Liquid biopsy for the assessment of adrenal cancer heterogeneity: where do we stand?

Endocrine - Tập 77 - Trang 425-431 - 2022
Pál Perge1, Gábor Nyirő2,3,4, Bálint Vékony2, Peter Igaz1,2,3
1Department of Internal Medicine and Oncology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
2Department of Endocrinology, ENS@T Research Center of Excellence, Faculty of Medicine, Semmelweis University, Budapest, Hungary
3MTA-SE Molecular Medicine Research Group, Eötvös Loránd Research Network, Budapest, Hungary
4Institute of Laboratory Medicine, Faculty of Medicine, Semmelweis University, Budapest, Hungary

Tóm tắt

Almost 10 years have passed since the first attempts of liquid biopsy aimed at the characterisation of tumor cells present in the bloodstream from a regular sample of peripheral blood were performed. Liquid biopsy has been used to characterise tumor heterogeneity in various types of solid tumors including adrenocortical carcinoma. The development of molecular biology, genetics, and methodological advances such as digital PCR and next-generation sequencing allowed us to use besides circulating tumor cells a variety of circulating cell-free nucleic acids, DNAs, RNAs and microRNAs secreted by tumors into blood and other body fluids as specific molecular markers. These markers are used for diagnosis, to check tumor development, selecting efficient therapies, therapy monitoring and even possess prognostic power. In adrenocortical carcinoma, there are some studies reporting analysis of circulating tumor cells, circulating cell free DNA and microRNAs for assessing tumor heterogeneity. Among microRNAs, hsa-miR-483-5p seems to be the most important player. Combined with other microRNAs like hsa-miR-195, their expression correlates with recurrence-free survival. Most studies support the applicability of liquid biopsy for assessing temporal tumor heterogeneity (i.e. tumor progression) in adrenocortical cancer. In this mini-review, the available findings of liquid biopsy for assessing tumor heterogeneity in adrenocortical cancer are presented.

Tài liệu tham khảo

A. Marusyk, K. Polyak, Tumor heterogeneity: causes and consequences. Biochim. Biophys. Acta 1805, 105–117 (2010). https://doi.org/10.1016/J.BBCAN.2009.11.002 M. Shackleton, E. Quintana, E.R. Fearon, S.J. Morrison, Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138, 822–829 (2009). https://doi.org/10.1016/J.CELL.2009.08.017 N. McGranahan, C. Swanton, Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell 168, 613–628 (2017). https://doi.org/10.1016/J.CELL.2017.01.018 S.K. Gara, J. Lack, L. Zhang, E. Harris, M. Cam, E. Kebebew, Metastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors. Nat.Commun. 9, (2018). https://doi.org/10.1038/S41467-018-06366-Z S.L. Carter, A.C. Eklund, I.S. Kohane, L.N. Harris, Z. Szallasi, A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat. Genet. 38, 1043–1048 (2006). https://doi.org/10.1038/NG1861 S. Popat, R. Hubner, R.S. Houlston, Systematic review of microsatellite instability and colorectal cancer prognosis. J. Clin. Oncol. 23, 609–618 (2005). https://doi.org/10.1200/JCO.2005.01.086 B.E. Johnson, T. Mazor, C. Hong, M. Barnes, K. Aihara, C.Y. McLean, S.D. Fouse, S. Yamamoto, H. Ueda, K. Tatsuno, S. Asthana, L.E. Jalbert, S.J. Nelson, A.W. Bollen, W.C. Gustafson, E. Charron, W.A. Weiss, I.V. Smirnov, J.S. Song, A.B. Olshen, S. Cha, Y. Zhao, R.A. Moore, A.J. Mungall, S.J.M. Jones, M. Hirst, M.A. Marra, N. Saito, H. Aburatani, A. Mukasa, M.S. Berger, S.M. Chang, B.S. Taylor, J.F. Costello, Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma. Science 343, 189–193 (2014). https://doi.org/10.1126/SCIENCE.1239947 P.C. Nowell, The clonal evolution of tumor cell populations. Science 194, 23–28 (1976). https://doi.org/10.1126/SCIENCE.959840 M. Gerlinger, A.J. Rowan, S. Horswell, J. Larkin, D. Endesfelder, E. Gronroos, P. Martinez, N. Matthews, A. Stewart, P. Tarpey, I. Varela, B. Phillimore, S. Begum, N.Q. McDonald, A. Butler, D. Jones, K. Raine, C. Latimer, C.R. Santos, M. Nohadani, A.C. Eklund, B. Spencer-Dene, G. Clark, L. Pickering, G. Stamp, M. Gore, Z. Szallasi, J. Downward, P.A. Futreal, C. Swanton, Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012). https://doi.org/10.1056/NEJMOA1113205 T. Wu, Y. Dai, Tumor microenvironment and therapeutic response. Cancer Lett. 387, 61–68 (2017). https://doi.org/10.1016/J.CANLET.2016.01.043 D.C. Hinshaw, L.A. Shevde, The Tumor Microenvironment Innately Modulates Cancer Progression. Cancer Res. 79, 4557–4567 (2019). https://doi.org/10.1158/0008-5472.CAN-18-3962 G.P. Dunn, L.J. Old, R.D. Schreiber, The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004). https://doi.org/10.1016/J.IMMUNI.2004.07.017 J.S. O’Donnell, M.W.L. Teng, M.J. Smyth, Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol 16, 151–167 (2019). https://doi.org/10.1038/S41571-018-0142-8 I. Dagogo-Jack, A.T. Shaw, Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018). https://doi.org/10.1038/NRCLINONC.2017.166 K. Onidani, H. Shoji, T. Kakizaki, S. Yoshimoto, S. Okaya, N. Miura, S. Sekikawa, K. Furuta, C.T. Lim, T. Shibahara, N. Boku, K. Kato, K. Honda, Monitoring of cancer patients via next-generation sequencing of patient-derived circulating tumor cells and tumor DNA. Cancer Sci. 110, 2590–2599 (2019). https://doi.org/10.1111/CAS.14092 G. Arnaldi, M. Boscaro, Adrenal incidentaloma. Best Pract. Res. Clin. Endocrinol. Metab. 26, 405–419 (2012). https://doi.org/10.1016/j.beem.2011.12.006 M. Terzolo, F. Daffara, A. Ardito, B. Zaggia, V. Basile, L. Ferrari, A. Berruti, J. Management of adrenal cancer: a 2013 update. Endocrinol. Invest 37, 207–217 (2014). https://doi.org/10.1007/s40618-013-0049-2 R. Libé, I. Borget, C.L. Ronchi, B. Zaggia, M. Kroiss, T. Kerkhofs, J. Bertherat, M. Volante, M. Quinkler, O. Chabre, M. Bala, A. Tabarin, F. Beuschlein, D. Vezzosi, T. Deutschbein, F. Borson-Chazot, I. Hermsen, A. Stell, C. Fottner, S. Leboulleux, S. Hahner, M. Mannelli, A. Berruti, H. Haak, M. Terzolo, M. Fassnacht, E. Baudin; ENSAT network, Prognostic factors in stage III–IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study. Ann. Oncol. 26, 2119–2125 (2015). https://doi.org/10.1093/annonc/mdv329 M. Fassnacht, O.M. Dekkers, T. Else, E. Baudin, A. Berruti, R.R. De Krijger, H.R. Haak, R. Mihai, G. Assie, M. Terzolo, European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur. J. Endocrinol 179, G1–G46 (2018). https://doi.org/10.1530/EJE-18-0608 K. Pantel, C. Alix-Panabières, Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 73, 6384–6388 (2013). https://doi.org/10.1158/0008-5472.CAN-13-2030 E. Crowley, F. Di Nicolantonio, F. Loupakis, A. Bardelli, Liquid biopsy: monitoring cancer-genetics in the blood. Nat. Rev. Clin. Oncol. 10, 472–484 (2013). https://doi.org/10.1038/NRCLINONC.2013.110 C. Alix-Panabières, K. Pantel, Clinical applications of circulating tumor cells and circulating tumor dna as liquid biopsy. Cancer Discov. 6, 479–491 (2016). https://doi.org/10.1158/2159-8290.CD-15-1483 W. Zhang, W. Xia, Z. Lv, C. Ni, Y. Xin, L. Yang, Liquid Biopsy for Cancer: Circulating Tumor Cells, Circulating Free DNA or Exosomes? Cell. Physiol. Biochem. 41, 755–768 (2017). https://doi.org/10.1159/000458736 M. Russano, A. Napolitano, G. Ribelli, M. Iuliani, S. Simonetti, F. Citarella, F. Pantano, E. Dell’aquila, C. Anesi, N. Silvestris, A. Argentiero, A. Solimando, B. Vincenzi, G. Tonini, D. Santini, Liquid biopsy and tumor heterogeneity in metastatic solid tumors: the potentiality of blood samples. J. Exp. Clin. Cancer Res. 39, (2020). https://doi.org/10.1186/s13046-020-01601-2. M. Cristofanilli, G.T. Budd, M.J. Ellis, A. Stopeck, J. Matera, M.C. Miller, J.M. Reuben, G.V. Doyle, W.J. Allard, L.W.M.M. Terstappen, D.F. Hayes, Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 351, 781–791 (2004). https://doi.org/10.1056/NEJMOA040766 Y.F. Sun, X.R. Yang, J. Zhou, S.J. Qiu, J. Fan, Y. Xu, Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. J. Cancer Res. Clin. Oncol. 137, 1151–1173 (2011). https://doi.org/10.1007/S00432-011-0988-Y W.J. Allard, J. Matera, M.C. Miller, M. Repollet, M.C. Connelly, C. Rao, A.G.J. Tibbe, J.W. Uhr, L.W.M.M. Terstappen, Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 10, 6897–6904 (2004). https://doi.org/10.1158/1078-0432.CCR-04-0378 S. Riethdorf, H. Wikman, K. Pantel, Review: biological relevance of disseminated tumor cells in cancer patients. Int. J. Cancer 123, 1991–2006 (2008). https://doi.org/10.1002/ijc.23825 K.E. Sundling, A.C. Lowe, Circulating tumor cells: overview and opportunities in cytology. Adv. Anat. Pathol 26, 56–63 (2019). https://doi.org/10.1002/IJC.23825 M. Yu, A. Bardia, B.S. Wittner, S.L. Stott, M.E. Smas, D.T. Ting, S.J. Isakoff, J.C. Ciciliano, M.N. Wells, A.M. Shah, K.F. Concannon, M.C. Donaldson, L.V. Sequist, E. Brachtel, D. Sgroi, J. Baselga, S. Ramaswamy, M. Toner, D.A. Haber, S. Maheswaran, Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584 (2013). https://doi.org/10.1126/SCIENCE.1228522 A. Satelli, A. Mitra, Z. Brownlee, X. Xia, S. Bellister, M.J. Overman, S. Kopetz, L.M. Ellis, Q.H. Meng, S. Li, Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin. Cancer Res. 21, 899–906 (2015). https://doi.org/10.1158/1078-0432.CCR-14-0894 N. Aceto, A. Bardia, D.T. Miyamoto, M.C. Donaldson, B.S. Wittner, J.A. Spencer, M. Yu, A. Pely, A. Engstrom, H. Zhu, B.W. Brannigan, R. Kapur, S.L. Stott, T. Shioda, S. Ramaswamy, D.T. Ting, C.P. Lin, M. Toner, D.A. Haber, S. Maheswaran, Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110–1122 (2014). https://doi.org/10.1016/J.CELL.2014.07.013 N. Aceto, M. Toner, S. Maheswaran, D.A. Haber, En route to metastasis: circulating tumor cell clusters and epithelial-to-mesenchymal transition. Trends in Cancer. 1, 44–52 (2015). https://doi.org/10.1016/J.TRECAN.2015.07.006 K. Kolostova, J. Spicka, R. Matkowski, V. Bobek, Isolation, primary culture, morphological and molecular characterization of circulating tumor cells in gynecological cancers. Am. J. Transl. Res. 7, 1203–1213 (2015) S. Maheswaran, D.A. Haber, Ex Vivo Culture of CTCs: An Emerging Resource to Guide Cancer Therapy. Cancer Res. 75, 2411–2415 (2015). https://doi.org/10.1158/0008-5472.CAN-15-0145 P. Pinzani, C. Scatena, F. Salvianti, E. Corsini, L. Canu, G. Poli, M. Paglierani, V. Piccini, M. Pazzagli, G. Nesi, M. Mannelli, M. Luconi, Detection of circulating tumor cells in patients with adrenocortical carcinoma: a monocentric preliminary study. J. Clin. Endocrinol. Metab. 98, 3731–3738 (2013). https://doi.org/10.1210/jc.2013-1396 G. Cantini, L. Canu, R. Armignacco, F. Salvianti, G. De Filpo, T. Ercolino, G. Nesi, M. Maggi, M. Mannelli, P. Pinzani, M. Luconi, Prognostic and Monitoring Value of Circulating Tumor Cells in Adrenocortical Carcinoma: A Preliminary Monocentric Study. Cancers 12, 1–23 (2020). https://doi.org/10.3390/CANCERS12113176 S.A. Leon, B. Shapiro, D.M. Sklaroff, M.J. Yaros, Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 37, 646–650 (1977) C. Bettegowda, M. Sausen, R.J. Leary, I. Kinde, Y. Wang, N. Agrawal, B.R. Bartlett, H. Wang, B. Luber, R.M. Alani, E.S. Antonarakis, N.S. Azad, A. Bardelli, H. Brem, J.L. Cameron, C.C. Lee, L.A. Fecher, G.L. Gallia, P. Gibbs, D. Le, R.L. Giuntoli, M. Goggins, M.D. Hogarty, M. Holdhoff, S.M. Hong, Y. Jiao, H.H. Juhl, J.J. Kim, G. Siravegna, D.A. Laheru, C. Lauricella, M. Lim, E.J. Lipson, S.K.N. Marie, G.J. Netto, K.S. Oliner, A. Olivi, L. Olsson, G.J. Riggins, A. Sartore-Bianchi, K. Schmidt, I.M. Shih, S.M. Oba-Shinjo, S. Siena, D. Theodorescu, J. Tie, T.T. Harkins, S. Veronese, T.L. Wang, J.D. Weingart, C.L. Wolfgang, L.D. Wood, D. Xing, R.H. Hruban, J. Wu, P.J. Allen, C.M. Schmidt, M.A. Choti, V.E. Velculescu, K.W. Kinzler, B. Vogelstein, N. Papadopoulos, L.A. Diaz, Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 6, (2014). https://doi.org/10.1126/SCITRANSLMED.3007094. F. Diehl, K. Schmidt, M.A. Choti, K. Romans, S. Goodman, M. Li, K. Thornton, N. Agrawal, L. Sokoll, S.A. Szabo, K.W. Kinzler, B. Vogelstein, L.A. Diaz, Circulating mutant DNA to assess tumor dynamics. Nat. Med. 14, 985–990 (2008). https://doi.org/10.1038/NM.1789 C. Alix-Panabières, H. Schwarzenbach, K. Pantel, Circulating tumor cells and circulating tumor DNA. Annu. Rev. Med. 63, 199–215 (2012). https://doi.org/10.1146/ANNUREV-MED-062310-094219 C. Fiala, E.P. Diamandis, Utility of circulating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med. 16, (2018). https://doi.org/10.1186/S12916-018-1157-9. V. Villaflor, B. Won, R. Nagy, K. Banks, R.B. Lanman, A.A. Talasaz, R. Salgia, Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer. Oncotarget 7, 66880–66891 (2016). https://doi.org/10.18632/ONCOTARGET.11801 C. Abbosh, N.J. Birkbak, G.A. Wilson, M. Jamal-Hanjani, T. Constantin, R. Salari, J. Le Quesne, D.A. Moore, S. Veeriah, R. Rosenthal, T. Marafioti, E. Kirkizlar, T.B.K. Watkins, N. McGranahan, S. Ward, L. Martinson, J. Riley, F. Fraioli, M. Al Bakir, E. Grönroos, F. Zambrana, R. Endozo, W.L. Bi, F.M. Fennessy, N. Sponer, D. Johnson, J. Laycock, S. Shafi, J. Czyzewska-Khan, A. Rowan, T. Chambers, N. Matthews, S. Turajlic, C. Hiley, S.M. Lee, M.D. Forster, T. Ahmad, M. Falzon, E. Borg, D. Lawrence, M. Hayward, S. Kolvekar, N. Panagiotopoulos, S.M. Janes, R. Thakrar, A. Ahmed, F. Blackhall, Y. Summers, D. Hafez, A. Naik, A. Ganguly, S. Kareht, R. Shah, L. Joseph, A.M. Quinn, P.A. Crosbie, B. Naidu, G. Middleton, G. Langman, S. Trotter, M. Nicolson, H. Remmen, K. Kerr, M. Chetty, L. Gomersall, D.A. Fennell, A. Nakas, S. Rathinam, G. Anand, S. Khan, P. Russell, V. Ezhil, B. Ismail, M. Irvin-Sellers, V. Prakash, J.F. Lester, M. Kornaszewska, R. Attanoos, H. Adams, H. Davies, D. Oukrif, A.U. Akarca, J.A. Hartley, H.L. Lowe, S. Lock, N. Iles, H. Bell, Y. Ngai, G. Elgar, Z. Szallasi, R.F. Schwarz, J. Herrero, A. Stewart, S.A. Quezada, K.S. Peggs, P. Van Loo, C. Dive, C.J. Lin, M. Rabinowitz, H.J.W.L. Aerts, A. Hackshaw, J.A. Shaw, B.G. Zimmermann, C. Swanton, L. Bosshard-Carter, G. Goh, P. Gorman, N. Murugaesu, R.E. Hynds, S. Horswell, R. Mitter, M. Escudero, H. Xu, J. Goldman, R.K. Stone, T. Denner, J. Biggs, M. Costa, S. Begum, B. Phillimore, E. Nye, S. Graca, K. Joshi, A. Furness, A. Ben Aissa, Y.N.S. Wong, A. Georgiou, C. Simeon, G. Hector, A. Smith, M. Aranda, M. Novelli, D. Papadatos-Pastos, D. Carnell, R. Mendes, J. George, N. Navani, M. Taylor, J. Choudhary, R. Califano, P. Taylor, P. Krysiak, K. Rammohan, E. Fontaine, R. Booton, M. Evison, S. Moss, F. Idries, P. Bishop, A. Chaturvedi, H. Doran, A. Leek, P. Harrison, R. Waddington, J. Novasio, J. Rogan, E. Smith, J. Tugwood, G. Brady, D.G. Rothwell, F. Chemi, J. Pierce, S. Gulati, M. Bellamy, H. Bancroft, A. Kerr, S. Kadiri, J. Webb, M. Djearaman, A. Thomas, H. Walter, W. Monteiro, H. Marshall, L. Nelson, J. Bennett, L. Primrose, A. Amadi, S. Palmer, J. Miller, K. Buchan, A. Edwards, F. Morgan, A. Verjee, M. MacKenzie, M. Wilcox, S. Smith, N. Gower, C. Ottensmeier, S. Chee, B. Johnson, A. Alzetani, E. Shaw, E. Lim, P. De Sousa, M.T. Barbosa, A. Bowman, S. Jordan, A. Rice, H. Raubenheimer, C. Proli, M.E. Cufari, J.C. Ronquillo, A. Kwayie, H. Bhayani, M. Hamilton, Y. Bakar, N. Mensah, L. Ambrose, A. Devaraj, S. Buderi, J. Finch, L. Azcarate, H. Chavan, S. Green, H. Mashinga, A.G. Nicholson, K. Lau, M. Sheaff, P. Schmid, J. Conibear, T. Light, T. Horey, S. Danson, J. Bury, J. Edwards, J. Hill, S. Matthews, Y. Kitsanta, K. Suvarna, P. Fisher, A.D. Keerio, M. Shackcloth, J. Gosney, P. Postmus, S. Feeney, J. Asante-Siaw, S. Dentro, C. Dessimoz, Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545, 446–451 (2017). https://doi.org/10.1038/nature22364 T. Forshew, M. Murtaza, C. Parkinson, D. Gale, D.W.Y. Tsui, F. Kaper, S.J. Dawson, A.M. Piskorz, M. Jimenez-Linan, D. Bentley, J. Hadfield, A.P. May, C. Caldas, J.D. Brenton, and N. Rosenfeld, Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci. Transl. Med. 4, (2012). https://doi.org/10.1126/SCITRANSLMED.3003726. H.H. Popper, Commentary on tumor heterogeneity. Transl. Lung Cancer Res. 5, 433–435 (2016). https://doi.org/10.21037/TLCR.2016.08.07 S. Cristiano, A. Leal, J. Phallen, J. Fiksel, V. Adleff, D.C. Bruhm, S.Ø. Jensen, J.E. Medina, C. Hruban, J.R. White, D.N. Palsgrove, N. Niknafs, V. Anagnostou, P. Forde, J. Naidoo, K. Marrone, J. Brahmer, B.D. Woodward, H. Husain, K.L. van Rooijen, M.B.W. Ørntoft, A.H. Madsen, C.J.H. van de Velde, M. Verheij, A. Cats, C.J.A. Punt, G.R. Vink, N.C.T. van Grieken, M. Koopman, R.J.A. Fijneman, J.S. Johansen, H.J. Nielsen, G.A. Meijer, C.L. Andersen, R.B. Scharpf, V.E. Velculescu, Genome-wide cell-free DNA fragmentation in patients with cancer. Nature 570, 385–389 (2019). https://doi.org/10.1038/S41586-019-1272-6 A. Dasari, V.K. Morris, C.J. Allegra, C. Atreya, A.B. Benson, P. Boland, K. Chung, M.S. Copur, R.B. Corcoran, D.A. Deming, A. Dwyer, M. Diehn, C. Eng, T.J. George, M.J. Gollub, R.A. Goodwin, S.R. Hamilton, J.F. Hechtman, H. Hochster, T.S. Hong, F. Innocenti, A. Iqbal, S.A. Jacobs, H.F. Kennecke, J.J. Lee, C.H. Lieu, H.J. Lenz, O.W. Lindwasser, C. Montagut, B. Odisio, F.S. Ou, L. Porter, K. Raghav, D. Schrag, A.J. Scott, Q. Shi, J.H. Strickler, A. Venook, R. Yaeger, G. Yothers, Y.N. You, J.A. Zell, S. Kopetz, ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper. Nat. Rev. Clin. Oncol. 17, 757–770 (2020). https://doi.org/10.1038/S41571-020-0392-0 K. Tóth, B.K. Barták, Z. Tulassay, B. Molnár, Circulating cell-free nucleic acids as biomarkers in colorectal cancer screening and diagnosis. Expert Rev. Mol. Diagn. 16, 239–252 (2016). https://doi.org/10.1586/14737159.2016.1132164 B. Molnár, O. Galamb, A. Kalmár, B.K. Barták, Z.B. Nagy, K. Tóth, Z. Tulassay, P. Igaz, M. Dank, Circulating cell-free nucleic acids as biomarkers in colorectal cancer screening and diagnosis - an update. Expert Rev. Mol. Diagn. 19, 477–498 (2019). https://doi.org/10.1080/14737159.2019.1613891 M.J.M. Magbanua, L.B. Swigart, H.T. Wu, G.L. Hirst, C. Yau, D.M. Wolf, A. Tin, R. Salari, S. Shchegrova, H. Pawar, A.L. Delson, A. DeMichele, M.C. Liu, A.J. Chien, D. Tripathy, S. Asare, C.H.J. Lin, P. Billings, A. Aleshin, H. Sethi, M. Louie, B. Zimmermann, L.J. Esserman, L.J. van ‘t Veer, Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 32, 229–239 (2021). https://doi.org/10.1016/J.ANNONC.2020.11.007 Y. Wang, L. Yang, H. Bao, X. Fan, F. Xia, J. Wan, L. Shen, Y. Guan, H. Bao, X. Wu, Y. Xu, Y. Shao, Y. Sun, T. Tong, X. Li, Y. Xu, S. Cai, J. Zhu, Z. Zhang, Utility of ctDNA in predicting response to neoadjuvant chemoradiotherapy and prognosis assessment in locally advanced rectal cancer: A prospective cohort study. PLoS Med. 18, (2021). https://doi.org/10.1371/JOURNAL.PMED.1003741. S.G. Creemers, E. Korpershoek, P.N. Atmodimedjo, W.N.M. Dinjens, P.M. Van Koetsveld, R.A. Feelders, L.J. Hofland, Identification of Mutations in Cell-Free Circulating Tumor DNA in Adrenocortical Carcinoma: A Case Series. J. Clin. Endocrinol. Metab 102, 3611–3615 (2017). https://doi.org/10.1210/JC.2017-00174 S. Garinet, J. Nectoux, M. Neou, E. Pasmant, A. Jouinot, M. Sibony, L. Orhant, J.P. Da Fonseca, K. Perlemoine, L. Bricaire, L. Groussin, O. Soubrane, B. Dousset, R. Libe, F. Letourneur, J. Bertherat, G. Assié, Detection and monitoring of circulating tumor DNA in adrenocortical carcinoma. Endocr. Relat. Cancer 25, L13–L17 (2018). https://doi.org/10.1530/ERC-17-0467 M.J. McCabe, M. Pinese, C.L. Chan, N. Sheriff, T.J. Thompson, J. Grady, M. Wong, M.E.A. Gauthier, C. Puttick, V. Gayevskiy, E. Hajdu, S.Q. Wong, W. Barrett, P. Earls, R. Lukeis, Y.Y. Cheng, R.C.Y. Lin, D.M. Thomas, D.N. Watkins, M.E. Dinger, A.I. McCormack, M.J. Cowley, Genomic stratification and liquid biopsy in a rare adrenocortical carcinoma (ACC) case, with dual lung metastases Cold Spring Harb. Mol. Case Stud. 5, (2019). https://doi.org/10.1101/mcs.a003764. D.P. Bartel, MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004). https://doi.org/10.1016/s0092-8674(04)00045-5 J.A. Weber, D.H. Baxter, S. Zhang, D.Y. Huang, K.H. Huang, M.J. Lee, D.J. Galas, K. Wang, The microRNA spectrum in 12 body fluids.Clin. Chem. 56, 1733–1741 (2010). https://doi.org/10.1373/clinchem.2010.147405 X. Chen, Y. Ba, L. Ma, X. Cai, Y. Yin, K. Wang, J. Guo, Y. Zhang, J. Chen, X. Guo, Q. Li, X. Li, W. Wang, Y. Zhang, J. Wang, X. Jiang, Y. Xiang, C. Xu, P. Zheng, J. Zhang, R. Li, H. Zhang, X. Shang, T. Gong, G. Ning, J. Wang, K. Zen, J. Zhang, C.-Y. Zhang, Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18, 997–1006 (2008). https://doi.org/10.1038/cr.2008.282 P.S. Mitchell, R.K. Parkin, E.M. Kroh, B.R. Fritz, S.K. Wyman, E.L. Pogosova-Agadjanyan, A. Peterson, J. Noteboom, K.C. O’Briant, A. Allen, D.W. Lin, N. Urban, C.W. Drescher, B.S. Knudsen, D.L. Stirewalt, R. Gentleman, R.L. Vessella, P.S. Nelson, D.B. Martin, M. Tewari, Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. U. S. A 105, 10513–10518 (2008). https://doi.org/10.1073/pnas.0804549105. I. Igaz, P. Igaz, Diagnostic Relevance of microRNAs in Other Body Fluids Including Urine, Feces, and Saliva. In Exp. Suppl. 245–252 (2015). https://doi.org/10.1007/978-3-0348-0955-9_11. I. Igaz, P. Igaz, Tumor surveillance by circulating microRNAs: a hypothesis. Cell. Mol. Life Sci. 71, 4081–4087 (2014). https://doi.org/10.1007/s00018-014-1682-4 J.S. McDonald, D. Milosevic, H.V. Reddi, S.K. Grebe, A. Algeciras-Schimnich, Analysis of circulating microRNA: preanalytical and analytical challenges. Clin. Chem. 57, 833–840 (2011). https://doi.org/10.1373/clinchem.2010.157198 K. Page, D.S. Guttery, N. Zahra, L. Primrose, S.R. Elshaw, J.H. Pringle, K. Blighe, S.D. Marchese, A. Hills, L. Woodley, J. Stebbing, R.C. Coombes, J.A. Shaw, Influence of Plasma Processing on Recovery and Analysis of Circulating Nucleic Acids. PLoS One 8, e77963 (2013). https://doi.org/10.1371/journal.pone.0077963 P. Igaz, Circulating microRNAs in adrenal tumors. Curr. Opin. Endocrinol. Diabetes Obes. 26, 155–159 (2019). https://doi.org/10.1097/MED.0000000000000472 A. Decmann, P. Perge, P.I. Turai, A. Patócs, P. Igaz, Non-Coding RNAs in Adrenocortical Cancer: From Pathogenesis to Diagnosis. Cancers. 12, (2020). https://doi.org/10.3390/CANCERS12020461. O. Chabre, R. Libé, G. Assie, O. Barreau, J. Bertherat, X. Bertagna, J.J. Feige, N. Cherradi, Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. Endocr. Relat. Cancer 20, 579–594 (2013). https://doi.org/10.1530/ERC-13-0051 P. Perge, H. Butz, R. Pezzani, I. Bancos, Z. Nagy, K. Pálóczi, G. Nyírő, Á. Decmann, E. Pap, M. Luconi, M. Mannelli, E.I. Buzás, M. Tóth, M. Boscaro, A. Patócs, P. Igaz, Evaluation and diagnostic potential of circulating extracellular vesicle-associated microRNAs in adrenocortical tumors. Sci. Rep. 7, 5474 (2017). https://doi.org/10.1038/s41598-017-05777-0 F. Salvianti, L. Canu, G. Poli, R. Armignacco, C. Scatena, G. Cantini, A. Di Franco, S. Gelmini, T. Ercolino, M. Pazzagli, G. Nesi, M. Mannelli, P. Pinzani, M. Luconi, New insights in the clinical and translational relevance of miR483-5p in adrenocortical cancer. Oncotarget 8, 65525–65533 (2017). https://doi.org/10.18632/ONCOTARGET.19118 M. Oreglia, S. Sbiera, M. Fassnacht, L. Guyon, J. Denis, J. Cristante, O. Chabre, and N. Cherradi, early postoperative circulating mir-483-5p is a prognosis marker for adrenocortical cancer. Cancers. 12, (2020). https://doi.org/10.3390/CANCERS12030724. Z. Nagy, K. Baghy, É. Hunyadi-Gulyás, T. Micsik, G. Nyírő, G. Rácz, H. Butz, P. Perge, I. Kovalszky, K.F. Medzihradszky, K. Rácz, A. Patócs, P. Igaz, Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model. Am. J. Cancer Res. 5, 3645–3658 (2015) S. Jung, Z. Nagy, M. Fassnacht, G. Zambetti, M. Weiss, M. Reincke, P. Igaz, F. Beuschlein, C. Hantel, Preclinical progress and first translational steps for a liposomal chemotherapy protocol against adrenocortical carcinoma. Endocr. Relat. Cancer 23, 825–837 (2016). https://doi.org/10.1530/ERC-16-0249 G. Huszty, A. Doros, K. Farkas, L. Kóbori, P. Reismann, J. Tőke, M. Tóth, P. Igaz, Case Report: Complete Necrosis of a Large Adrenocortical Cancer and Liver Metastases Achieved by Selective Arterial Embolization: A Case Study and Review of Literature. Front. Endocrinol. 12, (2021). https://doi.org/10.3389/FENDO.2021.677187.