He X, Bao G, Liu X, Wan S, Xing J. Short leukocyte telomere length predicts poor prognosis and indicates altered immune functions in colorectal cancer patients. Ann Oncol 2014; 25(4): 869–876

[32] Weischer M, Nordestgaard BG, Cawthon RM, Freiberg JJ, Tybjærg-Hansen A, Bojesen SE. Short telomere length, cancer survival, and cancer risk in 47102 individuals. J Natl Cancer Inst 2013; 105(7): 459–468

[33] Liu HQ, An JZ, Liu J, Yang YF, Zhang HX, Zhao BY, Li JB, Yang HS, Chen ZN, Xing JL. Leukocyte telomere length predicts overall survival in hepatocellular carcinoma treated with transarterial chemoembolization. Carcinogenesis 2012; 33(5): 1040–1045

[34] Shen J, Gammon MD, Terry MB, Bradshaw PT, Wang Q, Teitelbaum SL, Neugut AI, Santella RM. Genetic polymorphisms in telomere pathway genes, telomere length, and breast cancer survival. Breast Cancer Res Treat 2012; 134(1): 393–400

[35] Willeit P, Willeit J, Mayr A, Weger S, Oberhollenzer F, Brandstätter A, Kronenberg F, Kiechl S. Telomere length and risk of incident cancer and cancer mortality. JAMA 2010; 304(1): 69–75

[36] Svenson U, Ljungberg B, Roos G. Telomere length in peripheral blood predicts survival in clear cell renal cell carcinoma. Cancer Res 2009; 69(7): 2896–2901

[37] Svenson U, Nordfjäll K, Stegmayr B, Manjer J, Nilsson P, Tavelin B, Henriksson R, Lenner P, Roos G. Breast cancer survival is associated with telomere length in peripheral blood cells. Cancer Res 2008; 68(10): 3618–3623

[38] Russo A, Modica F, Guarrera S, Fiorito G, Pardini B, Viberti C, Allione A, Critelli R, Bosio A, Casetta G, Cucchiarale G, Destefanis P, Gontero P, Rolle L, Zitella A, Fontana D, Frea B, Vineis P, Sacerdote C, Matullo G. Shorter leukocyte telomere length is independently associated with poor survival in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev 2014; 23(11): 2439–2446

[39] Lin J, Blalock JA, Chen M, Ye Y, Gu J, Cohen L, Cinciripini PM, Wu X. Depressive symptoms and short telomere length are associated with increased mortality in bladder cancer patients. Cancer Epidemiol Biomarkers Prev 2015; 24(2): 336–343

[40] Chen Y, Wu Y, Huang X, Qu P, Li G, Jin T, Xing J, He S. Leukocyte telomere length: a novel biomarker to predict the prognosis of glioma patients. J Cancer Res Clin Oncol 2015; 141(10): 1739–1747

[41] Qu F, Li R, He X, Li Q, Xie S, Gong L, Ji G, Lu J, Bao G. Short telomere length in peripheral blood leukocyte predicts poor prognosis and indicates an immunosuppressive phenotype in gastric cancer patients. Mol Oncol 2015; 9(3): 727–739

[42] Lin TT, Norris K, Heppel NH, Pratt G, Allan JM, Allsup DJ, Bailey J, Cawkwell L, Hills R, Grimstead JW, Jones RE, Britt-Compton B, Fegan C, Baird DM, Pepper C. Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease. Br J Haematol 2014; 167(2): 214–223

[43] Mansouri L, Grabowski P, Degerman S, Svenson U, Gunnarsson R, Cahill N, Smedby KE, Geisler C, Juliusson G, Roos G, Rosenquist R. Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients. Am J Hematol 2013; 88(8): 647–651

[44] Rampazzo E, Bonaldi L, Trentin L, Visco C, Keppel S, Giunco S, Frezzato F, Facco M, Novella E, Giaretta I, Del Bianco P, Semenzato G, De Rossi A. Telomere length and telomerase levels delineate subgroups of B-cell chronic lymphocytic leukemia with different biological characteristics and clinical outcomes. Haematologica 2012; 97(1): 56–63

[45] Sellmann L, de Beer D, Bartels M, Opalka B, Nückel H, Dührsen U, Dürig J, Seifert M, Siemer D, Küppers R, Baerlocher GM, Röth A. Telomeres and prognosis in patients with chronic lymphocytic leukaemia. Int J Hematol 2011; 93(1): 74–82

[46] Rossi D, Bodoni CL, Zucchetto A, Rasi S, De Paoli L, Fangazio M, Rossi FM, Ladetto M, Gattei V, Gaidano G. Low CD49d expression and long telomere identify a chronic lymphocytic leukemia subset with highly favourable outcome. Am J Hematol 2010; 85(8): 619–622

[47] Rossi D, Lobetti Bodoni C, Genuardi E, Monitillo L, Drandi D, Cerri M, Deambrogi C, Ricca I, Rocci A, Ferrero S, Bernocco E, Capello D, De Paoli L, Bergui L, Boi M, Omedè P, Massaia M, Tarella C, Passera R, Boccadoro M, Gaidano G, Ladetto M. Telomere length is an independent predictor of survival, treatment requirement and Richter’s syndrome transformation in chronic lymphocytic leukemia. Leukemia 2009; 23(6): 1062–1072

[48] Roos G, Kröber A, Grabowski P, Kienle D, Bühler A, Döhner H, Rosenquist R, Stilgenbauer S. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Blood 2008; 111(4): 2246–2252

[49] Ghaffari SH, Shayan-Asl N, Jamialahmadi AH, Alimoghaddam K, Ghavamzadeh A. Telomerase activity and telomere length in patients with acute promyelocytic leukemia: indicative of proliferative activity, disease progression, and overall survival. Ann Oncol 2008; 19(11): 1927–1934

[50] Ricca I, Rocci A, Drandi D, Francese R, Compagno M, Lobetti Bodoni C, De Marco F, Astolfi M, Monitillo L, Vallet S, Calvi R, Ficara F, Omedè P, Rosato R, Gallamini A, Marinone C, Bergui L, Boccadoro M, Tarella C, Ladetto M. Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients. Leukemia 2007; 21(4): 697–705

[51] Avigad S, Naumov I, Ohali A, Jeison M, Berco GH, Mardoukh J, Stark B, Ash S, Cohen IJ, Meller I, Kollender Y, Issakov J, Yaniv I. Short telomeres: a novel potential predictor of relapse in Ewing sarcoma. Clin Cancer Res 2007; 13(19): 5777–5783

[52] Grabowski P, Hultdin M, Karlsson K, Tobin G, Aleskog A, Thunberg U, Laurell A, Sundström C, Rosenquist R, Roos G. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status. Blood 2005; 105(12): 4807–4812

[53] Rigolin GM, Porta MD, Bugli AM, Castagnari B, Mauro E, Bragotti LZ, Ciccone M, Cuneo A, Castoldi G. Flow cytometric detection of accelerated telomere shortening in myelodysplastic syndromes: correlations with aetiological and clinical-biological findings. Eur J Haematol 2004; 73(5): 351–358

[54] Hultdin M, Rosenquist R, Thunberg U, Tobin G, Norrback KF, Johnson A, Sundström C, Roos G. Association between telomere length and V(H) gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications. Br J Cancer 2003; 88(4): 593–598

[55] Bechter OE, Eisterer W, Pall G, Hilbe W, Kühr T, Thaler J. Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia. Cancer Res 1998; 58(21): 4918–4922

[56] Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Kawakubo K, Shay JW, Toyama K. The relationship between telomere length and therapy-associated cytogenetic responses in patients with chronic myeloid leukemia. Cancer 1997; 79(8): 1552–1560

[57] Spanoudakis E, Bazdiara I, Pantelidou D, Kotsianidis I, Papadopoulos V, Margaritis D, Xanthopoulidis G, Moustakidis E, Mantzourani S, Bourikas G, Tsatalas C. Dynamics of telomere’s length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms. Leuk Res 2011; 35(4): 459–464

[58] Borssén M, Cullman I, Norén-Nyström U, Sundström C, Porwit A, Forestier E, Roos G. hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia: associations with immunophenotype and cytogenetic subgroup. Exp Hematol 2011; 39(12): 1144–1151

[59] Jebaraj BM, Kienle D, Lechel A, Mertens D, Heuberger M, Ott G, Rosenwald A, Barth TF, Möller P, Zenz T, Döhner H, Stilgenbauer S. Telomere length in mantle cell lymphoma. Blood 2013; 121(7): 1184–1187

[60] Lu L, Zhang C, Zhu G, Irwin M, Risch H, Menato G, Mitidieri M, Katsaros D, Yu H. Telomerase expression and telomere length in breast cancer and their associations with adjuvant treatment and disease outcome. Breast Cancer Res 2011; 13(3): R56

[61] Heaphy CM, Baumgartner KB, Bisoffi M, Baumgartner RN, Griffith JK. Telomere DNA content predicts breast cancer-free survival interval. Clin Cancer Res 2007; 13(23): 7037–7043

[62] Ohali A, Avigad S, Ash S, Goshen Y, Luria D, Feinmesser M, Zaizov R, Yaniv I. Telomere length is a prognostic factor in neuroblastoma. Cancer 2006; 107(6): 1391–1399

[63] Fordyce CA, Heaphy CM, Bisoffi M, Wyaco JL, Joste NE, Mangalik A, Baumgartner KB, Baumgartner RN, Hunt WC, Griffith JK. Telomere content correlates with stage and prognosis in breast cancer. Breast Cancer Res Treat 2006; 99(2): 193–202

[64] Garcia-Aranda C, de Juan C, Diaz-Lopez A, Sanchez-Pernaute A, Torres AJ, Diaz-Rubio E, Balibrea JL, Benito M, Iniesta P. Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma. Cancer 2006; 106(3): 541–551

[65] Patel MM, Parekh LJ, Jha FP, Sainger RN, Patel JB, Patel DD, Shah PM, Patel PS. Clinical usefulness of telomerase activation and telomere length in head and neck cancer. Head Neck 2002; 24(12): 1060–1067

[66] Jeon HS, Choi YY, Choi JE, Lee WK, Lee E, Yoo SS, Lee SY, Lee J, Cha SI, Kim CH, Park JY. Telomere length of tumor tissues and survival in patients with early stage non-small cell lung cancer. Mol Carcinog 2014; 53(4): 272–279

[67] Augustine TA, Baig M, Sood A, Budagov T, Atzmon G, Mariadason JM, Aparo S, Maitra R, Goel S. Telomere length is a novel predictive biomarker of sensitivity to anti-EGFR therapy in metastatic colorectal cancer. Br J Cancer 2015; 112(2): 313–318

[68] Pezzolo A, Pistorio A, Gambini C, Haupt R, Ferraro M, Erminio G, De Bernardi B, Garaventa A, Pistoia V. Intratumoral diversity of telomere length in individual neuroblastoma tumors. Oncotarget 2015; 6(10): 7493–7503

[69] Zhang DH, Chen JY, Hong CQ, Yi DQ, Wang F, Cui W. High-risk human papillomavirus infection associated with telomere elongation in patients with esophageal squamous cell carcinoma with poor prognosis. Cancer 2014; 120(17): 2673–2683

[70] Kuhn E, Meeker AK, Visvanathan K, Gross AL, Wang TL, Kurman RJ, Shih IeM. Telomere length in different histologic types of ovarian carcinoma with emphasis on clear cell carcinoma. Mod Pathol 2011; 24(8): 1139–1145

[71] Valls C, Piñol C, Reñé JM, Buenestado J, Viñas J. Telomere length is a prognostic factor for overall survival in colorectal cancer. Colorectal Dis 2011; 13(11): 1265–1272

[72] Baydar DE, Ozen H, Geyik PO, Gurel B. Can telomere alterations predict biochemical recurrence in prostate adenocarcinoma? A preliminary study. Pathol Res Pract 2010; 206(10): 700–704

[73] Gertler R, Doll D, Maak M, Feith M, Rosenberg R. Telomere length and telomerase subunits as diagnostic and prognostic biomarkers in Barrett carcinoma. Cancer 2008; 112(10): 2173–2180

[74] Frías C, García-Aranda C, De Juan C, Morán A, Ortega P, Gómez A, Hernando F, López-Asenjo JA, Torres AJ, Benito M, Iniesta P. Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer. Lung Cancer 2008; 60(3): 416–425

[75] Sainger RN, Telang SD, Shukla SN, Patel PS. Clinical significance of telomere length and associated proteins in oral cancer. Biomark Insights 2007; 2: 9–19

[76] Hsu CP, Lee LW, Shai SE, Chen CY. Clinical significance of telomerase and its associate genes expression in the maintenance of telomere length in squamous cell carcinoma of the esophagus. World J Gastroenterol 2005; 11(44): 6941–6947

[77] Peng SY, Chen WJ, Lai PL, Jeng YM, Sheu JC, Hsu HC. High α-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and beta-catenin mutations. Int J Cancer 2004; 112(1): 44–50

[78] Lötsch D, Ghanim B, Laaber M, Wurm G, Weis S, Lenz S, Webersinke G, Pichler J, Berger W, Spiegl-Kreinecker S. Prognostic significance of telomerase-associated parameters in glioblastoma: effect of patient age. Neuro-oncol 2013; 15(4): 423–432

[79] Hsu CP, Miaw J, Shai SE, Chen CY. Correlation between telomerase expression and terminal restriction fragment length ratio in non-small cell lung cancer—an adjusted measurement and its clinical significance. Eur J Cardiothorac Surg 2004; 26(2): 425–431

[80] Zhang C, Chen X, Li L, Zhou Y, Wang C, Hou S. The association between telomere length and cancer prognosis: evidence from a meta-analysis. PLoS ONE 2015; 10(7): e0133174

[81] Svenson U, Roos G. Telomere length as a biological marker in malignancy. Biochim Biophys Acta 2009; 1792(4): 317–323

[82] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res 2002; 30(10): e47

[83] Baird DM, Rowson J, Wynford-Thomas D, Kipling D. Extensive allelic variation and ultrashort telomeres in senescent human cells. Nat Genet 2003; 33(2): 203–207

Acknowledgements

This research was supported by the National Natural Science Foundation of China (No. 81402022) and the Fund of China Scholarship Council (No. 201406280106).

Compliance with ethics guidelines

Xinsen Xu, Kai Qu, Qing Pang, Zhixin Wang, Yanyan Zhou, and Chang Liu declare that they have no conflict of interest. The experiments comply with the current laws of the country in which they were performed.

Electronic Supplementary MaterialƒSupplementary material is available in the online version of this article at http://dx.doi.org/ 10.1007/s11684-016-0450-2 and is accessible for authorized users.

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