Diabetes and Cancer Biomarkers: Cell-Free DNA and RNA

Yıl 2026, Cilt: 48 Sayı: 2, 408 - 415, 11.02.2026

Sema Bolkent

https://doi.org/10.20515/otd.1790136

https://izlik.org/JA79LL72GN

Öz

This review focuses on cell-free (cf)DNA and cfRNA biomarkers, describing the latest developments in their application to diabetes and various cancers. Both diabetes and cancer involve several shared pathophysiological pathways, including chronic inflammation, oxidative stress, and epigenetic changes. These changes can be detected in blood or other bodily fluids, which are referred to as liquid biopsies. cfDNA reflects the various molecular characteristics e.g., methylation of the origin tissue. cfRNA biomarkers such as messenger(m)RNA, micro(mi)RNA, circular RNA, long non-coding RNA, indicate the post-transcriptional modifications and expression characteristics of RNAs. In recent years, circulating cf- DNA methylation, mRNA, and miRNAs have been identified as potential cancer biomarkers. cfDNA analysis studies utilize technologies and a variety of methods including polymerase chain reaction-based single-locus tests as well as genome-wide next-generation sequencing. The isolation of circulating tumor (t)DNA from blood or urine is a proposed non-invasive molecular diagnostic method for understanding tumor biology and monitoring treatment response. Circulating unmethylated insulin DNA is considered a diabetes biomarker as it is associated with human beta cell death. Liquid biopsies show promise in the non-invasive detection of tissue-specific pathologies and offer a variety of potential clinical applications. As technology advances and more evidence emerges, cell-free nucleic acids may become the preferred method for diagnosing and personalizing treatment of cancer and diabetes innovatively.

Anahtar Kelimeler

Cell-free DNA and RNA , liquid biopsy , biomarkers , diabetes , cancer

Diyabet ve Kanser Biyobelirteçleri: Hücre Dışı DNA ve RNA

https://izlik.org/JA79LL72GN

Öz

Bu derleme, hücre dışı (hd) DNA ve hdRNA biyobelirteçlerine odaklanarak bunların diyabet ve çeşitli kanserlerde kullanımına ilişkin gelişmeleri açıklamaktadır. Diyabet ve kanser hastalıklarının ortak patofizyolojik yolları olarak kronik inflamasyon, oksidatif stres ve epigenetik değişiklikler sayılabilir. Bu değişikliklerin saptanmasında yaygın olarak kullanılan kan ve diğer vücut sıvıları sıvı biyopsi olarak adlandırılmıştır. hdDNA, köken dokunun çeşitli moleküler özelliklerini örneğin, metilasyonunu yansıtır. hdRNA biyobelirteçleri olarak haberci(m)RNA, mikro(mi)RNA, dairesel RNA, uzun kodlamayan RNA gibi moleküller RNA'ların transkripsiyon sonrası değişikliklerini ve ekspresyon özelliklerini gösterir. Son yıllarda dolaşımdaki hdDNA metilasyonu, mRNA ve miRNA’lar potansiyel kanser biyobelirteçleri olarak tanımlanmaktadır. hdDNA inceleme çalışmalarında, polimeraz zincir reaksiyonu temelli tek lokus analizleri yanı sıra genom çapında yeni nesil dizileme gibi çeşitli yöntemler ve teknolojiler de kullanılmaktadır. Kan veya idrardan izole edilen dolaşımdaki tümör (t)DNA’sı, tümörün biyolojik davranışını anlamak ve tedaviye yanıtı izlemek için invaziv olmayan moleküler tanı yöntemi olarak önerilmektedir. Dolaşımdaki metillenmemiş insülin DNA'sı insan β hücre ölümü ile ilişkili olduğundan diyabet hastalığının biyobelirteci olarak düşünülmektedir. Sıvı biyopsiler, dokuya özgü patolojilerin minimal invaziv tespiti konusunda umut vaat etmekte ve çeşitli potansiyel klinik uygulamalar sunmaktadır. Teknoloji ilerledikçe ve daha fazla kanıt ortaya çıktıkça, serbest nükleik asitler kanser ve diyabetin yenilikçi bir şekilde teşhis ve kişisel tedavisi için tercih edilen yöntemler haline gelebilir.

Anahtar Kelimeler

Hücre dışı DNA ve RNA , Sıvı biyopsi , Biyobelirteç , Diyabet , Kanser

Kaynakça

• 1. Suzuki N, Kamataki A, Yamaki J, Homma Y. Characterization of circulating DNA in healthy human plasma. Clin Chim Acta. 2008;387(1-2):55-8.
• 2. Eibl RH, Schneemann M. Cell-free DNA as a biomarker in cancer. Extracell Vesicles Circ Nucl Acids. 2022;3:195-215.
• 3. Su JY, Wang YL, Hsieh YT, Chang YC, Yang CH, Kang Y, et al. Multiplexed assays of human disease-relevant mutations reveal UTR dinucleotide composition as a major determinant of RNA stability. Elife. 2025;13:RP97682.
• 4. De Sota RE, Quake SR, Sninsky JJ, Toden S. Decoding bioactive signals of the RNA secretome: the cell-free messenger RNA catalogue. Expert Rev Mol Med. 2024;26:e12.
• 5. https://health.uconn.edu/pepper-center/wp-content/uploads/sites/272/2023/12/BEST-Biomarkers-EndpointS-and-other-Tools-Resource.pdf
• 6. Guo CJ, Xu G, Chen LL. Mechanisms of long noncoding RNA nuclear retention. Trends Biochem Sci. 2020;45(11):947-960.
• 7. Dennis Lo YM, Diana S, Jiang P, Chiu WK. Epigenetics, fragmentomics, and topology of cell-free DNA in liquid biopsies. Science 2021;372(6538).
• 8. Akirav EM, Lebastchi J, Galvan EM, Henegariu O, Akirav M, Ablamunits V, et al. Detection of β cell death in diabetes using differentially methylated circulating DNA. 2011; 108 (47) 19018-19023.
• 9. Chu JL, Bi SH, He Y, Ma RY, Wan XY, Wang ZH, et al. 5-Hydroxymethylcytosine profiles in plasma cell-free DNA reflect molecular characteristics of diabetic kidney disease. Front Endocrinol. 2022;13:910907.
• 10. Jiang Y, Sun J, Chen Y, Cheng L, Feng S, Wang Y. et al. NSUN2-mediated RNA m5C modification drives multiple myeloma progression by enhancing the stability of HIP1 mRNA. Sci Rep. 2025; 15: 27888.
• 11. Li B, Gan J, Li T, Chen J, Kuanh Y, Li J, et al. Comprehensive analysis of RNA methylation-related genes to identify molecular cluster for predicting prognosis and immune profiles in bladder cancer. Sci Rep. 2025;15, 9147.
• 12. Zaporozhchenko IA, Ponomaryova AA, Rykova EY, Laktionov PP. The potential of circulating cell-free RNA as a cancer biomarker: challenges and opportunities. Expert Rev Mol Diagn. 2018;18(2):133-145.
• 13. Jin N, Kan CM, Pei XM, Cheung WL, Ng SSM, Wong HT, et al. Cell-free circulating tumor RNAs in plasma as the potential prognostic biomarkers in colorectal cancer. Front Oncol. 2023;13:1134445.
• 14. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 2008;141(5):672-5.
• 15. Sahin Y. LncRNA H19 is a potential biomarker and correlated with immune infiltration in thyroid carcinoma. Clin Exp Med. 2023 Jul;23(3):841-851.
• 16. Zhang N, Geng T, Wang Z, Zhang R, Cao T, Camporez JP, et al. Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia. JCI Insight. 2018 ;3(10):e120304.
• 17. Xu H, Guo S, Li W, Yu P. The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells. Sci Rep. 2015;27;5:12453.
• 18. Su H, Lin F, Deng X, Shen L, Fang Y, Fei Z, et al. Profiling and bioinformatics analyses reveal differential circular RNA expression in radioresistant esophageal cancer cells. J Transl Med. 2016; 28;14(1):225.
• 19. Xie H, Ren X, Xin S, Lan X, Lu G, Lin Y, et al. Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer. Oncotarget. 2016; 3;7(18):26680-91.
• 20. Wan L, Zhang L, Fan K, Cheng ZX, Sun QC, Wang JJ. Circular RNA-ITCH suppresses lung cancer proliferation via inhibiting the Wnt/β-catenin pathway. Biomed Res Int. 2016; 1579490.
• 21. Barutta F, Bruno G, Matullo G, Chaturvedi N, Grimaldi S, Schalkwijk C, et al. MicroRNA-126 and micro-/macrovascular complications of type 1 diabetes in the EURODIAB Prospective Complications Study. Acta Diabetol. 2017;54(2):133-139.
• 22. Sun Y, Zhou Y, Shi Y, Zhang Y, Liu K, Liang R, et al. Expression of miRNA-29 in pancreatic β cells promotes inflammation and diabetes via TRAF3. Cell Rep. 2021;34(1):108576.
• 23. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646-50.
• 24. Underhill HR, Kitzman JO, Hellwig S, Welker NC, Daza R, Baker DN, et. al. Fragment length of circulating tumor DNA. PLoS Genet. 2016;12(7):e1006162.
• 25. https://www.fda.gov/drugs/resources-information-approved-drugs/cobas-egfr-mutation-test-v2 (Accessed on 12 January 2026).
• 26. Volckmar AL, Sültmann H, Riediger A, Fioretos T, Schirmacher P, Endris V, et al. A field guide for cancer diagnostics using cell-free DNA: From principles to practice and clinical applications. Genes Chromosomes Cancer. 2018;57(3):123-139.
• 27. Bettegowda C, Sausen M, Leary RC, Kinde I, Wang Y, Agrawal N et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014 19;6(224):224ra24.
• 28. Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, et al. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015;9(9):1773-82.
• 29. Tchekmedyian N, Mudad R, Blanco FF, Raymond VM, Garst J, Erlander MG, et al. Longitudinal monitoring of ctDNA EGFR mutation burden from urine correlates with patient response to EGFR TKIs: A case series. Lung Cancer. 2017;108:22-28.
• 30. Sun Q, Long L. Diagnostic performances of methylated septin9 gene, CEA, CA19-9 and platelet-to-lymphocyte ratio in colorectal cancer. BMC Cancer. 2024;24(1):906.
• 31. Ju J, Zhao X, An Y, Yang M, Zhang Z, Liu X, et al. Cell-free DNA end characteristics enable accurate and sensitive cancer diagnosis. Cell Rep Methods. 2024;4(10):100877.
• 32. Hou Y, Meng XY, Zhou X. Systematically evaluating cell-free DNA fragmentation patterns for cancer diagnosis and enhanced cancer detection via integrating multiple fragmentation patterns. Adv Sci (Weinh). 2024;11(30):e2308243.
• 33. Mathios D, Niknafs N, Annapragada AV, Bobeff EJ, Chiao EJ, Boyapati K, et al. Detection of brain cancer using genome-wide cell-free DNA fragmentomes. Cancer Discov. 2025 ;15(8):1593-1608.
• 34. Asif R, Khalid A, Mercantepe T, Klisic A, Rafaqat S, Rafaqat S, et al. Role of interleukins in type 1 and type 2 diabetes. Diagnostics (Basel). 2025;15(15):1906.
• 35. Lu J, Liu J, Li L, Lan Y, Liang Y. Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets. Clin Transl Immunology. 2020;9(3):e1122.
• 36. Belinda A, Humardani FM, Dwi Putra SE, Widyadhana B. The potential of circulating free DNA of methylated IGFBP as a biomarker for type 2 diabetes mellitus: A Comprehensive review. Clin Chim Acta. 2025;567:120104.
• 37. Karaglani M, Panagopoulou M, Cheimonidi C, Tsamardinos I, Maltezos E, Papanas N, et al. Liquid biopsy in type 2 diabetes mellitus management: Building specific biosignatures via machine learning. J Clin Med. 2022;11(4):1045.
• 38. Yu C, Lin Y, Luo Y, Guo Y, Ye Z, Ou R, et. al. The fragmentomic property of plasma cell-free DNA enables the non-invasive detection of diabetic nephropathy in patients with diabetes mellitus. Front Endocrinol (Lausanne).2023;14:1164822.
• 39. Speake C, Ylescupidez A, Neiman D, Shemer R, Glaser B, Tersey SA, et al. Circulating unmethylated insulin DNA as a biomarker of human beta cell death: A multi-laboratory assay comparison. J Clin Endocrinol Metab. 2020;105(3):781–91.
• 40. Syed F, Tersey S A, Turatsinze J V, Felton J L, Kang N J, Nelson J B, et al. Circulating unmethylated CHTOP and INS DNA fragments provide evidence of possible islet cell death in youth with obesity and diabetes. In: Fekadu Gadissa, editor. Prime Archives in Genetics: 2nd Edition. Hyderabad, India: Vide Leaf. 2021.
• 41. Nesic M, Bødker JS, Terp SK, Dybkær K. Optimization of preanalytical variables for cfDNA processing and detection of ctDNA in archival plasma samples. Biomed Res Int. 2021; 2021:5585148.
• 42. Rothwell DG, Smith N, Morris D, Leong HS, Li Y, Hollebecque A, et al. Genetic profiling of tumours using both circulating free DNA and circulating tumour cells isolated from the same preserved whole blood sample. Mol Oncol. 2016;10(4):566-74.
• 43. Kang Q, Henry NL, Paoletti C, Jiang H, Vats P, Chinnaiyan AM, et al. Comparative analysis of circulating tumor DNA stability In K3EDTA, Streck, and CellSave blood collection tubes. Clin Biochem. 2016;49(18):1354-1360.
• 44. Diefenbach RJ, Lee JH, Kefford RF, Rizos H. Evaluation of commercial kits for purification of circulating free DNA. Cancer Genet. 2018;228-229:21-27.
• 45. Page K, Guttery DS, Zahra N, Primrose L, Elshaw SR, Pringle JH, et al. Influence of plasma processing on recovery and analysis of circulating nucleic acids. PLoS ONE 2013; 8(10): e77963.
• 46. Meddeb R, Pisareva E, Thierry AR. Guidelines for the preanalytical conditions for analyzing circulating cell-free DNA. Clin Chem. 2019;65(5):623-633.
• 47. Oellerich M, Christenson RH, Beck J, Schütz E, Sherwood K, Price CP, et al. Donor-derived cell-free DNA testing in solid organ transplantation: A value proposition. J Appl Lab Med. 2020;5(5):993-1004.
• 48. Gunning A, Kumar S, Williams CK, Berger BM, Naber SP, Gupta PB, et al. Analytical validation of NavDx, a cfDNA-based fragmentomic profiling assay for HPV-driven cancers. Diagnostics (Basel). 2023;13(4):725.
• 49. Nesselbush MC, Luca BA, Jeon YJ, Jabara I, Meador CB, Garofalo A, et al. An ultrasensitive method for detection of cell-free RNA. Nature. 2025;641(8063):759-768.
• 50. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, et al. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem. 2011;83(22):8604-10.
• 51. Corcoran RB, Chabner BA. Application of cell-free DNA analysis to cancer treatment. N Engl J Med. 2018;379(18):1754-1765.
• 52. Rossi G, Mu Z, Rademaker AW, Austin LK, Strickland KS, Costa RLB, et al. Cell-free DNA and circulating tumor cells: Comprehensive liquid biopsy analysis in advanced breast cancer. Clin Cancer Res. 2018;24(3):560-568.
• 53. Huang TY, Piunti A, Lulla RR, Qi J, Horbinski CM, Tomita T, et al. Detection of histone H3 mutations in cerebrospinal fluid-derived tumor DNA from children with diffuse midline glioma. Acta Neuropathol Commun. 2017;5(1):28.
• 54. Sui S, Xu C, Kanda M, Okugawa Y, Toiyama Y, Park JO, et al. Exosomal liquid biopsy for the early detection of gastric cancer: The DESTINEX multicenter study. JAMA Surg. 2025; Jul 30:e252493.
• 55. Zhang Q, Du Z, Wang X, Li F, Liu Y, Sun J, et al. Cell-free nucleic acid as promising diagnostic biomarkers for gastric cancer: a systematic review. J Cancer. 2024;15(10):2900-2912.
• 56. Abu-Toamih Atamni HJ, Shapira G, Ortenberg R, Sultan M, Twito O, Yoseph-Barzilay L, Shomron N, Rashid G. Circulating microRNA signatures as potential biomarkers differentiating diabetic, prediabetic, and healthy individuals. Front Endocrinol (Lausanne). 2025;16:1699100.
• 57. Reggiardo RE, Maroli SV, Peddu V, Davidson AE, Hill A, LaMontagne E, et al. Profiling of repetitive RNA sequences in the blood plasma of patients with cancer. Nat Biomed Eng. 2023;7(12):1627-1635.
• 58. Khojah R, Reggiardo RE, Ozen M, Maroli SV, Carrillo D, Demirci U, et al. Extracellular RNA signatures of mutant KRAS(G12C) lung adenocarcinoma cells. BioRxiv Feb 24, 2022.
• 59. Fettke H, Kwan EM, Docanto MM, Bukczynska P, Ng N, Graham LK, et al. Combined cell-free DNA and RNA profiling of the androgen receptor: Clinical utility of a novel multianalyte liquid biopsy assay for metastatic prostate cancer. Eur Urol. 2020;78(2):173-180.
• 60. Roperch JP, Hennion C. A novel ultra-sensitive method for the detection of FGFR3 mutations in urine of bladder cancer patients -Design of the Urodiag® PCR kit for surveillance of patients with non-muscle-invasive bladder cancer (NMIBC). BMC Med Genet. 2020;21(1):112.
• 61. Ahmad I, Suhail M, Ahmad A, Alhosin M, Tabrez S. Interlinking of diabetes mellitus and cancer: An overview. Cell Biochem Funct. 2023;41(5):506-516.
• 62. García-Jiménez C, García-Martínez JM, Chocarro-Calvo A, De la Vieja A. A new link between diabetes and cancer: enhanced WNT/β-catenin signaling by high glucose. J Mol Endocrinol. 2013 Dec 19;52(1):R51-66.
• 63. Gurney J, Stanley J, Teng A, Krebs J, Koea J, Lao C, et al. Cancer and diabetes co-occurrence: A national study with 44 million person-years of follow-up. PLoS One. 2022;17(11):e0276913.
• 64. Zhu B, Qu S. The relationship between diabetes mellitus and cancers and its underlying mechanisms. Front Endocrinol (Lausanne). 2022;13:800995.
• 65. Li Y, Gu S, Li X, Huang Q. To identify biomarkers associated with the transfer of diabetes combined with cancer in human genes using bioinformatics analysis. Medicine (Baltimore). 2023;102(37):e35080.
• 66. Fagery M, Khorshidi HA, Wong SQ, Vu M, IJzerman M. Health economic evidence and modeling challenges for liquid biopsy assays in cancer management: A systematic literature review. Pharmacoeconomics. 2023;41(10):1229-1248.
• 67. Phuong LN, Salas S, Benzekry S. Computational modeling for circulating cell-free DNA in clinical oncology. JCO Clin Cancer Inform. 2025;9:e2400224.
• 68. https://www.accessdata.fda.gov/cdrh_docs/pdf13/P130001C.pdf (Accessed on 12 January 2026).
• 69. https://www.accessdata.fda.gov/cdrh_docs/pdf19/P190032C.pdf (Accessed on 12 January 2026).
• 70. Woodhouse R, Li M, Hughes J, Delfosse D, Skoletsky J, Ma P, et al. Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin. PLoS One. 2020;15(9):e0237802.
• 71. Zhang X, Li J, Zhuang Z, Wang J, Bu Z, Lan X. Challenges and prospects of cell-free DNA in precision oncology. Medicine Plus. 2024,1:4.100059.
• 72. Yuan T, Huang X, Woodcock M, Du M, Dittmar R, Wang Y, et al. Plasma extracellular RNA profiles in healthy and cancer patients. Sci Rep. 2016;6:19413.
• 73. Yang Y, Zeng C, Lu X, Song Y, Nie J, Ran R, et al. 5-Hydroxymethylcytosines in circulating cell-free DNA reveal vascular complications of type 2 diabetes. Clin Chem. 2019;65(11):1414-1425.
• 74. Hsu CL, Chang YS, Li HP. Molecular diagnosis of nasopharyngeal carcinoma: Past and future. Biomed J. 2025;48(1):100748.
• 75. Albitar M, Zhang H, Charifa A, Ip A, Ma W, McCloskey J, et al. Combining cell-free RNA with cell-free DNA in liquid biopsy for hematologic and solid tumors. Heliyon. 2023;9(5):e16261..