Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors

Clinical Epigenetics

Janet L. Stanford⁸  Christiane Maier⁷  Ziding Feng⁹  Jian-Bing Fan¹  Elaine A. Ostrander⁵  Piet A. van den Brandt⁶  Brandy Klotzle¹  Marina Bibikova¹  Irene M. Shui⁴  Shanshan Zhao²  Antje Rinckleb⁷  Manuel Luedeke⁷  Joshi J. Alumkal³  Milan S. Geybels⁶ 

[1] Illumina, Inc., San Diego, CA, USA;Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA;Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA;Cancer Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA;Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands;Institute of Human Genetics and Department of Urology, Faculty of Medicine, University of Ulm, Ulm, Germany;Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA;MD Anderson Cancer Center, Houston, TX, USA

关键词: TCGA;    TRIB2;    SEPT9;    RAB40C;    PDE4D;    NT5C;    KLK10;    GREM1;    CACNA1D;    C3orf14;    mRNA expression;    Unsupervised clustering;    Tumor tissue;    ERG;    TMPRSS2;    Gene fusion;    Prostate cancer;    Epigenomic profiling;    Epigenetics;    CpG site;    DNA methylation;   

Others  :  1235005
DOI  :  10.1186/s13148-015-0161-6

 received in 2015-09-11, accepted in 2015-12-03,  发布年份 2015

【 摘 要 】

Background

About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status.

Results

The study included 496 patients with clinically localized PCa who had a radical prostatectomy as primary treatment for PCa. Fluorescence in situ hybridization (FISH) “break-apart” assays were used to determine tumor T2E-fusion status, which showed that 266 patients (53.6 %) had T2E-positive PCa. The study showed global DNA methylation differences between tumor subtypes. A large number of differentially methylated CpG sites were identified (false-discovery rate [FDR] Q-value <0.00001; n = 27,876) and DNA methylation profiles accurately distinguished between tumor T2E subgroups. A number of top-ranked differentially methylated CpGs in genes (FDR Q-values ≤1.53E−29) were identified: C3orf14, CACNA1D, GREM1, KLK10, NT5C, PDE4D, RAB40C, SEPT9, and TRIB2, several of which had a corresponding alteration in mRNA expression. These genes may have various roles in the pathogenesis of PCa, and the calcium-channel gene CACNA1D is a known ERG-target. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings.

Conclusions

This study identified substantial differences in DNA methylation profiles of T2E-positive and T2E-negative tumors, thereby providing further evidence that different underlying oncogenic pathways characterize these molecular subtypes.

【 授权许可】

   
2015 Geybels et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, Sun XW, et al.: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005, 310(5748):644-8.
• [2]Clark JP, Cooper CS: ETS gene fusions in prostate cancer. Nat Rev Urol 2009, 6(8):429-39.
• [3]Gasi Tandefelt D, Boormans J, Hermans K, Trapman J: ETS fusion genes in prostate cancer. Endocr Relat Cancer 2014, 21(3):R143-52.
• [4]Magi-Galluzzi C, Tsusuki T, Elson P, Simmerman K, LaFargue C, Esgueva R, et al.: TMPRSS2-ERG gene fusion prevalence and class are significantly different in prostate cancer of Caucasian, African-American and Japanese patients. Prostate 2011, 71(5):489-97.
• [5]Boormans JL, Korsten H, der Made AJ Z-v, van Leenders GJ, de Vos CV, Jenster G, et al.: Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer. Int J Cancer 2013, 133(2):335-45.
• [6]Brase JC, Johannes M, Mannsperger H, Falth M, Metzger J, Kacprzyk LA, et al.: TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer 2011, 11:507. BioMed Central Full Text
• [7]Chen R, Zeng X, Zhang R, Huang J, Kuang X, Yang J, et al.: Cav1.3 channel alpha1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers. Urol Oncol 2014, 32(5):524-36.
• [8]Jhavar S, Brewer D, Edwards S, Kote-Jarai Z, Attard G, Clark J, et al.: Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer. BJU Int 2009, 103(9):1256-69.
• [9]Paulo P, Ribeiro FR, Santos J, Mesquita D, Almeida M, Barros-Silva JD, et al.: Molecular subtyping of primary prostate cancer reveals specific and shared target genes of different ETS rearrangements. Neoplasia 2012, 14(7):600-11.
• [10]Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, et al.: Estrogen-dependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Inst 2008, 100(11):815-25.
• [11]Tomlins SA, Laxman B, Varambally S, Cao X, Yu J, Helgeson BE, et al.: Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 2008, 10(2):177-88.
• [12]Wang CY, Liu PY, Liao JK: Pleiotropic effects of statin therapy: molecular mechanisms and clinical results. Trends Mol Med 2008, 14(1):37-44.
• [13]Washington MN, Weigel NL: 1{alpha},25-Dihydroxyvitamin D3 inhibits growth of VCaP prostate cancer cells despite inducing the growth-promoting TMPRSS2:ERG gene fusion. Endocrinology 2010, 151(4):1409-17.
• [14]Tomlins SA, Day JR, Lonigro RJ, Hovelson DH, Siddiqui J, Kunju LP, et al.: Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2015.
• [15]Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, et al.: The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev 2012, 21(9):1497-509.
• [16]Attard G, Parker C, Eeles RA, Schroder F, Tomlins SA, Tannock I et al. Prostate cancer. Lancet. 2015. doi:10.1016/S0140-6736(14)61947-4.
• [17]Rubin MA, Maher CA, Chinnaiyan AM: Common gene rearrangements in prostate cancer. J Clin Oncol 2011, 29(27):3659-68.
• [18]Herman JG, Baylin SB: Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003, 349(21):2042-54.
• [19]Jones PA, Baylin SB: The epigenomics of cancer. Cell 2007, 128(4):683-92.
• [20]Lou S, Lee HM, Qin H, Li JW, Gao Z, Liu X, et al.: Whole-genome bisulfite sequencing of multiple individuals reveals complementary roles of promoter and gene body methylation in transcriptional regulation. Genome Biol 2014, 15(7):408. BioMed Central Full Text
• [21]Yang X, Han H, De Carvalho DD, Lay FD, Jones PA, Liang G: Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 2014, 26(4):577-90.
• [22]Jeronimo C, Bastian PJ, Bjartell A, Carbone GM, Catto JW, Clark SJ, et al.: Epigenetics in prostate cancer: biologic and clinical relevance. Eur Urol 2011, 60(4):753-66.
• [23]Borno ST, Fischer A, Kerick M, Falth M, Laible M, Brase JC, et al.: Genome-wide DNA methylation events in TMPRSS2-ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. Cancer Discov 2012, 2(11):1024-35.
• [24]Kim JH, Dhanasekaran SM, Prensner JR, Cao X, Robinson D, Kalyana-Sundaram S, et al.: Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer. Genome Res 2011, 21(7):1028-41.
• [25]Kim JW, Kim ST, Turner AR, Young T, Smith S, Liu W, et al.: Identification of new differentially methylated genes that have potential functional consequences in prostate cancer. PLoS One 2012., 7(10) Article ID e48455
• [26]Jhavar S, Reid A, Clark J, Kote-Jarai Z, Christmas T, Thompson A, et al.: Detection of TMPRSS2-ERG translocations in human prostate cancer by expression profiling using GeneChip Human Exon 1.0 ST arrays. J Mol Diagn 2008, 10(1):50-7.
• [27]Smit FP, Salagierski M, Jannink S, Schalken JA: High-resolution ERG-expression profiling on GeneChip exon 1.0 ST arrays in primary and castration-resistant prostate cancer. BJU Int 2013, 111(5):836-42.
• [28]Font-Tello A, Juanpere N, de Muga S, Lorenzo M, Lorente JA, Fumado L, et al.: Association of ERG and TMPRSS2-ERG with grade, stage, and prognosis of prostate cancer is dependent on their expression levels. Prostate 2015.
• [29]Berger SM, Bartsch D: The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function. Cell Tissue Res 2014, 357(2):463-76.
• [30]Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, et al.: Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013, 45(9):1050-4.
• [31]Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, et al.: Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 2010, 466(7303):253-7.
• [32]Dubois C, Vanden Abeele F, Lehen'kyi V, Gkika D, Guarmit B, Lepage G, et al.: Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer. Cancer Cell 2014, 26(1):19-32.
• [33]Warnier M, Roudbaraki M, Derouiche S, Delcourt P, Bokhobza A, Prevarskaya N et al. CACNA2D2 promotes tumorigenesis by stimulating cell proliferation and angiogenesis. Oncogene. 2015. doi:10.1038/onc.2014.467.
• [34]Weaver EM, Zamora FJ, Puplampu-Dove YA, Kiessu E, Hearne JL, Martin-Caraballo M: Regulation of T-type calcium channel expression by sodium butyrate in prostate cancer cells. Eur J Pharmacol 2015, 749:20-31.
• [35]Brazil DP, Church RH, Surae S, Godson C, Martin F: BMP signalling: agony and antagony in the family. Trends Cell Biol 2015, 25(5):249-64.
• [36]Yang Q, Jie Z, Cao H, Greenlee AR, Yang C, Zou F, et al.: Low-level expression of let-7a in gastric cancer and its involvement in tumorigenesis by targeting RAB40C. Carcinogenesis 2011, 32(5):713-22.
• [37]Rahrmann EP, Collier LS, Knutson TP, Doyal ME, Kuslak SL, Green LE, et al.: Identification of PDE4D as a proliferation promoting factor in prostate cancer using a Sleeping Beauty transposon-based somatic mutagenesis screen. Cancer Res 2009, 69(10):4388-97.
• [38]Powers GL, Hammer KD, Domenech M, Frantskevich K, Malinowski RL, Bushman W, et al.: Phosphodiesterase 4D inhibitors limit prostate cancer growth potential. Mol Cancer Res 2015, 13(1):149-60.
• [39]Russell SE, Hall PA: Do septins have a role in cancer? Br J Cancer 2005, 93(5):499-503.
• [40]Geybels MS, Zhao SS, Wong CJ, Bibikova M, Klotzle B, Wu M, et al.: Epigenome-wide profiling of DNA methylation in paired prostate tumor versus adjacent benign tissue. Prostate 2015, 75(16):1941-50.
• [41]Gyparaki MT, Basdra EK, Papavassiliou AG: DNA methylation biomarkers as diagnostic and prognostic tools in colorectal cancer. J Mol Med 2013, 91(11):1249-56.
• [42]Yousef GM, Diamandis EP: The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev 2001, 22(2):184-204.
• [43]Olkhov-Mitsel E, Van der Kwast T, Kron KJ, Ozcelik H, Briollais L, Massey C, et al.: Quantitative DNA methylation analysis of genes coding for kallikrein-related peptidases 6 and 10 as biomarkers for prostate cancer. Epigenetics 2012, 7(9):1037-45.
• [44]Yokoyama T, Nakamura T: Tribbles in disease: signaling pathways important for cellular function and neoplastic transformation. Cancer Sci 2011, 102(6):1115-22.
• [45]Etcheverry A, Aubry M, de Tayrac M, Vauleon E, Boniface R, Guenot F, et al.: DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC Genomics 2010, 11:701. BioMed Central Full Text
• [46]Kulkarni SS, Karlsson HK, Szekeres F, Chibalin AV, Krook A, Zierath JR: Suppression of 5'-nucleotidase enzymes promotes AMP-activated protein kinase (AMPK) phosphorylation and metabolism in human and mouse skeletal muscle. J Biol Chem 2011, 286(40):34567-74.
• [47]Braun M, Stomper J, Boehm D, Vogel W, Scheble VJ, Wernert N, et al.: Improved method of detecting the ERG gene rearrangement in prostate cancer using combined dual-color chromogenic and silver in situ hybridization. J Mol Diagn 2012, 14(4):322-7.
• [48]Agalliu I, Salinas CA, Hansten PD, Ostrander EA, Stanford JL: Statin use and risk of prostate cancer: results from a population-based epidemiologic study. Am J Epidemiol 2008, 168(3):250-60.
• [49]Stanford JL, Wicklund KG, McKnight B, Daling JR, Brawer MK: Vasectomy and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 1999, 8(10):881-6.
• [50]Summersgill B, Clark J, Shipley J: Fluorescence and chromogenic in situ hybridization to detect genetic aberrations in formalin-fixed paraffin embedded material, including tissue microarrays. Nat Protoc 2008, 3(2):220-34.
• [51]FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, et al.: Association of TMPRSS2-ERG gene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer 2008, 8:230. BioMed Central Full Text
• [52]Maksimovic J, Gordon L, Oshlack A: SWAN: subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. Genome Biol 2012, 13(6):R44. BioMed Central Full Text
• [53]Johnson WE, Li C, Rabinovic A: Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007, 8(1):118-27.