Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular Diagnostics

Non-coding RNAs as liquid biopsy biomarkers in cancer

Subjects

Abstract

Although non-coding RNAs have long been considered as non-functional “junk” RNAs, accumulating evidence in the past decade indicates that they play a critical role in pathogenesis of various cancers. In addition to their biological significance, the recognition that their expression levels are frequently dysregulated in multiple cancers have fueled the interest for exploiting their clinical potential as cancer biomarkers. In particular, microRNAs (miRNAs), a subclass of small non-coding RNAs that epigenetically modulate gene-transcription, have become one of the most well-studied substrates for the development of liquid biopsy biomarkers for cancer patients. The emergence of high-throughput sequencing technologies has enabled comprehensive molecular characterisation of various non-coding RNA expression profiles in multiple cancers. Furthermore, technological advances for quantifying lowly expressed RNAs in the circulation have facilitated robust identification of previously unrecognised and undetectable biomarkers in cancer patients. Here we summarise the latest progress on the utilisation of non-coding RNAs as non-invasive cancer biomarkers. We evaluated the suitability of multiple non-coding RNA types as blood-based cancer biomarkers and examined the impact of recent technological breakthroughs on the development of non-invasive molecular biomarkers in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: An overview of blood-based noncoding RNA cancer biomarker development.
Fig. 2: Molecular biomarker types in cancer.

Similar content being viewed by others

References

  1. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A. Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013;10:472–84.

    Article  CAS  PubMed  Google Scholar 

  2. Ignatiadis M, Lee M, Jeffrey SS. Circulating tumor cells and circulating tumor DNA: challenges and opportunities on the path to clinical utility. Clin Cancer Res. 2015;21:4786–4800.

    Article  CAS  PubMed  Google Scholar 

  3. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer. 2011;11:426–37.

    Article  CAS  PubMed  Google Scholar 

  4. Toiyama Y, Okugawa Y, Fleshman J, Richard Boland C, Goel A. MicroRNAs as potential liquid biopsy biomarkers in colorectal cancer: A systematic review. Biochim Biophys Acta Rev Cancer. 2018;1870:274–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wada, Y, Shimada, M, Murano, T, Takamaru, H, Morine, Y, Ikemoto, T et al. A liquid biopsy assay for noninvasive identification of lymph node metastases in T1 colorectal cancer. Gastroenterology. 2021;161:151–62.e1.

  6. Campos-Carrillo A, Weitzel JN, Sahoo P, Rockne R, Mokhnatkin JV, Murtaza M, et al. Circulating tumor DNA as an early cancer detection tool. Pharm Ther. 2020;207:107458.

    Article  CAS  Google Scholar 

  7. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6:224ra224.

    Article  CAS  Google Scholar 

  8. Shigeyasu K, Toden S, Zumwalt TJ, Okugawa Y, Goel A. Emerging Role of MicroRNAs as Liquid Biopsy Biomarkers in Gastrointestinal Cancers. Clin Cancer Res. 2017;23:2391–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zen K, Zhang CY. Circulating microRNAs: a novel class of biomarkers to diagnose and monitor human cancers. Med Res Rev. 2012;32:326–48.

    Article  PubMed  CAS  Google Scholar 

  10. Volovat SR, Volovat C, Hordila I, Hordila DA, Mirestean CC, Miron OT, et al. MiRNA and LncRNA as Potential Biomarkers in Triple-Negative Breast Cancer: A Review. Front Oncol. 2020;10:526850.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Dvinge H, Git A, Gräf S, Salmon-Divon M, Curtis C, Sottoriva A, et al. The shaping and functional consequences of the microRNA landscape in breast cancer. Nature. 2013;497:378–82.

    Article  CAS  PubMed  Google Scholar 

  12. Niknafs YS, Han S, Ma T, Speers C, Zhang C, Wilder-Romans K, et al. The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression. Nat Commun. 2016;7:12791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu S, Kong D, Chen Q, Ping Y, Pang D. Oncogenic long noncoding RNA landscape in breast cancer. Mol Cancer. 2017;16:129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Toden S, Zumwalt TJ, Goel A. Non-coding RNAs and potential therapeutic targeting in cancer. Biochim Biophys Acta Rev Cancer. 2021;1875:188491.

    Article  CAS  PubMed  Google Scholar 

  15. Pauli A, Rinn JL, Schier AF. Non-coding RNAs as regulators of embryogenesis. Nat Rev Genet. 2011;12:136–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jung G, Hernandez-Illan E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol. 2020;17:111–30.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Link A, Balaguer F, Shen Y, Nagasaka T, Lozano JJ, Boland CR, et al. Fecal MicroRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol Biomark Prev. 2010;19:1766–74.

    Article  CAS  Google Scholar 

  18. Okugawa Y, Toiyama Y, Goel A. An update on microRNAs as colorectal cancer biomarkers: where are we and what’s next? Expert Rev Mol Diagn. 2014;14:999–1021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lan H, Lu H, Wang X, Jin H. MicroRNAs as potential biomarkers in cancer: opportunities and challenges. Biomed Res Int. 2015;2015:125094.

    PubMed  PubMed Central  Google Scholar 

  20. Brase JC, Wuttig D, Kuner R, Sültmann H. Serum microRNAs as non-invasive biomarkers for cancer. Mol Cancer. 2010;9:306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26:2799–803.

    Article  CAS  PubMed  Google Scholar 

  22. Tili E, Croce CM, Michaille JJ. miR-155: on the crosstalk between inflammation and cancer. Int Rev Immunol. 2009;28:264–84.

    Article  CAS  PubMed  Google Scholar 

  23. Toiyama Y, Takahashi M, Hur K, Nagasaka T, Tanaka K, Inoue Y, et al. Serum miR-21 as a diagnostic and prognostic biomarker in colorectal cancer. J Natl Cancer Inst. 2013;105:849–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Abue M, Yokoyama M, Shibuya R, Tamai K, Yamaguchi K, Sato I, et al. Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer. Int J Oncol. 2015;46:539–47.

    Article  CAS  PubMed  Google Scholar 

  25. Sun Y, Wang M, Lin G, Sun S, Li X, Qi J, et al. Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS ONE. 2012;7:e47003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu R, Liao J, Yang M, Shi Y, Peng Y, Wang Y, et al. Circulating miR-155 expression in plasma: a potential biomarker for early diagnosis of esophageal cancer in humans. J Toxicol Environ Health A. 2012;75:1154–62.

    Article  CAS  PubMed  Google Scholar 

  27. Shi C, Yang Y, Xia Y, Okugawa Y, Yang J, Liang Y, et al. Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer. Gut. 2016;65:1470–81.

    Article  CAS  PubMed  Google Scholar 

  28. Urbich C, Kuehbacher A, Dimmeler S. Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res. 2008;79:581–8.

    Article  CAS  PubMed  Google Scholar 

  29. Statello L, Guo CJ, Chen LL, Huarte M. Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol. 2021;22:96–118.

    Article  CAS  PubMed  Google Scholar 

  30. Schmitt AM, Chang HY. Long Noncoding RNAs in Cancer Pathways. Cancer Cell. 2016;29:452–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tseng YY, Moriarity BS, Gong W, Akiyama R, Tiwari A, Kawakami H, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512:82–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464:1071–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gutschner T, Hämmerle M, Eissmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73:1180–9.

    Article  CAS  PubMed  Google Scholar 

  34. Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47:199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang J, Gao Y, Wang X, Li L, Zhang J, Zhang L, et al. Circulating lncRNAs as noninvasive biomarkers in bladder cancer: A diagnostic meta-analysis based on 15 published articles. Int J Biol Markers. 2020;35:40–48.

    Article  PubMed  Google Scholar 

  36. Zhou X, Yin C, Dang Y, Ye F, Zhang G. Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer. Sci Rep. 2015;5:11516.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Zheng ZK, Pang C, Yang Y, Duan Q, Zhang J, Liu WC. Serum long noncoding RNA urothelial carcinoma-associated 1: A novel biomarker for diagnosis and prognosis of hepatocellular carcinoma. J Int Med Res. 2018;46:348–56.

    Article  CAS  PubMed  Google Scholar 

  38. Chen Q, Su Y, He X, Zhao W, Wu C, Zhang W, et al. Plasma long non-coding RNA MALAT1 is associated with distant metastasis in patients with epithelial ovarian cancer. Oncol Lett. 2016;12:1361–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Okugawa Y, Toiyama Y, Hur K, Toden S, Saigusa S, Tanaka K, et al. Metastasis-associated long non-coding RNA drives gastric cancer development and promotes peritoneal metastasis. Carcinogenesis. 2014;35:2731–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yousefi H, Maheronnaghsh M, Molaei F, Mashouri L, Reza Aref A, Momeny M, et al. Long noncoding RNAs and exosomal lncRNAs: classification, and mechanisms in breast cancer metastasis and drug resistance. Oncogene. 2020;39:953–74.

    Article  CAS  PubMed  Google Scholar 

  41. Zang X, Gu J, Zhang J, Shi H, Hou S, Xu X, et al. Exosome-transmitted lncRNA UFC1 promotes non-small-cell lung cancer progression by EZH2-mediated epigenetic silencing of PTEN expression. Cell Death Dis. 2020;11:215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lane, JS, Hoff, DV, Cridebring, D & Goel, A. Extracellular vesicles in diagnosis and treatment of pancreatic cancer: current state and future perspectives. Cancers (Basel) 2020;12:1530.

  43. Chen LL, Yang L. Regulation of circRNA biogenesis. RNA Biol. 2015;12:381–8.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci USA. 1976;73:3852–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Qu S, Yang X, Li X, Wang J, Gao Y, Shang R, et al. Circular RNA: a new star of noncoding RNAs. Cancer Lett. 2015;365:141–8.

    Article  CAS  PubMed  Google Scholar 

  46. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8.

    Article  CAS  PubMed  Google Scholar 

  47. Hsiao KY, Lin YC, Gupta SK, Chang N, Yen L, Sun HS, et al. Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and Metastasis. Cancer Res. 2017;77:2339–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen J, Li Y, Zheng Q, Bao C, He J, Chen B, et al. Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer. Cancer Lett. 2017;388:208–19.

    Article  CAS  PubMed  Google Scholar 

  49. Hang D, Zhou J, Qin N, Zhou W, Ma H, Jin G, et al. A novel plasma circular RNA circFARSA is a potential biomarker for non-small cell lung cancer. Cancer Med. 2018;7:2783–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lin J, Cai D, Li W, Yu T, Mao H, Jiang S, et al. Plasma circular RNA panel acts as a novel diagnostic biomarker for colorectal cancer. Clin Biochem. 2019;74:60–68.

    Article  CAS  PubMed  Google Scholar 

  51. Chen J, Cui L, Yuan J, Zhang Y, Sang H. Circular RNA WDR77 target FGF-2 to regulate vascular smooth muscle cells proliferation and migration by sponging miR-124. Biochem Biophys Res Commun. 2017;494:126–32.

    Article  CAS  PubMed  Google Scholar 

  52. Li Z, Zhou Y, Yang G, He S, Qiu X, Zhang L, et al. Using circular RNA SMARCA5 as a potential novel biomarker for hepatocellular carcinoma. Clin Chim Acta. 2019;492:37–44.

    Article  CAS  PubMed  Google Scholar 

  53. Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA. 2013;19:141–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Giannoukos G, Ciulla DM, Huang K, Haas BJ, Izard J, Levin JZ, et al. Efficient and robust RNA-seq process for cultured bacteria and complex community transcriptomes. Genome Biol. 2012;13:R23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Wu YM, et al. The Landscape of Circular RNA in Cancer. Cell. 2019;176:869–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Czech B, Hannon GJ. One loop to rule them all: the ping-pong cycle and piRNA-guided silencing. Trends Biochem Sci. 2016;41:324–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu Y, Dou M, Song X, Dong Y, Liu S, Liu H, et al. The emerging role of the piRNA/piwi complex in cancer. Mol Cancer. 2019;18:123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Weng W, Li H, Goel A. Piwi-interacting RNAs (piRNAs) and cancer: Emerging biological concepts and potential clinical implications. Biochim Biophys Acta Rev Cancer. 2019;1871:160–9.

    Article  CAS  PubMed  Google Scholar 

  60. Ross RJ, Weiner MM, Lin H. PIWI proteins and PIWI-interacting RNAs in the soma. Nature. 2014;505:353–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Watanabe T, Lin H. Posttranscriptional regulation of gene expression by Piwi proteins and piRNAs. Mol Cell. 2014;56:18–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Weng W, Liu N, Toiyama Y, Kusunoki M, Nagasaka T, Fujiwara T, et al. Novel evidence for a PIWI-interacting RNA (piRNA) as an oncogenic mediator of disease progression, and a potential prognostic biomarker in colorectal cancer. Mol Cancer. 2018;17:16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Mai D, Zheng Y, Guo H, Ding P, Bai R, Li M, et al. Serum piRNA-54265 is a new biomarker for early detection and clinical surveillance of human colorectal cancer. Theranostics. 2020;10:8468–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Qu A, Wang W, Yang Y, Zhang X, Dong Y, Zheng G, et al. A serum piRNA signature as promising non-invasive diagnostic and prognostic biomarkers for colorectal cancer. Cancer Manag Res. 2019;11:3703–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gu X, Wang C, Deng H, Qing C, Liu R, Liu S, et al. Exosomal piRNA profiling revealed unique circulating piRNA signatures of cholangiocarcinoma and gallbladder carcinoma. Acta Biochim Biophys Sin (Shanghai). 2020;52:475–84.

    Article  CAS  Google Scholar 

  66. Jia Y, Tan W, Zhou Y. Transfer RNA-derived small RNAs: potential applications as novel biomarkers for disease diagnosis and prognosis. Ann Transl Med. 2020;8:1092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Gebetsberger J, Polacek N. Slicing tRNAs to boost functional ncRNA diversity. RNA Biol. 2013;10:1798–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fu H, Feng J, Liu Q, Sun F, Tie Y, Zhu J, et al. Stress induces tRNA cleavage by angiogenin in mammalian cells. FEBS Lett. 2009;583:437–42.

    Article  CAS  PubMed  Google Scholar 

  69. Gehrke CW, Kuo KC, Waalkes TP, Borek E. Patterns of urinary excretion of modified nucleosides. Cancer Res. 1979;39:1150–3.

    CAS  PubMed  Google Scholar 

  70. Lakings DB, Waalkes TP, Borek E, Gehrke CW, Mrochek JE, Longmore J, et al. Composition, associated tissue methyltransferase activity, and catabolic end products of transfer RNA from carcinogen-induced hepatoma and normal monkey livers. Cancer Res. 1977;37:285–92.

    CAS  PubMed  Google Scholar 

  71. Dhahbi JM, Spindler SR, Atamna H, Boffelli D, Martin DI. Deep Sequencing of Serum Small RNAs Identifies Patterns of 5’ tRNA Half and YRNA Fragment Expression Associated with Breast Cancer. Biomark Cancer. 2014;6:37–47.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Zhu L, Li J, Gong Y, Wu Q, Tan S, Sun D, et al. Exosomal tRNA-derived small RNA as a promising biomarker for cancer diagnosis. Mol Cancer. 2019;18:74.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Hoshino I. The usefulness of microRNA in urine and saliva as a biomarker of gastroenterological cancer. Int J Clin Oncol. 2021;26:1431–40.

    Article  CAS  PubMed  Google Scholar 

  74. Li L, Wang A, Cai M, Tong M, Chen F, Huang L. Identification of stool miR-135b-5p as a non-invasive diaognostic biomarker in later tumor stage of colorectal cancer. Life Sci. 2020;260:118417.

    Article  CAS  PubMed  Google Scholar 

  75. Duran-Sanchon S, Moreno L, Gómez-Matas J, Augé JM, Serra-Burriel M, Cuatrecasas M, et al. Fecal microRNA-based algorithm increases effectiveness of fecal immunochemical test-based screening for colorectal cancer. Clin Gastroenterol Hepatol. 2021;19:323–30.

    Article  CAS  PubMed  Google Scholar 

  76. Xie Z, Chen X, Li J, Guo Y, Li H, Pan X, et al. Salivary HOTAIR and PVT1 as novel biomarkers for early pancreatic cancer. Oncotarget. 2016;7:25408–19.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Zhan Y, Du L, Wang L, Jiang X, Zhang S, Li J, et al. Expression signatures of exosomal long non-coding RNAs in urine serve as novel non-invasive biomarkers for diagnosis and recurrence prediction of bladder cancer. Mol Cancer. 2018;17:142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Gharib E, Nazemalhosseini-Mojarad E, Baghdar K, Nayeri Z, Sadeghi H, Rezasoltani S, et al. Identification of a stool long non-coding RNAs panel as a potential biomarker for early detection of colorectal cancer. J Clin Lab Anal. 2021;35:e23601.

    Article  CAS  PubMed  Google Scholar 

  79. Bahn JH, Zhang Q, Li F, Chan TM, Lin X, Kim Y, et al. The landscape of microRNA, Piwi-interacting RNA, and circular RNA in human saliva. Clin Chem. 2015;61:221–30.

    Article  CAS  PubMed  Google Scholar 

  80. Vidal J, Muinelo L, Dalmases A, Jones F, Edelstein D, Iglesias M, et al. Plasma ctDNA RAS mutation analysis for the diagnosis and treatment monitoring of metastatic colorectal cancer patients. Ann Oncol. 2017;28:1325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kruger S, Heinemann V, Ross C, Diehl F, Nagel D, Ormanns S, et al. Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer. Ann Oncol. 2018;29:2348–55.

    Article  CAS  PubMed  Google Scholar 

  82. Ruiz-Banobre J, Goel A. Genomic and epigenomic biomarkers in colorectal cancer: from diagnosis to therapy. Adv Cancer Res. 2021;151:231–304.

    Article  PubMed  Google Scholar 

  83. Stroun M, Anker P, Beljanski M, Henri J, Lederrey C, Ojha M, et al. Presence of RNA in the nucleoprotein complex spontaneously released by human lymphocytes and frog auricles in culture. Cancer Res. 1978;38:3546–54.

    CAS  PubMed  Google Scholar 

  84. Sokolova V, Ludwig AK, Hornung S, Rotan O, Horn PA, Epple M, et al. Characterisation of exosomes derived from human cells by nanoparticle tracking analysis and scanning electron microscopy. Colloids Surf B Biointerfaces. 2011;87:146–50.

    Article  CAS  PubMed  Google Scholar 

  85. Kalra H, Adda CG, Liem M, Ang CS, Mechler A, Simpson RJ, et al. Comparative proteomics evaluation of plasma exosome isolation techniques and assessment of the stability of exosomes in normal human blood plasma. Proteomics. 2013;13:3354–64.

    Article  CAS  PubMed  Google Scholar 

  86. Winter J, Diederichs S. Argonaute proteins regulate microRNA stability: increased microRNA abundance by Argonaute proteins is due to microRNA stabilization. RNA Biol. 2011;8:1149–57.

    Article  CAS  PubMed  Google Scholar 

  87. Fuji T, Umeda Y, Nyuya A, Taniguchi F, Kawai T, Yasui K, et al. Detection of circulating microRNAs with Ago2 complexes to monitor the tumor dynamics of colorectal cancer patients during chemotherapy. Int J Cancer. 2019;144:2169–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Enderle D, Spiel A, Coticchia CM, Berghoff E, Mueller R, Schlumpberger M, et al. Characterization of RNA from Exosomes and Other Extracellular Vesicles Isolated by a Novel Spin Column-Based Method. PLoS ONE. 2015;10:e0136133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Chen, Y, Wu, T, Zhu, Z, Huang, H, Zhang, L, Goel, A et al. An integrated workflow for biomarker development using microRNAs in extracellular vesicles for cancer precision medicine. Semin Cancer Biol 2021;74:134–55.

  90. Chatterjee SK, Zetter BR. Cancer biomarkers: knowing the present and predicting the future. Future Oncol. 2005;1:37–50.

    Article  CAS  PubMed  Google Scholar 

  91. Goel A, Boland CR. Epigenetics of colorectal cancer. Gastroenterology. 2012;143:1442–60.

    Article  CAS  PubMed  Google Scholar 

  92. Okugawa Y, Grady WM, Goel A. Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology. 2015;149:1204–25.

    Article  CAS  PubMed  Google Scholar 

  93. Lam K, Pan K, Linnekamp JF, Medema JP, Kandimalla R. DNA methylation based biomarkers in colorectal cancer: A systematic review. Biochim Biophys Acta. 2016;1866:106–20.

    CAS  PubMed  Google Scholar 

  94. Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, et al. Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res. 1999;59:2307–12.

    CAS  PubMed  Google Scholar 

  95. Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut. 2014;63:317–25.

    Article  CAS  PubMed  Google Scholar 

  96. Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L, et al. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst. 2005;97:1124–32.

    Article  CAS  PubMed  Google Scholar 

  97. Luo, H, Zhao, Q, Wei, W, Zheng, L, Yi, S, Li, G et al. Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med.2020;12:eaax7533.

  98. Yokoi A, Villar-Prados A, Oliphint PA, Zhang J, Song X, De Hoff P, et al. Mechanisms of nuclear content loading to exosomes. Sci Adv. 2019;5:eaax8849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lui YY, Chik KW, Chiu RW, Ho CY, Lam CW, Lo YM. Predominant hematopoietic origin of cell-free DNA in plasma and serum after sex-mismatched bone marrow transplantation. Clin Chem. 2002;48:421–7.

    Article  CAS  PubMed  Google Scholar 

  100. Lui YY, Woo KS, Wang AY, Yeung CK, Li PK, Chau E, et al. Origin of plasma cell-free DNA after solid organ transplantation. Clin Chem. 2003;49:495–6.

    Article  CAS  PubMed  Google Scholar 

  101. Cancer Genome Atlas Research, N., Analysis Working Group: Asan, U., Agency, B. C. C., Brigham, Women’s, H., Broad, I. et al. Integrated genomic characterization of oesophageal carcinoma. Nature. 2017;541:169–75.

    Article  CAS  Google Scholar 

  102. Network CGA. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

    Article  CAS  Google Scholar 

  103. Network CGA. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

    Article  CAS  Google Scholar 

  104. Network CGAR. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  CAS  Google Scholar 

  105. Izumi D, Zhu Z, Chen Y, Toden S, Huo X, Kanda M, et al. Assessment of the diagnostic efficiency of a liquid biopsy assay for early detection of gastric cancer. JAMA Netw Open. 2021;4:e2121129.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Kandimalla R, Wang W, Yu F, Zhou N, Gao F, Spillman M, et al. OCaMIR-A noninvasive, diagnostic signature for early-stage ovarian cancer: a multi-cohort retrospective and prospective study. Clin Cancer Res. 2021;27:4277–86.

    Article  CAS  PubMed  Google Scholar 

  107. Kandimalla, R, Shimura, T, Mallik, S, Sonohara, F, Tsai, S, Evans, DB et al. Identification of serum miRNA signature and establishment of a nomogram for risk stratification in patients with pancreatic ductal adenocarcinoma. Ann Surg. 2020; https://doi.org/10.1097/sla.0000000000003945.

  108. Ko J, Baldassano SN, Loh PL, Kording K, Litt B, Issadore D. Machine learning to detect signatures of disease in liquid biopsies - a user’s guide. Lab Chip. 2018;18:395–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.

    Article  CAS  PubMed  Google Scholar 

  110. Tian T, Wang Y, Wang H, Zhu Z, Xiao Z. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem. 2010;111:488–96.

    Article  CAS  PubMed  Google Scholar 

  111. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Nabet BY, Qiu Y, Shabason JE, Wu TJ, Yoon T, Kim BC, et al. Exosome RNA Unshielding Couples Stromal Activation to Pattern Recognition Receptor Signaling in Cancer. Cell. 2017;170:352–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Loher P, Londin ER, Rigoutsos I. IsomiR expression profiles in human lymphoblastoid cell lines exhibit population and gender dependencies. Oncotarget. 2014;5:8790–802.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Telonis AG, Loher P, Jing Y, Londin E, Rigoutsos I. Beyond the one-locus-one-miRNA paradigm: microRNA isoforms enable deeper insights into breast cancer heterogeneity. Nucleic Acids Res. 2015;43:9158–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Telonis AG, Magee R, Loher P, Chervoneva I, Londin E, Rigoutsos I. Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types. Nucleic Acids Res. 2017;45:2973–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Mathivanan S, Lim JW, Tauro BJ, Ji H, Moritz RL, Simpson RJ. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature. Mol Cell Proteom: MCP. 2010;9:197–208.

    Article  CAS  Google Scholar 

  118. Vallabhajosyula P, Korutla L, Habertheuer A, Yu M, Rostami S, Yuan CX, et al. Tissue-specific exosome biomarkers for noninvasively monitoring immunologic rejection of transplanted tissue. J Clin Invest. 2017;127:1375–91.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Melo SA, Sugimoto H, O’Connell JT, Kato N, Villanueva A, Vidal A, et al. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell. 2014;26:707–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Castillo J, Bernard V, San Lucas FA, Allenson K, Capello M, Kim DU, et al. Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients. Ann Oncol. 2018;29:223–9.

    Article  CAS  PubMed  Google Scholar 

  121. Xiang M, Zeng Y, Yang R, Xu H, Chen Z, Zhong J, et al. U6 is not a suitable endogenous control for the quantification of circulating microRNAs. Biochem Biophys Res Commun. 2014;454:210–4.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable

Funding

The present work was supported by the grants CA72851, CA181572, CA184792, CA187956 and CA202797 from the National Institute of Health (NIH) to AG.

Author information

Authors and Affiliations

Authors

Contributions

The review article was conceived and wrote by ST and AG.

Corresponding author

Correspondence to Ajay Goel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.

Consent to publish

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Toden, S., Goel, A. Non-coding RNAs as liquid biopsy biomarkers in cancer. Br J Cancer 126, 351–360 (2022). https://doi.org/10.1038/s41416-021-01672-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-021-01672-8

This article is cited by

Search

Quick links