Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer

BMC Cancer

Peter JK Kuppen¹  Cornelis JH van de Velde¹  Eliane CM Zeestraten¹  Hein Putter²  Hamed Horati¹  Wouter de Graaf¹  Anneke Q van Hoesel¹  Inès J Goossens-Beumer¹  Anne Benard¹ 

[1]Department of Surgery, K6-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands

[2]Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

关键词: Tumor recurrence;    Patient survival;    Prognosis;    Colon cancer;    Epigenetics;    Trimethylation;    Histone modifications;   

Others  :  1125310
DOI  :  10.1186/1471-2407-14-531

 received in 2014-05-06, accepted in 2014-07-17,  发布年份 2014

【 摘 要 】

Background

Post-translational modification of histone tails by methylation plays an important role in tumorigenesis. In this study, we investigated the nuclear expression of H3K4me3, H3K9me3 and H4K20me3 in early-stage colon cancer in relation to clinical outcome.

Methods

Tumor tissue cores of 254 TNM stage I-III colorectal cancer patients were immunohistochemically stained for H3K4me3, H3K9me3 and H4K20me3 and scored using the semi-automated Ariol system. Cox proportional hazard trend analyses were performed to assess the prognostic value of the combined markers with respect to patient survival and tumor recurrence.

Results

The histone methylation markers only showed prognostic value in early-stage (TNM stage I and II) colon cancer. Therefore, only this patient set (n = 121) was used for further statistical analyses. Low nuclear expression of H3K4me3, and high expression of H3K9me3 and H4K20me3 were associated with good prognosis. In combined marker analyses, the patient group showing most favorable expression (low H3K4me3, high H3K9me3 and high H4K20me3) was associated with the best prognosis. Multivariate trend analyses showed significantly increased hazard ratios (HR) for each additional marker showing unfavorable expression, as compared to the “all favorable” reference group. The HR for disease-free survival was 3.81 (1.72-8.45; p = 0.001), for locoregional recurrence-free survival 2.86 (1.59-5.13; p < 0.001) and for distant recurrence-free survival 2.94 (1.66-5.22; p < 0.001).

Conclusions

Combined nuclear expression of histone modifications H3K4me3, H3K9me3 and H4K20me3 is prognostic in early-stage colon cancer. The combination of expression of the three histone modifications provides better stratification of patient groups as compared to the individual markers and provides a good risk assessment for each patient group.

【 授权许可】

   
2014 Benard et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Sarkar S, Horn G, Moulton K, Oza A, Byler S, Kokolus S, Longacre M: Cancer development, progression, and therapy: an epigenetic overview. Int J Mol Sci 2013, 14:21087-21113.
• [2]Kouzarides T: Chromatin modifications and their function. Cell 2007, 128:693-705.
• [3]Chi P, Allis CD, Wang GG: Covalent histone modifications–miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer 2010, 10:457-469.
• [4]He C, Xu J, Zhang J, Xie D, Ye H, Xiao Z, Cai M, Xu K, Zeng Y, Li H, Wang J: High expression of trimethylated histone H3 lysine 4 is associated with poor prognosis in hepatocellular carcinoma. Hum Pathol 2012, 43:1425-1435.
• [5]Ellinger J, Kahl P, Mertens C, Rogenhofer S, Hauser S, Hartmann W, Bastian PJ, Buttner R, Muller SC, Von RA: Prognostic relevance of global histone H3 lysine 4 (H3K4) methylation in renal cell carcinoma. Int J Cancer 2010, 127:2360-2366.
• [6]Muller-Tidow C, Klein HU, Hascher A, Isken F, Tickenbrock L, Thoennissen N, Agrawal-Singh S, Tschanter P, Disselhoff C, Wang Y, Becker A, Thiede C, Ehninger G, Zur SU, Koschmieder S, Seidl M, Muller FU, Schmitz W, Schlenke P, McClelland M, Berdel WE, Dugas M, Serve H: Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia. Blood 2010, 116:3564-3571.
• [7]Xia R, Zhou R, Tian Z, Zhang C, Wang L, Hu Y, Han J, Li J: High expression of H3K9me3 is a strong predictor of poor survival in patients with salivary adenoid cystic carcinoma. Arch Pathol Lab Med 2013, 137:1761-1769.
• [8]Ellinger J, Bachmann A, Goke F, Behbahani TE, Baumann C, Heukamp LC, Rogenhofer S, Muller SC: Alterations of global histone H3K9 and H3K27 methylation levels in bladder cancer. Urol Int 2014, 93:113-118.
• [9]Van Den Broeck A, Brambilla E, Moro-Sibilot D, Lantuejoul S, Brambilla C, Eymin B, Khochbin S, Gazzeri S: Loss of histone H4K20 trimethylation occurs in preneoplasia and influences prognosis of non-small cell lung cancer. Clin Cancer Res 2008, 14:7237-7245.
• [10]Marion RM, Schotta G, Ortega S, Blasco MA: Suv4-20h abrogation enhances telomere elongation during reprogramming and confers a higher tumorigenic potential to iPS cells. PLoS One 2011, 6:e25680.
• [11]Wang H, Cao R, Xia L, Erdjument-Bromage H, Borchers C, Tempst P, Zhang Y: Purification and functional characterization of a histone H3-lysine 4-specific methyltransferase. Mol Cell 2001, 8:1207-1217.
• [12]Jorgensen S, Schotta G, Sorensen CS: Histone H4 lysine 20 methylation: key player in epigenetic regulation of genomic integrity. Nucleic Acids Res 2013, 41:2797-2806.
• [13]Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G, Reinberg D, Jenuwein T: A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev 2004, 18:1251-1262.
• [14]McEwen KR, Ferguson-Smith AC: Distinguishing epigenetic marks of developmental and imprinting regulation. Epigenetics Chromatin 2010, 3:2.
• [15]McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM: Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 2005, 97:1180-1184.
• [16]Zeestraten EC, Reimers MS, Saadatmand S, Dekker JW, Liefers GJ, van den Elsen PJ, van de Velde CJ, Kuppen PJ: Combined analysis of HLA class I, HLA-E and HLA-G predicts prognosis in colon cancer patients. Br J Cancer 2014, 110:459-468.
• [17]van Nes JG, de Kruijf EM, Faratian D, van de Velde CJ, Putter H, Falconer C, Smit VT, Kay C, van de Vijver MJ, Kuppen PJ, Bartlett JM: COX2 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients. Breast Cancer Res Treat 2011, 125:671-685.
• [18]Putter H, Fiocco M, Geskus RB: Tutorial in biostatistics: competing risks and multi-state models. Stat Med 2007, 26:2389-2430.
• [19]Chen X, Song N, Matsumoto K, Nanashima A, Nagayasu T, Hayashi T, Ying M, Endo D, Wu Z, Koji T: High expression of trimethylated histone H3 at lysine 27 predicts better prognosis in non-small cell lung cancer. Int J Oncol 2013, 43:1467-1480.
• [20]Stypula-Cyrus Y, Damania D, Kunte DP, Cruz MD, Subramanian H, Roy HK, Backman V: HDAC up-regulation in early colon field carcinogenesis is involved in cell tumorigenicity through regulation of chromatin structure. PLoS One 2013, 8:e64600.
• [21]Benard A, van de Velde CJ, Lessard L, Putter H, Takeshima L, Kuppen PJ, Hoon DS: Epigenetic status of LINE-1 predicts clinical outcome in early-stage rectal cancer. Br J Cancer 2013, 109:3073-3083.
• [22]Ronchetti D, Tuana G, Rinaldi A, Agnelli L, Cutrona G, Mosca L, Fabris S, Matis S, Colombo M, Gentile M, Recchia AG, Kwee I, Bertoni F, Morabito F, Ferrarini M, Neri A: Distinct patterns of global promoter methylation in early stage chronic lymphocytic leukemia. Genes Chromosomes Cancer 2014, 53:264-273.
• [23]Nadal E, Chen G, Gallegos M, Lin L, Ferrer-Torres D, Truini A, Wang Z, Lin J, Reddy RM, Llatjos R, Escobar I, Moya J, Chang AC, Cardenal F, Capella G, Beer DG: Epigenetic inactivation of microRNA-34b/c predicts poor disease-free survival in early-stage lung adenocarcinoma. Clin Cancer Res 2013, 19:6842-6852.
• [24]Birkenkamp-Demtroder K, Olesen SH, Sorensen FB, Laurberg S, Laiho P, Aaltonen LA, Orntoft TF: Differential gene expression in colon cancer of the caecum versus the sigmoid and rectosigmoid. Gut 2005, 54:374-384.
• [25]Slattery ML, Wolff E, Hoffman MD, Pellatt DF, Milash B, Wolff RK: MicroRNAs and colon and rectal cancer: differential expression by tumor location and subtype. Genes Chromosomes Cancer 2011, 50:196-206.
• [26]Kimura H: Histone modifications for human epigenome analysis. J Hum Genet 2013, 58:439-445.
• [27]Yokoyama Y, Hieda M, Nishioka Y, Matsumoto A, Higashi S, Kimura H, Yamamoto H, Mori M, Matsuura S, Matsuura N: Cancer-associated upregulation of histone H3 lysine 9 trimethylation promotes cell motility in vitro and drives tumor formation in vivo. Cancer Sci 2013, 104:889-895.
• [28]Derks S, Bosch LJ, Niessen HE, Moerkerk PT, van den Bosch SM, Carvalho B, Mongera S, Voncken JW, Meijer GA, De Bruine AP, Herman JG, Van EM: Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21. Carcinogenesis 2009, 30:1041-1048.
• [29]Gezer U, Ustek D, Yoruker EE, Cakiris A, Abaci N, Leszinski G, Dalay N, Holdenrieder S: Characterization of H3K9me3- and H4K20me3-associated circulating nucleosomal DNA by high-throughput sequencing in colorectal cancer. Tumour Biol 2013, 34:329-336.
• [30]Hunter RG, Murakami G, Dewell S, Seligsohn M, Baker ME, Datson NA, McEwen BS, Pfaff DW: Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response. Proc Natl Acad Sci U S A 2012, 109:17657-17662.
• [31]Rangasamy D: Distinctive patterns of epigenetic marks are associated with promoter regions of mouse LINE-1 and LTR retrotransposons. Mob DNA 2013, 4:27.
• [32]Leszinski G, Gezer U, Siegele B, Stoetzer O, Holdenrieder S: Relevance of histone marks H3K9me3 and H4K20me3 in cancer. Anticancer Res 2012, 32:2199-2205.
• [33]Enroth S, Rada-Iglesisas A, Andersson R, Wallerman O, Wanders A, Pahlman L, Komorowski J, Wadelius C: Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa. BMC Cancer 2011, 11:450.
• [34]Schneider AC, Heukamp LC, Rogenhofer S, Fechner G, Bastian PJ, Von RA, Muller SC, Ellinger J: Global histone H4K20 trimethylation predicts cancer-specific survival in patients with muscle-invasive bladder cancer. BJU Int 2011, 108:E290-E296.
• [35]Biron VL, Mohamed A, Hendzel MJ, Alan UD, Seikaly H: Epigenetic differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinomas. J Otolaryngol Head Neck Surg 2012, 41(Suppl 1):S65-S70.
• [36]Chen T, Zhang Y, Guo WH, Meng MB, Mo XM, Lu Y: Effects of heterochromatin in colorectal cancer stem cells on radiosensitivity. Chin J Cancer 2010, 29:270-276.
• [37]Chen YW, Kao SY, Wang HJ, Yang MH: Histone modification patterns correlate with patient outcome in oral squamous cell carcinoma. Cancer 2013, 119:4259-4267.