Histone Methylation Marks on Circulating Nucleosomes As Novel Blood-Based Biomarker in Colorectal Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2015 Dec 23

PMID 26690425

Citations 35

Authors

Ugur Gezer

Ebru E Yoruker

Metin Keskin

Cemil Burak Kulle

Yoganiranjana Dharuman

Stefan Holdenrieder

Affiliations

Soon will be listed here.

Abstract

Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer as potential non-invasive biomarkers, as stable structure in circulation nucleosomes could be valuable sources for detection of cancer-specific alterations in histone modifications. Our interest is in histone methylation marks with a focus on colorectal cancer, one of the leading cancers respective the incidence and mortality. Our previous work included the analysis of trimethylations of lysine 9 on histone 3 (H3K9me3) and of lysine 20 on histone 4 (H4K20me3) by chromatin immuno- precipitation-related PCR in circulating nucleosomes. Here we asked whether global immunologic measurement of histone marks in circulation could be a suitable approach to show their potential as biomarkers. In addition to H3K9me3 and H4K20me3 we also measured H3K27me3 in plasma samples from CRC patients (n = 63) and cancer free individuals (n = 40) by ELISA-based methylation assays. Our results show that of three marks, the amounts of H3K27me3 (p = 0.04) and H4K20me3 (p < 0.001) were significantly lower in CRC patients than in healthy controls. For H3K9me3 similar amounts were measured in both groups. Areas under the curve (AUC) in receiver operating characteristic (ROC) curves indicating the power of CRC detection were 0.620 for H3K27me3, 0.715 for H4K20me3 and 0.769 for the combination of both markers. In conclusion, findings of this preliminary study reveal the potential of blood-based detection of CRC by quantification of histone methylation marks and the additive effect of the marker combination.

Citing Articles

Artificial intelligence and machine learning in cell-free-DNA-based diagnostics.

Tsui W, Ding S, Jiang P, Lo Y Genome Res. 2025; 35(1):1-19.

PMID: 39843210 PMC: 11789496. DOI: 10.1101/gr.278413.123.

Single-molecule systems for the detection and monitoring of plasma-circulating nucleosomes and oncoproteins in diffuse midline glioma.

Erez N, Furth N, Fedyuk V, Wadden J, Aittaleb R, Adam T Cell Rep Med. 2025; 6(1):101918.

PMID: 39809263 PMC: 11866549. DOI: 10.1016/j.xcrm.2024.101918.

Emerging biomarkers for non-invasive diagnosis and treatment of cancer: a systematic review.

Zakari S, Niels N, Olagunju G, Nnaji P, Ogunniyi O, Tebamifor M Front Oncol. 2024; 14:1405267.

PMID: 39132504 PMC: 11313249. DOI: 10.3389/fonc.2024.1405267.

The roles of histone modifications in tumorigenesis and associated inhibitors in cancer therapy.

Yang Y, Zhang M, Wang Y J Natl Cancer Cent. 2024; 2(4):277-290.

PMID: 39036551 PMC: 11256729. DOI: 10.1016/j.jncc.2022.09.002.

Advances in liquid biopsy in neuroblastoma.

Zhuo Z, Lin L, Miao L, Li M, He J Fundam Res. 2024; 2(6):903-917.

PMID: 38933377 PMC: 11197818. DOI: 10.1016/j.fmre.2022.08.005.

References

Holdenrieder S, Stieber P . Clinical use of circulating nucleosomes. Crit Rev Clin Lab Sci. 2008; 46(1):1-24. DOI: 10.1080/10408360802485875. View

Schwarzenbach H, Hoon D, Pantel K . Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011; 11(6):426-37. DOI: 10.1038/nrc3066. View

Yokoyama Y, Matsumoto A, Hieda M, Shinchi Y, Ogihara E, Hamada M . Loss of histone H4K20 trimethylation predicts poor prognosis in breast cancer and is associated with invasive activity. Breast Cancer Res. 2014; 16(3):R66. PMC: 4229880. DOI: 10.1186/bcr3681. View

Umetani N, Hiramatsu S, Hoon D . Higher amount of free circulating DNA in serum than in plasma is not mainly caused by contaminated extraneous DNA during separation. Ann N Y Acad Sci. 2006; 1075:299-307. DOI: 10.1196/annals.1368.040. View

Gonzalez-Masia J, Garcia-Olmo D, Garcia-Olmo D . Circulating nucleic acids in plasma and serum (CNAPS): applications in oncology. Onco Targets Ther. 2013; 6:819-32. PMC: 3711950. DOI: 10.2147/OTT.S44668. View

Benard A, Goossens-Beumer I, van Hoesel A, de Graaf W, Horati H, Putter H . Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer. BMC Cancer. 2014; 14:531. PMC: 4223547. DOI: 10.1186/1471-2407-14-531. View

Mallinson E, Newton K, Bowen J, Lalloo F, Clancy T, Hill J . The impact of screening and genetic registration on mortality and colorectal cancer incidence in familial adenomatous polyposis. Gut. 2010; 59(10):1378-82. DOI: 10.1136/gut.2010.212449. View

Fraga M, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G . Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 2005; 37(4):391-400. DOI: 10.1038/ng1531. View

Gezer U, Holdenrieder S . Post-translational histone modifications in circulating nucleosomes as new biomarkers in colorectal cancer. In Vivo. 2014; 28(3):287-92. View

10.

Barski A, Cuddapah S, Cui K, Roh T, Schones D, Wang Z . High-resolution profiling of histone methylations in the human genome. Cell. 2007; 129(4):823-37. DOI: 10.1016/j.cell.2007.05.009. View

11.

Strahl B, Allis C . The language of covalent histone modifications. Nature. 2000; 403(6765):41-5. DOI: 10.1038/47412. View

12.

Alexiadis V, Ballestas M, Sanchez C, Winokur S, Vedanarayanan V, Warren M . RNAPol-ChIP analysis of transcription from FSHD-linked tandem repeats and satellite DNA. Biochim Biophys Acta. 2007; 1769(1):29-40. PMC: 1802126. DOI: 10.1016/j.bbaexp.2006.11.006. View

13.

Leszinski G, Gezer U, Siegele B, Stoetzer O, Holdenrieder S . Relevance of histone marks H3K9me3 and H4K20me3 in cancer. Anticancer Res. 2012; 32(5):2199-205. View

14.

Gezer U, Ustek D, Yoruker E, Cakiris A, Abaci N, Leszinski G . Characterization of H3K9me3- and H4K20me3-associated circulating nucleosomal DNA by high-throughput sequencing in colorectal cancer. Tumour Biol. 2012; 34(1):329-36. DOI: 10.1007/s13277-012-0554-5. View

15.

Colussi D, Brandi G, Bazzoli F, Ricciardiello L . Molecular pathways involved in colorectal cancer: implications for disease behavior and prevention. Int J Mol Sci. 2013; 14(8):16365-85. PMC: 3759916. DOI: 10.3390/ijms140816365. View

16.

Waldmann T, Schneider R . Targeting histone modifications--epigenetics in cancer. Curr Opin Cell Biol. 2013; 25(2):184-9. DOI: 10.1016/j.ceb.2013.01.001. View

17.

Gezer U, Mert U, Ozgur E, Yoruker E, Holdenrieder S, Dalay N . Correlation of histone methyl marks with circulating nucleosomes in blood plasma of cancer patients. Oncol Lett. 2012; 3(5):1095-1098. PMC: 3389626. DOI: 10.3892/ol.2012.600. View

18.

Coppede F . The role of epigenetics in colorectal cancer. Expert Rev Gastroenterol Hepatol. 2014; 8(8):935-48. DOI: 10.1586/17474124.2014.924397. View

19.

Choong M, Tsafnat G . Genetic and epigenetic biomarkers of colorectal cancer. Clin Gastroenterol Hepatol. 2011; 10(1):9-15. DOI: 10.1016/j.cgh.2011.04.020. View

20.

Holdenrieder S, von Pawel J, Nagel D, Stieber P . Long-term stability of circulating nucleosomes in serum. Anticancer Res. 2010; 30(5):1613-5. View