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BMP3 promoter hypermethylation in plasma-derived cell-free DNA in colorectal cancer patients

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Abstract

Detecting cfDNA in plasma or serum could serve as a ‘liquid biopsy’, for circulating tumor DNA with aberrant methylation patterns offer a possible method for early detection of several cancers which could avoid the need for tumor tissue biopsies. Bone Morphogenetic Protein 3 (BMP3) was identified as a candidate tumor suppressor gene putatively down-regulated in colorectal cancer (CRC). In this study, we aimed to assess the potential role of BMP3 promoter methylation changes in plasma DNA for detection of colorectal cancerous and precancerous lesions. Plasma DNA samples were extracted from 50 patients with histologically diagnosed polyps or tumor and 50 patients reported negative for polyps or tumors. The procedure consists of bisulfite conversion of the extracted DNA, purification of bis-DNA, and BMP3 methylation status analysis by using the bisulfite specific high resolution melting analysis. This study demonstrated that there was a significantly higher frequency of BMP3 methylated DNA in plasma in patients with polyps versus healthy controls with a sensitivity and specificity of 40 and 94%, respectively. In conclusion, our results demonstrated that BMP3 DNA methylation in plasma had not have sufficient sensitivity and it should be used in combination with other biomarkers for the detection of CRC.

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References

  • Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, Boardman LA, Berger BM, Lidgard GP (2012a) The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol 10:272–277.e271

    Article  CAS  PubMed  Google Scholar 

  • Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML, Thibodeau SN, Rabeneck L, Paszat LF et al (2012b) Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142:248–226

    Article  CAS  PubMed  Google Scholar 

  • Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F (2017) Global patterns and trends in colorectal cancer incidence and mortality. Gut 66:683–691

    Article  PubMed  Google Scholar 

  • Ashktorab H, Daremipouran M, Goel A, Varma S, Leavitt R, Sun X, Brim H (2014) DNA methylome profiling identifies novel methylated genes in African American patients with colorectal neoplasia. Epigenetics 9:503–512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Behrouz Sharif S, Hashemzadeh S, Mousavi Ardehaie R, Eftekharsadat A, Ghojazadeh M, Mehrtash AH, Estiar MA, Teimoori-Toolabi L, Sakhinia E (2016) Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker. Oncol Lett 12:5335–5343

    Article  PubMed  PubMed Central  Google Scholar 

  • Berger BM, Levin B, Hilsden RJ (2016) Multitarget stool DNA for colorectal cancer screening: a review and commentary on the United States preventive services draft guidelines. World J Gastrointest Oncol 8:450–458

    Article  PubMed  PubMed Central  Google Scholar 

  • Danese E, Minicozzi AM, Benati M, Montagnana M, Paviati E, Salvagno GL, Lima-Oliveira G, Gusella M, Pasini F, Lippi G et al (2015) Comparison of genetic and epigenetic alterations of primary tumors and matched plasma samples in patients with colorectal cancer. PLoS ONE 10:e0126417

    Article  PubMed  PubMed Central  Google Scholar 

  • Diaz LA Jr, Bardelli A (2014) Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol 32:579–586

    Article  PubMed  PubMed Central  Google Scholar 

  • Elshimali YI, Khaddour H, Sarkissyan M, Wu Y, Vadgama JV (2013) The clinical utilization of circulating cell free DNA (CCFDNA) in blood of cancer patients. Int J Mol Sci 14:18925–18958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galanopoulos M, Tsoukalas N, Papanikolaou IS, Tolia M, Gazouli M, Mantzaris GJ (2017) Abnormal DNA methylation as a cell-free circulating DNA biomarker for colorectal cancer detection: a review of literature. World J Gastrointest Oncol 9:142–152

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Pons M, Cruz-Correa M (2015) Colorectal cancer biomarkers: where are we now?. Biomed Res Int 2015:149014

    Article  PubMed  PubMed Central  Google Scholar 

  • Grützmann R, Molnar B, Pilarsky C, Habermann JK, Schlag PM, Saeger HD, Miehlke S, Stolz T, Model F, Roblick UJ et al (2008) Sensitive detection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. PLoS ONE 3:e3759

    Article  PubMed  PubMed Central  Google Scholar 

  • Haggar FA, Boushey RP (2009) Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors. Clin Colon Rectal Surg 22:191–197

    Article  PubMed  PubMed Central  Google Scholar 

  • Hessami Arani S, Kerachian MA (2017) Rising rates of colorectal cancer among younger Iranians: is diet to blame? Curr Oncol 24:e131–e137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Houshmand M, Abbaszadegan MR, Kerachian MA (2017) Assessment of bone morphogenetic protein 3 methylation in Iranian patients with colorectal cancer. Middle East J Dig Dis 9:158–163

    Article  PubMed  PubMed Central  Google Scholar 

  • Jin P, Kang Q, Wang X, Yang L, Yu Y, Li N, He Y, Han X, Hang J, Zhang J (2015) Performance of a second-generation methylated SEPT9 test in detecting colorectal neoplasm. J Gastroenterol Hepatol 30:830–833

    Article  CAS  Google Scholar 

  • Kamat AA, Bischoff FZ, Dang D, Baldwin MF, Han LY, Lin YG, Merritt WM, Landen CN Jr, Lu C, Gershenson DM et al (2006) Circulating cell-free DNA: a novel biomarker for response to therapy in ovarian carcinoma. Cancer Biol Ther 5:1369–1374

    Article  CAS  PubMed  Google Scholar 

  • Kim HJ, Yu MH, Kim H, Byun J, Lee C (2008) Noninvasive molecular biomarkers for the detection of colorectal cancer. BMB Rep 41:685–692

    Article  CAS  PubMed  Google Scholar 

  • Lamb YN, Dhillon S (2017) Epi proColon® 2.0 CE: a blood-based screening test for colorectal cancer. Mol Diagn Ther 21:225–232

    Article  PubMed  Google Scholar 

  • Lange CP, Laird PW (2013) Clinical applications of DNA methylation biomarkers in colorectal cancer. Epigenomics 5:105–108

    Article  CAS  PubMed  Google Scholar 

  • Lange CP, Campan M, Hinoue T, Schmitz RF, van der Meulen-de Jong AE, Slingerland H, Kok PJ, van Dijk CM, Weisenberger DJ, Shen H et al (2012) Genome-scale discovery of DNA-methylation biomarkers for blood-based detection of colorectal cancer. PLoS ONE 7:e50266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levin B, Lieberman DA, McFarland B, Smith RA, Brooks D, Andrews KS, Dash C, Giardiello FM, Glick S, Levin TR et al. (2008) Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the american cancer society, the US multi-society task force on colorectal cancer, and the american college of radiology. CA Cancer J Clin 58:130–160

    Article  PubMed  Google Scholar 

  • Loh K, Chia JA, Greco S, Cozzi SJ, Buttenshaw RL, Bond CE, Simms LA, Pike T, Young JP, Jass JR et al (2008) Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer development. Genes Chromosomes Cancer 47:449–460

    Article  CAS  PubMed  Google Scholar 

  • Mansour H (2014) Cell-free nucleic acids as noninvasive biomarkers for colorectal cancer detection. Front Genet 5:182

    Article  PubMed  PubMed Central  Google Scholar 

  • Okugawa Y, Grady WM, Goel A (2015) Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology 149:1204–1225.e1212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park SK, Baek HL, Yu J, Kim JY, Yang HJ, Jung YS, Choi KY, Kim H, Kim HO, Jeong KU et al (2017) Is methylation analysis of SFRP2, TFPI2, NDRG4, and BMP3 promoters suitable for colorectal cancer screening in the Korean population? Intest Res 15:495–501

    Article  PubMed  PubMed Central  Google Scholar 

  • Schwarzenbach H, Hoon DS, Pantel K (2011) Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 11:426–437

    Article  CAS  PubMed  Google Scholar 

  • Tanzer M, Balluff B, Distler J, Hale K, Leodolter A, Rocken C, Molnar B, Schmid R, Lofton-Day C, Schuster T et al (2010) Performance of epigenetic markers SEPT9 and ALX4 in plasma for detection of colorectal precancerous lesions. PLoS ONE 5:e9061

    Article  PubMed  PubMed Central  Google Scholar 

  • Wojdacz TK, Dobrovic A (2007) Methylation-sensitive high resolution melting (MS-HRM): a new approach for sensitive and high-throughput assessment of methylation. Nucleic Acids Res 35:e41

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhai RL, Xu F, Zhang P, Zhang WL, Wang H, Wang JL, Cai KL, Long YP, Lu XM, Tao KX et al (2016) The diagnostic performance of stool DNA testing for colorectal cancer: a systematic review and meta-analysis. Medicine (Baltimore) 95:e2129

    Article  CAS  Google Scholar 

  • Zou H, Harrington JJ, Shire AM, Rego RL, Wang L, Campbell ME, Oberg AL, Ahlquist DA (2007) Highly methylated genes in colorectal neoplasia: implications for screening. Cancer Epidemiol Biomark Prev 16:2686–2696

    Article  CAS  Google Scholar 

  • Zou H, Allawi H, Cao X, Domanico M, Harrington J, Taylor WR, Yab T, Ahlquist DA, Lidgard G (2012) Quantification of methylated markers with a multiplex methylation-specific technology. Clin Chem 58:375–383

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported financially by Tabriz University of Medical Sciences, and Reza Radiotherapy and Oncology Center, Mashhad, Iran. Our sincere thanks also go to Mr. Ebrahim Pouladin and Mrs. Nafiseh Shalchi for their close support in CRC research programs. We would also give special thanks to Dr. Abdorasoul Hayatbakhsh, Miss. Maryam Yassi and Adeleh Rezaie, Mrs. Neda Ziafati, and Zohreh Alizadeh for their cooperation in this study.

Funding

This study was supported financially by Tabriz University of Medical Sciences (Grant # 54125388), and Reza Radiotherapy and Oncology Center, Mashhad, Iran.

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Authors and Affiliations

  1. Connective Tissue Research Center, Department of Medical Genetics, Faculty of Medicine and Tabriz Genetic Analysis Centre (TGAC), Tabriz University of Medical Sciences, Tabriz, Iran

    Parisa Rokni & Ebrahim Sakhinia

  2. Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran

    Afsaneh Mojtabanezhad Shariatpanahi & Mohammad Amin Kerachian

  3. Division of Regenerative Medicine, Faculty of Medical and Human Sciences, School of Medicine, The University of Manchester, Manchester, UK

    Ebrahim Sakhinia

  4. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Amin Kerachian

  5. Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Amin Kerachian

Authors
  1. Parisa Rokni
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  2. Afsaneh Mojtabanezhad Shariatpanahi
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  3. Ebrahim Sakhinia
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  4. Mohammad Amin Kerachian
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Corresponding authors

Correspondence to Ebrahim Sakhinia or Mohammad Amin Kerachian.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consents were obtained from all individual participants included in this study.

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Rokni, P., Shariatpanahi, A.M., Sakhinia, E. et al. BMP3 promoter hypermethylation in plasma-derived cell-free DNA in colorectal cancer patients. Genes Genom 40, 423–428 (2018). https://doi.org/10.1007/s13258-017-0644-2

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  • DOI: https://doi.org/10.1007/s13258-017-0644-2

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