Skip to main content

Circulating tumor DNA for malignant peripheral nerve sheath tumors in neurofibromatosis type 1



The leading cause of early death in patients with neurofibromatosis type 1 (NF1) is malignant peripheral nerve sheath tumor (MPNST). The principles of management include early diagnosis, surgical clearance and close monitoring for tumor recurrence. Current methods for diagnosis, detection of residual disease and monitoring tumor burden are inadequate, as clinical and radiological features are non-specific for malignancy in patients with multiple tumors and lack the sensitivity to identify early evidence of malignant transformation or tumor recurrence. Circulating tumor DNA (ctDNA) is a promising tool in cancer management and has the potential to improve the care of patients with NF1. In the following article we summarise the current understanding of the genomic landscape of MPNST, report on the previous literature of ctDNA in MPNST and outline the potential clinical applications for ctDNA in NF1 associated MPNST. Finally, we describe our prospective cohort study protocol investigating the utility of using ctDNA as an early diagnostic tool for MPNSTs in NF1 patients.

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

Fig. 1
Fig. 2
Fig. 3

Data availability

Not applicable.


  1. 1.

    Gutmann DH, Wood DL, Collins FS (1991) Identification of the neurofibromatosis type 1 gene product. Proc Natl Acad Sci USA 88:9658–9662.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A 152a:327–332.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ (2017) Neurofibromatosis type 1. Nat Rev Dis Primers 3:17004.

    Article  PubMed  Google Scholar 

  4. 4.

    Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D (2010) NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat 31:E1506-1518.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    DeClue JE, Cohen BD, Lowy DR (1991) Identification and characterization of the neurofibromatosis type 1 protein product. Proc Natl Acad Sci USA 88:9914–9918.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Zöller M, Rembeck B, Akesson HO, Angervall L (1995) Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg. Sweden Acta Derm Venereol 75:136–140.

    Article  PubMed  Google Scholar 

  7. 7.

    Airewele GE, Sigurdson AJ, Wiley KJ, Frieden BE, Caldarera LW, Riccardi VM, Lewis RA, Chintagumpala MM, Ater JL, Plon SE, Bondy ML (2001) Neoplasms in neurofibromatosis 1 are related to gender but not to family history of cancer. Genet Epidemiol 20:75–86

    CAS  Article  Google Scholar 

  8. 8.

    Mussi C, Schildhaus H-U, Gronchi A, Wardelmann E, Hohenberger P (2008) Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 14:4550.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A (2002) Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39:311–314.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Sandberg A, Stone J (2008) Malignant peripheral nerve sheath tumours. The genetics and molecular biology of neural tumours. Humana Press, Totowa, pp 43–81

    Chapter  Google Scholar 

  11. 11.

    Lothe RA, Smith-Sorensen B, Hektoen M, Stenwig AE, Mandahl N, Saeter G, Mertens F (2001) Biallelic inactivation of TP53 rarely contributes to the development of malignant peripheral nerve sheath tumors. Genes Chromosom Cancer 30:202–206

    CAS  Article  Google Scholar 

  12. 12.

    Pemov A, Li H, Presley W, Wallace MR, Miller DT (2020) Genetics of human malignant peripheral nerve sheath tumors. Neurooncol Adv 2:i50–i61.

    Article  PubMed  Google Scholar 

  13. 13.

    Bottillo I, Ahlquist T, Brekke H, Danielsen SA, van den Berg E, Mertens F, Lothe RA, Dallapiccola B (2009) Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. J Pathol 217:693–701.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M, Zhu S, Cao Z, Liang Y, Sboner A, Tap WD, Fletcher JA, Huberman KH, Qin LX, Viale A, Singer S, Zheng D, Berger MF, Chen Y, Antonescu CR, Chi P (2014) PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet 46:1227–1232.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Korfhage J, Lombard DB (2019) Malignant peripheral nerve sheath tumors: from epigenome to bedside. Mol Cancer Res 17:1417–1428

    CAS  Article  Google Scholar 

  16. 16.

    Cleven AH, Al Sannaa GA, Briaire-de Bruijn I, Ingram DR, van de Rijn M, Rubin BP, de Vries MW, Watson KL, Torres KE, Wang WL, van Duinen SG, Hogendoorn PC, Lazar AJ, Bovee JV (2016) Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol 29:1113.

    Article  PubMed  Google Scholar 

  17. 17.

    Zhang M, Wang Y, Jones S, Sausen M, McMahon K, Sharma R, Wang Q, Belzberg AJ, Chaichana K, Gallia GL, Gokaslan ZL, Riggins GJ, Wolinksy JP, Wood LD, Montgomery EA, Hruban RH, Kinzler KW, Papadopoulos N, Vogelstein B, Bettegowda C (2014) Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet 46:1170–1172.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    De Raedt T, Beert E, Pasmant E, Luscan A, Brems H, Ortonne N, Helin K, Hornick JL, Mautner V, Kehrer-Sawatzki H, Clapp W, Bradner J, Vidaud M, Upadhyaya M, Legius E, Cichowski K (2014) PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature 514:247–251.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Brohl AS, Kahen E, Yoder SJ, Teer JK, Reed DR (2017) The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation. Sci Rep 7:14992.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Mandel P, Metais P (1948) Nuclear acids in human blood plasma. CR Seances Soc Biol Fil 142:241–243

    CAS  Google Scholar 

  21. 21.

    Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N (2017) Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 17:223–238.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL (1994) Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomark Prev 3:67–71

    CAS  Google Scholar 

  23. 23.

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

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Hogarty MD, Holdhoff M, Hong SM, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson EJ, Marie SK, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins GJ, Sartore-Bianchi A, Schmidt K, Shih LM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang TL, Weingart JD, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz LA Jr (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, Liu CL, Neal JW, Wakelee HA, Merritt RE, Shrager JB, Loo BW Jr, Alizadeh AA, Diehn M (2014) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med 20:548–554.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Oxnard GR, Paweletz CP, Kuang Y, Mach SL, O’Connell A, Messineo MM, Luke JJ, Butaney M, Kirschmeier P, Jackman DM, Jänne PA (2014) Noninvasive detection of response and resistance in EGFR-mutant lung cancer using quantitative next-generation genotyping of cell-free plasma DNA. Clin Cancer Res 20:1698–1705.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld N (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14:985–990.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Tie J, Wang Y, Tomasetti C, Li L, Springer S, Kinde I, Silliman N, Tacey M, Wong HL, Christie M, Kosmider S, Skinner I, Wong R, Steel M, Tran B, Desai J, Jones I, Haydon A, Hayes T, Price TJ, Strausberg RL, Diaz LA Jr, Papadopoulos N, Kinzler KW, Vogelstein B, Gibbs P (2016) Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer. Sci Transl Med.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Turner NC, Kingston B, Kilburn LS, Kernaghan S, Wardley AM, Macpherson IR, Baird RD, Roylance R, Stephens P, Oikonomidou O, Braybrooke JP, Tuthill M, Abraham J, Winter MC, Bye H, Hubank M, Gevensleben H, Cutts R, Snowdon C, Rea D, Cameron D, Shaaban A, Randle K, Martin S, Wilkinson K, Moretti L, Bliss JM, Ring A (2020) Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol 21:1296–1308.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Oxnard GR, Thress KS, Alden RS, Lawrance R, Paweletz CP, Cantarini M, Yang JC, Barrett JC, Jänne PA (2016) Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J Clin Oncol 34:3375–3382.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Chabon JJ, Simmons AD, Lovejoy AF, Esfahani MS, Newman AM, Haringsma HJ, Kurtz DM, Stehr H, Scherer F, Karlovich CA, Harding TC, Durkin KA, Otterson GA, Purcell WT, Camidge DR, Goldman JW, Sequist LV, Piotrowska Z, Wakelee HA, Neal JW, Alizadeh AA, Diehn M (2016) Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat Commun 7:11815.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Hummel TR, Jessen WJ, Miller SJ, Kluwe L, Mautner VF, Wallace MR, Lázaro C, Page GP, Worley PF, Aronow BJ, Schorry EK, Ratner N (2010) Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin. Clin Cancer Res 16:5048–5057.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Johansson G, Peng P-C, Huang P-Y, Chien H-F, Hua K-T, Kuo M-L, Chen C-T, Lee M-J (2014) Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden. PLoS ONE 9:e115916–e115916.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Kolanczyk M, Mautner V, Kossler N, Nguyen R, Kühnisch J, Zemojtel T, Jamsheer A, Wegener E, Thurisch B, Tinschert S, Holtkamp N, Park SJ, Birch P, Kendler D, Harder A, Mundlos S, Kluwe L (2011) MIA is a potential biomarker for tumour load in neurofibromatosis type 1. BMC Med 9:82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Park SJ, Sawitzki B, Kluwe L, Mautner VF, Holtkamp N, Kurtz A (2013) Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors. BMC Med 11:109.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Yoshida Y, Furumura M, Tahira M, Horie T, Yamamoto O (2012) Serum biomarker in neurofibromatosis type 1. J Dermatol Sci 67:155–158.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Kallionpää RA, Ahramo K, Aaltonen M, Pennanen P, Peltonen J, Peltonen S (2021) Circulating free DNA in the plasma of individuals with neurofibromatosis type 1. Am J Med Genet Part A.

    Article  PubMed  Google Scholar 

  40. 40.

    Eastley N, Sommer A, Ottolini B, Neumann R, Luo JL, Hastings RK, McCulloch T, Esler CP, Shaw JA, Ashford RU, Royle NJ (2020) The circulating nucleic acid characteristics of non-metastatic soft tissue sarcoma patients. Int J Mol Sci.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Shulman DS, Klega K, Imamovic-Tuco A, Clapp A, Nag A, Thorner AR, Van Allen E, Ha G, Lessnick SL, Gorlick R, Janeway KA, Leavey PJ, Mascarenhas L, London WB, Vo KT, Stegmaier K, Hall D, Krailo MD, Barkauskas DA, DuBois SG, Crompton BD (2018) Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group. Br J Cancer 119:615–621.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    George SL, Izquierdo E, Campbell J, Koutroumanidou E, Proszek P, Jamal S, Hughes D, Yuan L, Marshall LV, Carceller F, Chisholm JC, Vaidya S, Mandeville H, Angelini P, Wasti A, Bexelius T, Thway K, Gatz SA, Clarke M, Al-Lazikani B, Barone G, Anderson J, Tweddle DA, Gonzalez D, Walker BA, Barton J, Depani S, Eze J, Ahmed SW, Moreno L, Pearson A, Shipley J, Jones C, Hargrave D, Jacques TS, Hubank M, Chesler L (2019) A tailored molecular profiling programme for children with cancer to identify clinically actionable genetic alterations. Eur J Cancer 121:224–235.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Hemming ML, Klega KS, Rhoades J, Ha G, Acker KE, Andersen JL, Thai E, Nag A, Thorner AR, Raut CP, George S, Crompton BD (2019) Detection of circulating tumor DNA in patients with leiomyosarcoma with progressive disease. JCO Precis Oncol.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Gutteridge A, Rathbone VM, Gibbons R, Bi M, Archard N, Davies KEJ, Brown J, Plagnol V, Pillay N, Amary F, O’Donnell P, Gupta M, Tirabosco R, Flanagan AM, Forshew T (2017) Digital PCR analysis of circulating tumor DNA: a biomarker for chondrosarcoma diagnosis, prognostication, and residual disease detection. Cancer Med 6:2194–2202.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Klega K, Imamovic-Tuco A, Ha G, Clapp AN, Meyer S, Ward A, Clinton C, Nag A, Van Allen E, Mullen E, DuBois SG, Janeway K, Meyerson M, Thorner AR, Crompton BD (2018) Detection of somatic structural variants enables quantification and characterization of circulating tumor DNA in children with solid tumors. JCO Precis Oncol.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Prudner BC, Ball T, Rathore R, Hirbe AC (2020) Diagnosis and management of malignant peripheral nerve sheath tumors: current practice and future perspectives. Neurooncol Adv 2:i40–i49.

    Article  PubMed  Google Scholar 

  47. 47.

    Urban T, Lim R, Merker VL, Muzikansky A, Harris GJ, Kassarjian A, Bredella MA, Plotkin SR (2014) Anatomic and metabolic evaluation of peripheral nerve sheath tumors in patients with neurofibromatosis 1 using whole-body MRI and (18)F-FDG PET fusion. Clin Nucl Med 39:e301-307.

    Article  PubMed  Google Scholar 

  48. 48.

    Meany H, Dombi E, Reynolds J, Whatley M, Kurwa A, Tsokos M, Salzer W, Gillespie A, Baldwin A, Derdak J, Widemann B (2013) 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) evaluation of nodular lesions in patients with Neurofibromatosis type 1 and plexiform neurofibromas (PN) or malignant peripheral nerve sheath tumors (MPNST). Pediatr Blood Cancer 60:59–64.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Ahlawat S, Blakeley JO, Rodriguez FJ, Fayad LM (2019) Imaging biomarkers for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. Neurology 93:e1076

    CAS  Article  Google Scholar 

  50. 50.

    Miller DT, Cortes-Ciriano I, Pillay N, Hirbe AC, Snuderl M, Bui MM, Piculell K, Al-Ibraheemi A, Dickson BC, Hart J, Jones K, Jordan JT, Kim RH, Lindsay D, Nishida Y, Ullrich NJ, Wang X, Park PJ, Flanagan AM (2020) Genomics of MPNST (GeM) consortium: rationale and study design for multi-omic characterization of NF1-associated and sporadic MPNSTs. Genes.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, Anagnostou V, Fiksel J, Cristiano S, Papp E, Speir S, Reinert T, Orntoft MW, Woodward BD, Murphy D, Parpart-Li S, Riley D, Nesselbush M, Sengamalay N, Georgiadis A, Li QK, Madsen MR, Mortensen FV, Huiskens J, Punt C, van Grieken N, Fijneman R, Meijer G, Husain H, Scharpf RB, Diaz LA Jr, Jones S, Angiuoli S, Ørntoft T, Nielsen HJ, Andersen CL, Velculescu VE (2017) Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med.

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, Le Quesne J, Moore DA, Veeriah S, Rosenthal R, Marafioti T, Kirkizlar E, Watkins TBK, McGranahan N, Ward S, Martinson L, Riley J, Fraioli F, Al Bakir M, Grönroos E, Zambrana F, Endozo R, Bi WL, Fennessy FM, Sponer N, Johnson D, Laycock J, Shafi S, Czyzewska-Khan J, Rowan A, Chambers T, Matthews N, Turajlic S, Hiley C, Lee SM, Forster MD, Ahmad T, Falzon M, Borg E, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Hafez D, Naik A, Ganguly A, Kareht S, Shah R, Joseph L, Marie Quinn A, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Oukrif D, Akarca AU, Hartley JA, Lowe HL, Lock S, Iles N, Bell H, Ngai Y, Elgar G, Szallasi Z, Schwarz RF, Herrero J, Stewart A, Quezada SA, Peggs KS, Van Loo P, Dive C, Lin CJ, Rabinowitz M, Aerts H, Hackshaw A, Shaw JA, Zimmermann BG, Swanton C (2017) Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545:446–451.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366:883–892.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Knuever J, Weiss J, Persa OD, Kreuzer K, Mauch C, Hallek M, Schlaak M (2020) The use of circulating cell-free tumor DNA in routine diagnostics of metastatic melanoma patients. Sci Rep 10:4940.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Forschner A, Weißgraeber S, Hadaschik D, Schulze M, Kopp M, Kelkenberg S, Sinnberg T, Garbe C, Biskup S, Battke F (2020) Circulating tumor DNA correlates with outcome in metastatic melanoma treated by BRAF and MEK inhibitors—results of a prospective biomarker study. Onco Targets Ther 13:5017–5032.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Rothwell DG, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E, Smith N, Villa S, Dransfield J, Clipson A, White D, Nessa K, Ferdous S, Howell M, Gupta A, Kilerci B, Mohan S, Frese K, Gulati S, Miller C, Jordan A, Eaton H, Hickson N, O’Brien C, Graham D, Kelly C, Aruketty S, Metcalf R, Chiramel J, Tinsley N, Vickers AJ, Kurup R, Frost H, Stevenson J, Southam S, Landers D, Wallace A, Marais R, Hughes AM, Brady G, Dive C, Krebs MG (2019) Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat Med 25:738–743.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Nakamura Y, Taniguchi H, Ikeda M, Bando H, Kato K, Morizane C, Esaki T, Komatsu Y, Kawamoto Y, Takahashi N, Ueno M, Kagawa Y, Nishina T, Kato T, Yamamoto Y, Furuse J, Denda T, Kawakami H, Oki E, Nakajima T, Nishida N, Yamaguchi K, Yasui H, Goto M, Matsuhashi N, Ohtsubo K, Yamazaki K, Tsuji A, Okamoto W, Tsuchihara K, Yamanaka T, Miki I, Sakamoto Y, Ichiki H, Hata M, Yamashita R, Ohtsu A, Odegaard JI, Yoshino T (2020) Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med.

    Article  PubMed  Google Scholar 

  58. 58.

    Merker JD, Oxnard GR, Compton C, Diehn M, Hurley P, Lazar AJ, Lindeman N, Lockwood CM, Rai AJ, Schilsky RL, Tsimberidou AM, Vasalos P, Billman BL, Oliver TK, Bruinooge SS, Hayes DF, Turner NC (2018) Circulating tumor DNA analysis in patients with cancer: American Society of clinical oncology and college of American pathologists joint review. J Clin Oncol 36:1631–1641.

    CAS  Article  PubMed  Google Scholar 

Download references


Not applicable.

Author information




Conception, planning: GD, KD. Writing & editing manuscript: JJ, SC, JPS, PC, AM, KD, GD.

Corresponding author

Correspondence to Jordan Jones.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

Not applicable.

Consent for publication

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

Verify currency and authenticity via CrossMark

Cite this article

Jones, J., Cain, S., Pesic-Smith, J. et al. Circulating tumor DNA for malignant peripheral nerve sheath tumors in neurofibromatosis type 1. J Neurooncol 154, 265–274 (2021).

Download citation


  • Neurofibromatosis type 1
  • Malignant peripheral nerve sheath tumor
  • Circulating tumor DNA
  • Biomarkers
  • Liquid biopsy