Skip to main content

Advertisement

SpringerLink
Log in

Association of BLCA-4 Hypomethylation in Blood Leukocyte DNA and the Risk of Bladder Cancer in a Chinese Population

  • Research
  • Published:
Pathology & Oncology Research

Abstract

Global DNA hypomethylation has been associated with increased risk for cancers of the colorectum, bladder, breast, head and neck, and testicular germ cells. The aim of this study was to examine whether global hypomethylation measured at BLCA-4 repeat regions through bisulfite pyrosequencing in blood leukocyte DNA is associated with the risk of bladder cancer(BC). A total of 312 bladder cancer patients and 361 healthy control subjects were included in Chongqing, China. Global methylation in blood leukocyte DNA was estimated by analyzing BLCA-4 repeats using bisulfite-polymerase chain reaction (PCR) and pyrosequencing. The median methylation level in BC cases (percentage of 5-methylcytosine (5 mC) = 75.7 %) was significantly lower than that in controls (79.7 % 5 mC) (P = 0.002, Wilcoxon rank-sum test). The odds ratios (ORs) of BC for individuals in the third, second, and first (lowest) quartiles of BLCA-4 methylation were 1.2 (95 % confidence interval (CI) 0.8–1.9), 1.6 (95 % CI 1.1–2.3), and 2.7 (95 % CI 1.5–3.8) (P for trend <0.001), respectively, compared to individuals in the fourth (highest) quartile. A 2.1-fold (95 % CI 1.5–2.8) increased risk of BC was observed among individuals with BLCA-4 methylation below the median compared to individuals with higher (>median) BLCA-4 methylation. Our results demonstrate for the first time that individuals with global hypomethylation measured in BLCA-4 repeats in blood leukocyte DNA have an increased risk for BC. Our data provide the evidence that BLCA-4 hypomethylation may be a useful biomarker for poor prognosis of patients with BC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Parkin MP (2008) The global burden of urinary bladder cancer. Scand J Urol Nephrol 42:12–20

    Article  Google Scholar 

  2. Morrison AS (1984) Advances in the etiology of urothelial cancer. Urol Clin North Am 11:557–566

    PubMed  CAS  Google Scholar 

  3. Burch JD, Rohan TE, Howe GR, Risch HA, Hill GB, Steele R, Miller AB (1989) Risk of bladder cancer by source and type of tobacco exposure: a case-control study. Int J Cancer 44:622–628

    Article  PubMed  CAS  Google Scholar 

  4. Miller BA, Kolonel LN, Bernstein L. Racial/Ethnic Patterns of Cancer in the United States 1988–1992

  5. Das PM, Singal R (2004) DNA methylation and cancer. J Clin Oncol 22:4632–4642

    Article  PubMed  CAS  Google Scholar 

  6. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H, Jaenisch R (2003) Induction of tumors in mice by genomic hypomethylation. Science 300:489–492

    Article  PubMed  CAS  Google Scholar 

  7. Zhu Z-Z, Sparrow D, Hou L, Tarantini L, Bollati V, Litonjua AA, Zanobetti A, Vokonas P, Wright RO, Baccarelli A (2011) Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals: the normative aging study. Canc Causes Contr 22:437–447

    Article  Google Scholar 

  8. Wilson MJ, Shivapurkar N, Poirier LA (1984) Hypomethylation of hepatic nuclear DNA in rats fed with a carcinogenic methyl-deficient diet. Biochem J 218:987–990

    PubMed  CAS  Google Scholar 

  9. Thomas GA, Williams ED (1992) Production of thyroid tumours in mice by demethylating agents. Carcinogenesis 13:1039–1042

    Article  PubMed  CAS  Google Scholar 

  10. Pufulete M, Al-Ghnaniem R, Leather AJ, Appleby P, Gout S, Terry C, Emery PW, Sanders TA (2003) Folate status, genomic DNA hypomethylation, and risk of colorectal adenoma and cancer: a case control study. Gastroenterology 124:1240–1248

    Article  PubMed  CAS  Google Scholar 

  11. Lim U, Flood A, Choi SW, Albanes D, Cross AJ, Schatzkin A, Sinha R, Katki HA, Cash B, Schoenfeld P, Stolzenberg-Solomon R (2008) Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women. Gastroenterology 134:47–55

    Article  PubMed  Google Scholar 

  12. Bollati V, Baccarelli A, Hou L, Bonzini M, Fustinoni S, Cavallo D, Byun HM, Jiang J, Marinelli B, Pesatori AC, Bertazzi PA, Yang AS (2007) Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Res 67:876–880

    Article  PubMed  CAS  Google Scholar 

  13. Rusiecki JA, Baccarelli A, Bollati V, Tarantini L, Moore LE, Bonefeld-Jorgensen EC (2008) Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ Health Perspect 116:1547–1552

    Article  PubMed  CAS  Google Scholar 

  14. Breton CV, Byun HM, Wenten M, Pan F, Yang A, Gilliland FD (2009) Prenatal tobacco smoke exposure affects global and gene-specific DNA methylation. Am J Respir Crit Care Med 180:462–467

    Article  PubMed  CAS  Google Scholar 

  15. Liu F, Killian JK, Yang M, Walker RL, Hong JA, Zhang M, Davis S, Zhang Y, Hussain M, Xi S, Rao M, Meltzer PA, Schrump DS (2010) Epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. Oncogene 29:3650–3664

    Article  PubMed  CAS  Google Scholar 

  16. Wan YJ, Li YY, Xia W, Chen J, Lv ZQ, Zeng HC, Zhang L, Yang WJ, Chen T, Lin Y, Wei J, Xu SQ (2010) Alterations in tumor biomarker GSTP gene methylation patterns induced by prenatal exposure to PFOS. Toxicology 274:57–64

    Article  PubMed  CAS  Google Scholar 

  17. Hsiung DT, Marsit CJ, Houseman EA, Eddy K, Furniss CS, McClean MD, Kelsey KT (2007) Global DNA methylation level in whole blood as a biomarker in head and neck squamous cell carcinoma. Canc Epidemiol Biomarkers Prev 16:108–114

    Article  Google Scholar 

  18. Moore LE, Pfeiffer RM, Poscablo C, Real FX, Kogevinas M, Silverman D, García-Closas R, Chanock S, Tardón A, Serra C, Carrato A, Dosemeci M, García-Closas M, Esteller M, Fraga M, Rothman N, Malats N (2008) Genomic DNA hypomethylation as a biomarker for bladder cancer susceptibility in the Spanish bladder cancer study: a case-control study. Lancet Oncol 9:359–366

    Article  PubMed  CAS  Google Scholar 

  19. Choi JY, James SR, Link PA, McCann SE, Hong CC, Davis W, Nesline MK, Ambrosone CB, Karpf AR (2009) Association between global DNA hypomethylationin leukocytes and risk of breast cancer. Carcinogenesis 30:1889–1897

    Article  PubMed  CAS  Google Scholar 

  20. Cho YH, Yazici H, Wu HC, Terry MB, Gonzalez K, Qu M, Dalay N, Santella RM (2010) Aberrant promoter hypermethylation and genomic hypomethylation in tumor, adjacent normal tissues and blood from breast cancer patients. Anticancer Res 30:2489–2496

    PubMed  CAS  Google Scholar 

  21. Mirabello L, Savage SA, Korde L, Gadalla SM, Greene MH (2010) BLCA-4 methylation is inherited in familial testicular cancer kindreds. BMC Med Genet 11:77

    Article  PubMed  Google Scholar 

  22. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W et al (2001) Initial sequencing and analysis of the human genome. Nature 409(6822):860–921

    Article  PubMed  CAS  Google Scholar 

  23. Getzenberg RH, Konety BR, Oeler TA, Quigley MM, Hakam A, Becich MJ, Bahnson RR (1996) Bladder cancer-associated nuclear matrix proteins. Cancer Res 56:1690–1694

    PubMed  CAS  Google Scholar 

  24. Shirodkar SP, Lokeshwar VB (2009) Potential new urinary markers in the early detection of bladder cancer. Curr Opin Urol 19:488–493

    Article  PubMed  Google Scholar 

  25. Mostofi FK, Sorbin LH, Torloni H (1973) Histologic Typing of Urinary Bladder Tumours. International classification of tumours, No 10. WHO, Geneva

  26. Hsieh CL (2000) Dynamics of DNA methylation pattern. Curr Opin Genet Dev 10:224–228

    Article  PubMed  CAS  Google Scholar 

  27. Gluckman PD, Hanson MA, Cooper C, Thornburg KL (2008) Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359:61–73

    Article  PubMed  CAS  Google Scholar 

  28. Bjornsson HT, Sigurdsson MI, Fallin MD, Irizarry RA, Aspelund T, Cui H, Yu W, Rongione MA, Ekström TJ, Harris TB, Launer LJ, Eiriksdottir G, Leppert MF, Sapienza C, Gudnason V, Feinberg AP (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA 299:2877–2883

    Article  PubMed  CAS  Google Scholar 

  29. Hillemacher T, Frieling H, Moskau S, Muschler MA, Semmler A, Kornhuber J, Klockgether T, Bleich S, Linnebank M (2008) Global DNA methylation is influenced by smoking behaviour. Eur Neuropsychopharmacol 18:295–298

    Article  PubMed  CAS  Google Scholar 

  30. Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7:21–33

    Article  PubMed  CAS  Google Scholar 

  31. Lamprecht B, Walter K, Kreher S, Kumar R, Hummel M, Lenze D, Köchert K, Bouhlel MA, Richter J, Soler E, Stadhouders R, Jöhrens K, Wurster KD, Callen DF, Harte MF, Giefing M, Barlow R, Stein H, Anagnostopoulos I, Janz M, Cockerill PN, Siebert R, Dörken B, Bonifer C, Mathas S (2010) Derepression of an endogenous long terminal repeat activates the CSF1R proto-oncogene in human lymphoma. Nat Med 16:571–579

    Article  PubMed  CAS  Google Scholar 

  32. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159

    Article  PubMed  CAS  Google Scholar 

  33. Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8:286–298

    Article  PubMed  CAS  Google Scholar 

  34. Konety BR, Nguyen TS, Brenes G, Sholder A, Lewis N, Bastacky S, Potter DM, Getzenberg RH (2000) Clinical usefulness of the novel marker BLCA-4 for the detection of bladder cancer. J Urol 164:634–639

    Article  PubMed  CAS  Google Scholar 

  35. Van Le TS, Miller R, Barder T, Babjuk M, Potter DM, Getzenberg RH (2005) Highly specific urine-based marker of bladder cancer. Urology 66:1256–1260

    Article  PubMed  Google Scholar 

  36. Wolff EM, Byun HM, Han HF, Sharma S, Nichols PW, Siegmund KD, Yang AS, Jones PA, Liang G (2010) Hypomethylation of a LINE-1 promoter activates an alternate transcript of the MET oncogene in bladders with cancer. PLoS Genet 6:e1000917

    Article  PubMed  Google Scholar 

  37. Suzuki H, Toyota M, Sato H, Sonoda T, Sakauchi F, Mori M (2006) Roles and causes of abnormal DNA methylation in gastrointestinal cancers. Asian Pac J Cancer Prev 7:177–185

    PubMed  Google Scholar 

  38. Schernhammer ES, Giovannucci E, Kawasaki T, Rosner B, Fuchs CS, Ogino S (2010) Dietary folate, alcohol and B vitamins in relation to LINE-1 hypomethylation in colon cancer. Gut 59:794–799

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This study was supported by a grant from Chongqing Municipal Major Scientific and Technological Project (CSTC,2011AC5027).

Author information

Authors and Affiliations

  1. Urology Department, Southwest Hospital Affilated to Third Military Medical University, No. 33, Gaotanyanzheng RD, Chongqing, 400038, China

    Hui-Xiang Ji, Jin-Hong Pan, Wen-Hao Shen, Zhi-Wen Chen & Zhan-Song Zhou

  2. Urology Department, Kunming General Hospital of Chengdu Military Region, No. 212, Daguan RD, Kunming, 650032, China

    Qian Zhao

Authors
  1. Hui-Xiang Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin-Hong Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen-Hao Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhi-Wen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhan-Song Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhi-Wen Chen or Zhan-Song Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ji, HX., Zhao, Q., Pan, JH. et al. Association of BLCA-4 Hypomethylation in Blood Leukocyte DNA and the Risk of Bladder Cancer in a Chinese Population. Pathol. Oncol. Res. 19, 205–210 (2013). https://doi.org/10.1007/s12253-012-9570-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-012-9570-4

Keywords

Search

Navigation