We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Research Article

Predicting locus-specific DNA methylation levels in cancer and paracancer tissues

    Shuzheng Zhang

    School of Information Science & Technology, Dalian Maritime University, Dalian, 116026, China

    ,
    Baoshan Ma

    *Author for correspondence:

    E-mail Address: mabaoshan@dlmu.edu.cn

    School of Information Science & Technology, Dalian Maritime University, Dalian, 116026, China

    ,
    Yu Liu

    School of Information Science & Technology, Dalian Maritime University, Dalian, 116026, China

    ,
    Yiwen Shen

    School of Information Science & Technology, Dalian Maritime University, Dalian, 116026, China

    ,
    Di Li

    Department of Neuro Intervention, Dalian Medical University affiliated Dalian Municipal Central Hospital, Dalian, 116033, China

    ,
    Shuxin Liu

    Department of Nephrology, Dalian Medical University affiliated Dalian Municipal Central Hospital, Dalian, 116033, China

    &
    Fengju Song

    Department of Epidemiology & Biostatistics, Key Laboratory of Molecular Cancer Epidemiology, Tianjin, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300060, China

    Published Online:https://doi.org/10.2217/epi-2023-0114

    Aim: To predict base-resolution DNA methylation in cancerous and paracancerous tissues. Material & methods: We collected six cancer DNA methylation datasets from The Cancer Genome Atlas and five cancer datasets from Gene Expression Omnibus and established machine learning models using paired cancerous and paracancerous tissues. Tenfold cross-validation and independent validation were performed to demonstrate the effectiveness of the proposed method. Results: The developed cross-tissue prediction models can substantially increase the accuracy at more than 68% of CpG sites and contribute to enhancing the statistical power of differential methylation analyses. An XGBoost model leveraging multiple correlating CpGs may elevate the prediction accuracy. Conclusion: This study provides a powerful tool for DNA methylation analysis and has the potential to gain new insights into cancer research from epigenetics.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Li E. Chromatin modification and epigenetic reprogramming in mammalian development. Nat. Rev. Genet. 3(9), 662–673 (2002).
    • 2. Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev. Cell 19(5), 698–711 (2010).
    • 3. Koch A, Joosten SC, Feng Z et al. Analysis of DNA methylation in cancer: location revisited. Nat. Rev. Clin. Oncol. 15(7), 459–466 (2018).
    • 4. Das PM, Singal R. DNA methylation and cancer. J. Clin. Oncol. 22(22), 4632–4642 (2004).
    • 5. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10(8), 472–484 (2013).
    • 6. Li ADR, Liu Y, Plott J, Chen L, Montgomery JS, Shih A. Multi-bevel needle design enabling accurate insertion in biopsy for cancer diagnosis. IEEE Trans. Biomed. Eng. 68(5), 1477–1486 (2021).
    • 7. Kashiwagi S, Asano Y, Goto W et al. Optical see-through head-mounted display (OST-HMD)-assisted needle biopsy for breast tumor: a technical innovation. In Vivo 36(2), 848–852 (2022).
    • 8. Santiago L, Candelaria RP, Huang ML. MR imaging-guided breast interventions: indications, key principles, and imaging-pathology correlation. Magn. Reson. Imaging Clin. N. Am. 26(2), 235–246 (2018).
    • 9. Xu W, Liu X, Leng F, Li W. Blood-based multi-tissue gene expression inference with Bayesian ridge regression. Bioinformatics 36(12), 3788–3794 (2020).
    • 10. Okada H, Uza N, Matsumori T et al. A novel technique for mapping biopsy of bile duct cancer. Endoscopy 53(6), 647–651 (2021).
    • 11. Stępniak P, Maycock M, Wojdan K et al. Microarray Inspector: tissue cross contamination detection tool for microarray data. Acta Biochim. Pol. 60(4), 647–655 (2013).
    • 12. Guibert N, Tsukada H, Hwang DH et al. Liquid biopsy of fine-needle aspiration supernatant for lung cancer genotyping. Lung Cancer 122, 72–75 (2018).
    • 13. Masse R, Duvernay J, Korbi S, Majoufre C, Schlund M. Oral carcinoma cuniculatum, a rare variant of squamous cell carcinoma. J. Stomatol. Oral Maxillofac. Surg. 125(4), 101729 (2023).
    • 14. Halin S, Hammarsten P, Adamo H, Wikström P, Bergh A. Tumor indicating normal tissue could be a new source of diagnostic and prognostic markers for prostate cancer. Expert Opin. Med. Diagn. 5(1), 37–47 (2011). • A biopsy of prostate cancer commonly contains only normal prostate tissue.
    • 15. Ogawa T, Ito K, Koshita S et al. Usefulness of cholangioscopic-guided mapping biopsy using SpyGlass DS for preoperative evaluation of extrahepatic cholangiocarcinoma: a pilot study. Endosc. Int. Open 6(2), e199–e204 (2018).
    • 16. Deftereos G, Sandoval A, Furtado LV, Bronner M, Matynia AP. Successful lung cancer EGFR sequencing from DNA extracted from TTF-1 immunohistochemistry slides: a new means to extend insufficient tissue. Hum. Pathol. 97, 52–59 (2020).
    • 17. Teschendorff A, Gao Y, Jones A et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat. Commun. 7, 10478 (2016).
    • 18. Møller M, Strand SH, Mundbjerg K et al. Heterogeneous patterns of DNA methylation-based field effects in histologically normal prostate tissue from cancer patients. Sci. Rep. 7(1), 1–14 (2017).
    • 19. Hsu C-H, Hsiao C-W, Sun C-A et al. Multiple gene promoter methylation and clinical stage in adjacent normal tissues: effect on prognosis of colorectal cancer in Taiwan. Sci. Rep. 10(1), 1–11 (2020).
    • 20. Johnson KC, Houseman EA, King JE, Christensen BC. Normal breast tissue DNA methylation differences at regulatory elements are associated with the cancer risk factor age. Breast Cancer Res. 19(1), 81 (2017).
    • 21. Sun JX, He Y, Sanford E et al. A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal. PLoS Comp. Biol. 14(2), e1005965 (2018). • A key constraint in genomic testing in oncology is that matched normal specimens are not commonly obtained in clinical practice.
    • 22. Utsunomiya T, Ishikawa D, Asanoma M et al. Specific miRNA expression profiles of non-tumor liver tissue predict a risk for recurrence of hepatocellular carcinoma. Hepatol. Res. 44(6), 631–638 (2014).
    • 23. Tomimaru Y, Sasaki Y, Yamada T et al. Fibrosis in non-cancerous tissue is the unique prognostic factor for primary hepatocellular carcinoma without hepatitis B or C viral infection. World J. Surg. 30(9), 1729–1735 (2006).
    • 24. Gao K, Zhang F, Chen K et al. Expression patterns and prognostic value of RUNX genes in kidney cancer. Sci. Rep. 11(1), 14934 (2021).
    • 25. Pan R, Zhou C, Dai J et al. Endothelial PAS domain protein 1 gene hypomethylation is associated with colorectal cancer in Han Chinese. Exp. Ther. Med. 16(6), 4983–4990 (2018).
    • 26. Jia Z, Wang Y, Xue J et al. DNA methylation patterns at and beyond the histological margin of early-stage invasive lung adenocarcinoma radiologically manifested as pure ground-glass opacity. Clin. Epigenetics 13(1), 153 (2021).
    • 27. Byun HM, Siegmund KD, Pan F, Weisenberger DJ, Yang AS. Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Hum. Mol. Genet. 18(24), 4808–4817 (2009).
    • 28. Edgar RD, Jones MJ, Meaney MJ, Turecki G, Kobor MS. BECon: a tool for interpreting DNA methylation findings from blood in the context of brain. Transl. Psychiatry 7(8), e1187 (2017).
    • 29. Smith AK, Kilaru V, Klengel T et al. DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am. J. Med. Genet. B Neuropsychiatr. Genet. 168(1), 36–44 (2015).
    • 30. Lee Y-S, Zhang H, Jiang Y et al. Epigenome-scale comparison of DNA methylation between blood leukocytes and bronchial epithelial cells. Epigenomics 13(7), 485–498 (2021).
    • 31. Abraham JE, Maranian MJ, Spiteri I et al. Saliva samples are a viable alternative to blood samples as a source of DNA for high throughput genotyping. BMC Med. Genomics 5(1), 1–6 (2012).
    • 32. De Carli MM, Baccarelli AA, Trevisi L et al. Epigenome-wide cross-tissue predictive modeling and comparison of cord blood and placental methylation in a birth cohort. Epigenomics 9(3), 231–240 (2017).
    • 33. Ma B, Allard C, Bouchard L et al. Locus-specific DNA methylation prediction in cord blood and placenta. Epigenetics 14(4), 405–420 (2019). •• This study built prediction models for placenta methylation based on cord blood data.
    • 34. Ma B, Wilker EH, Willis-Owen SA et al. Predicting DNA methylation level across human tissues. Nucleic Acids Res. 42(6), 3515–3528 (2014). •• Using DNA methylation in easy-to-access tissues to predict DNA methylation in hard-to-access tissues is very meaningful.
    • 35. Chen T, Guestrin C. XGBoost: a scalable tree boosting system. In: Proceedings of the 22nd ACM SIGKDD International Conference on Knowledge Discovery and Data Mining. Association for Computing Machinery, NY, USA, 785–794 (2016).
    • 36. Li W, Yin Y, Quan X, Zhang H. Gene expression value prediction based on XGBoost algorithm. Front. Genet. 10, 1077 (2019).
    • 37. Ma B, Chai B, Dong H et al. Diagnostic classification of cancers using DNA methylation of paracancerous tissues. Sci. Rep. 12(1), 10646 (2022).
    • 38. Zhou W, Triche TJ Jr, Laird PW, Shen H. SeSAMe: reducing artifactual detection of DNA methylation by Infinium BeadChips in genomic deletions. Nucleic Acids Res. 46(20), e123 (2018).
    • 39. Zhou W, Laird PW, Shen H. Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes. Nucleic Acids Res. 45(4), e22 (2017).
    • 40. Chen YA, Lemire M, Choufani S et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics 8(2), 203–209 (2013).
    • 41. Vapnik VN. An overview of statistical learning theory. IEEE Trans. Neural Netw. 10(5), 988–999 (1999).
    • 42. Bell JT, Pai AA, Pickrell JK et al. DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol. 12(1), R10 (2011).
    • 43. Cecilia L, Dodd IB, Kim S, Haerter JO. DNA methylation in human epigenomes depends on local topology of CpG sites. Nucleic Acids Res. 44(11), 5123–5132 (2016).
    • 44. Eckhardt F, Lewin J, Cortese R et al. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat. Genet. 38(12), 1378–1385 (2006).
    • 45. Morris TJ, Butcher LM, Feber A et al. ChAMP: 450k chip analysis methylation pipeline. Bioinformatics 30(3), 428–430 (2014).
    • 46. Phipson B, Maksimovic J, Oshlack A. missMethyl: an R package for analyzing data from Illumina's HumanMethylation450 platform. Bioinformatics 32(2), 286–288 (2016).
    • 47. Sato T, Arai E, Kohno T et al. Epigenetic clustering of lung adenocarcinomas based on DNA methylation profiles in adjacent lung tissue: its correlation with smoking history and chronic obstructive pulmonary disease. Int. J. Cancer 135(2), 319–334 (2014).
    • 48. Robin X, Turck N, Hainard A et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics 12(1), 1–8 (2011).
    • 49. Çalışkan M, Cusanovich DA, Ober C, Gilad Y. The effects of EBV transformation on gene expression levels and methylation profiles. Hum. Mol. Genet. 20(8), 1643–1652 (2011).
    • 50. Sandoval J, Heyn H, Moran S et al. Validation of a DNA methylation microarray for 450,000 CpG sites in the human genome. Epigenetics 6(6), 692–702 (2011).
    • 51. Hachiya T, Furukawa R, Shiwa Y et al. Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies. NPJ Genom. Med. 2(1), 1–14 (2017).
    • 52. Du L, Pertsemlidis A. Cancer and neurodegenerative disorders: pathogenic convergence through microRNA regulation. J. Mol. Cell Biol. 3(3), 176–180 (2011).
    • 53. Li H, Siddiqui O, Zhang H, Guan Y. Joint learning improves protein abundance prediction in cancers. BMC Biol. 17(1), 107 (2019).
    • 54. Cokus SJ, Feng S, Zhang X et al. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning. Nature 452(7184), 215–219 (2008).
    • 55. Fang F, Fan S, Zhang X, Zhang MQ. Predicting methylation status of CpG islands in the human brain. Bioinformatics 22(18), 2204–2209 (2006). •• It is necessary to develop in silico approaches for predicting methylation status of CpG islands.
    • 56. Jones, Peter A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13(7), 484–492 (2012).
    • 57. Irizarry RA, Laddacosta C, Wen B et al. Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 41(2), 178–186 (2009).
    • 58. Meng J, Gao L, Zhang M, Gao S, Fan S, Liang C. Systematic investigation of the prognostic value of cell division cycle-associated proteins for clear cell renal cell carcinoma patients. Biomark. Med. 14(3), 223–238 (2020).
    • 59. Angermueller C, Lee HJ, Reik W, Stegle O. DeepCpG: accurate prediction of single-cell DNA methylation states using deep learning. Genome Biol. 18(1), 67 (2017).
    • 60. Ni P, Huang N, Zhang Z et al. DeepSignal: detecting DNA methylation state from Nanopore sequencing reads using deep-learning. Bioinformatics 35(22), 4586–4595 (2019).
    • 61. Wu C, Yao S, Li X, Chen C, Hu X. Genome-wide prediction of DNA methylation using DNA composition and sequence complexity in human. Int. J. Mol. Sci. 18(2), 420 (2017).
    • 62. Luo X, Wang F, Wang G, Zhao Y. Identification of methylation states of DNA regions for Illumina methylation BeadChip. BMC Genomics 21(1), 1–10 (2020).
    • 63. Tian Q, Zou J, Tang J, Fang Y, Yu Z, Fan S. MRCNN: a deep learning model for regression of genome-wide DNA methylation. BMC Genomics 20(2), 1–10 (2019).
    • 64. Rao JS, Zhang H, Kobetz E, Aldrich MC, Conway D. Predicting DNA methylation from genetic data lacking racial diversity using shared classified random effects. Genomics 113(1 Pt 2), 1018–1028 (2021).
    • 65. Fu L, Peng Q, Chai L. Predicting DNA methylation states with hybrid information based deep-learning model. IEEE/ACM Trans. Comput. Biol. Bioinform. 17(5), 1721–1728 (2019).
    • 66. Zhang W, Spector TD, Deloukas P, Bell JT, Engelhardt BE. Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements. Genome Bio. 16(1), 14 (2015). • This research characterized genome-wide DNA methylation patterns and built a random forest classifier to predict methylation levels based on multiple features.
    • 67. Tang J, Zou J, Zhang X et al. PretiMeth: precise prediction models for DNA methylation based on single methylation mark. BMC Genomics 21(1), 1–15 (2020).
    • 68. Bock C, Walter J, Paulsen M, Lengauer T. CpG island mapping by epigenome prediction. PLoS Comput. Biol. 3(6), e110 (2007).
    • 69. Bock C, Paulsen M, Tierling S, Mikeska T, Lengauer T, Walter J. CpG island methylation in human lymphocytes is highly correlated with DNA sequence, repeats, and predicted DNA structure. PLoS Genet. 2(3), e26 (2006).
    • 70. Zheng H, Wu H, Li J, Jiang S-W. CpGIMethPred: computational model for predicting methylation status of CpG islands in human genome. BMC Med. Genomics 6(1), 1–12 (2013).
    • 71. Fan S, Zhang MQ, Zhang X. Histone methylation marks play important roles in predicting the methylation status of CpG islands. Biochem. Biophys. Res. Commun. 374(3), 559–564 (2008).
    • 72. Feltus FA, Lee EK, Costello JF, Plass C, Vertino PM. Predicting aberrant CpG island methylation. Proc. Natl Acad. Sci. U. S. A. 100(21), 12253–12258 (2003).
    • 73. Das R, Dimitrova N, Xuan Z et al. Computational prediction of methylation status in human genomic sequences. Proc. Natl Acad. Sci. U. S. A. 103(28), 10713–10716 (2006).
    • 74. Hazra A, Gogtay N. Biostatistics series module 6: correlation and linear regression. Indian J. Dermatol. 61(6), 593–601 (2016).
    • 75. Hansen KD, Timp W, Bravo HC et al. Increased methylation variation in epigenetic domains across cancer types. Nat. Genet. 43(8), 768–775 (2011).