Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous disease that, even with current advancements in therapy, continues to have a poor prognosis. Recurrent somatic mutations have been identified in a core set of pathogenic genes including FLT3 (25–30% prevalence), NPM1 (25–30%), DNMT3A (25–30%), IDH1/2 (5–15%), and TET2 (5–15%), with direct diagnostic, prognostic, and targeted therapeutic implications. Advances in the understanding of the complex mechanisms of AML leukemogenesis have led to the development and recent US Food and Drug Administration (FDA) approval of several targeted therapies: midostaurin and gilteritinib targeting activated FLT3, and ivosidenib and enasidenib targeting mutated IDH1/2. Several additional drug candidates targeting other recurrently mutated gene pathways in AML are also being actively developed. Furthermore, outside of the realm of predicting responses to targeted therapies, many other mutated genes, which comprise the so-called long tail of oncogenic drivers in AML, have been shown to provide clinically useful diagnostic and prognostic information for AML patients. Many of these recurrently mutated genes have also been shown to be excellent biomarkers for post-treatment minimal residual disease (MRD) monitoring for assessing treatment response and predicting future relapse. In addition, the identification of germline mutations in a set of genes predisposing to myeloid malignancies may directly inform treatment decisions (particularly stem cell transplantation) and impact other family members. Recent advances in sequencing technology have made it practically and economically feasible to evaluate many genes simultaneously using next-generation sequencing (NGS). Mutation screening with NGS panels has been recommended by national and international professional guidelines as the standard of care for AML patients. NGS-based detection of the heterogeneous genes commonly mutated in AML has practical clinical utility for disease diagnosis, prognosis, prediction of targeted therapy response, and MRD monitoring.
Similar content being viewed by others
References
National Cancer Institute. Cancer stat facts: leukemia - acute myeloid leukemia (AML). 2019. https://seer.cancer.gov/statfacts/html/amyl.html. Accessed 22 Apr 2019.
American Society of Clinical Oncology. Leukemia - acute myeloid - AML: statistics. 2019. https://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/statistics. Accessed 22 Apr 2019.
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. https://doi.org/10.1182/blood-2016-08-733196.
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Rev. 4th ed. World Health Organization classification of tumours. Lyon: IARC; 2017.
Cancer Genome Atlas Research Network, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. https://doi.org/10.1056/NEJMoa1301689.
Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Gorlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686–98. https://doi.org/10.1182/blood-2016-01-693879.
Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–21. https://doi.org/10.1056/NEJMoa1516192.
Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, et al. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018;562(7728):526–31. https://doi.org/10.1038/s41586-018-0623-z.
Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109(2):431–48. https://doi.org/10.1182/blood-2006-06-001149.
Bullinger L, Dohner K, Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934–46. https://doi.org/10.1200/JCO.2016.71.2208.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451–8.
Bloomfield CD, Brunning RD. FAB M7: acute megakaryoblastic leukemia–beyond morphology. Ann Intern Med. 1985;103(3):450–2.
Lee EJ, Pollak A, Leavitt RD, Testa JR, Schiffer CA. Minimally differentiated acute nonlymphocytic leukemia: a distinct entity. Blood. 1987;70(5):1400–6.
Schnittger S, Dicker F, Kern W, Wendland N, Sundermann J, Alpermann T, et al. RUNX1 mutations are frequent in de novo AML with noncomplex karyotype and confer an unfavorable prognosis. Blood. 2011;117(8):2348–57. https://doi.org/10.1182/blood-2009-11-255976.
Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–91. https://doi.org/10.1182/blood-2008-04-150250.
National Comprehensive Cancer Network. Acute myeloid leukemia (version 1.2020—August 13, 2019. 2019. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed 22 Apr 2019.
Wang B, Liu Y, Hou G, Wang L, Lv N, Xu Y, et al. Mutational spectrum and risk stratification of intermediate-risk acute myeloid leukemia patients based on next-generation sequencing. Oncotarget. 2016;7(22):32065–78. https://doi.org/10.18632/oncotarget.7028.
Dunlap JB, Leonard J, Rosenberg M, Cook R, Press R, Fan G, et al. The combination of NPM1, DNMT3A, and IDH1/2 mutations leads to inferior overall survival in AML. Am J Hematol. 2019;94(8):913–20. https://doi.org/10.1002/ajh.25517.
Ma J, Dunlap J, Paliga A, Traer E, Press R, Shen L, et al. DNMT3A co-mutation is required for FLT3-ITD as an adverse prognostic indicator in intermediate-risk cytogenetic group AML. Leuk Lymphoma. 2018;59(8):1938–48. https://doi.org/10.1080/10428194.2017.1397659.
Patel SS, Kuo FC, Gibson CJ, Steensma DP, Soiffer RJ, Alyea EP 3rd, et al. High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML. Blood. 2018;131(25):2816–25. https://doi.org/10.1182/blood-2018-01-828467.
Alpermann T, Schnittger S, Eder C, Dicker F, Meggendorfer M, Kern W, et al. Molecular subtypes of NPM1 mutations have different clinical profiles, specific patterns of accompanying molecular mutations and varying outcomes in intermediate risk acute myeloid leukemia. Haematologica. 2016;101(2):e55–8. https://doi.org/10.3324/haematol.2015.133819.
Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125(9):1367–76. https://doi.org/10.1182/blood-2014-11-610543.
Kuo FC, Mar BG, Lindsley RC, Lindeman NI. The relative utilities of genome-wide, gene panel, and individual gene sequencing in clinical practice. Blood. 2017;130(4):433–9. https://doi.org/10.1182/blood-2017-03-734533.
Fernandez HF, Sun Z, Yao X, Litzow MR, Luger SM, Paietta EM, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249–59. https://doi.org/10.1056/NEJMoa0904544.
Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–89. https://doi.org/10.1056/NEJMoa1112304.
Luskin MR, Lee JW, Fernandez HF, Abdel-Wahab O, Bennett JM, Ketterling RP, et al. Benefit of high-dose daunorubicin in AML induction extends across cytogenetic and molecular groups. Blood. 2016;127(12):1551–8. https://doi.org/10.1182/blood-2015-07-657403.
Lancet JE, Uy GL, Cortes JE, Newell LF, Lin TL, Ritchie EK, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–92. https://doi.org/10.1200/JCO.2017.77.6112.
Welch JS, Petti AA, Miller CA, Fronick CC, O’Laughlin M, Fulton RS, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–36. https://doi.org/10.1056/NEJMoa1605949.
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454–64. https://doi.org/10.1056/NEJMoa1614359.
DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386–98. https://doi.org/10.1056/NEJMoa1716984.
Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–31. https://doi.org/10.1182/blood-2017-04-779405.
Perl AE, Altman JK, Cortes J, Smith C, Litzow M, Baer MR, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18(8):1061–75. https://doi.org/10.1016/S1470-2045(17)30416-3.
Carbonell D, Suarez-Gonzalez J, Chicano M, Andres-Zayas C, Trivino JC, Rodriguez-Macias G, et al. Next-generation sequencing improves diagnosis, prognosis and clinical management of myeloid neoplasms. Cancers (Basel). 2019;11(9):E1364. https://doi.org/10.3390/cancers11091364.
Watts J, Nimer S. Recent advances in the understanding and treatment of acute myeloid leukemia. F1000Res. 2018;7:F1000 Faculty Rev-1196. https://doi.org/10.12688/f1000research.14116.1.
Burd A, Levine RL, Shoben A, Mims AS, Borate U, Stein EM, et al. Initial report of the Beat AML umbrella study for previously untreated AML: evidence of feasibility and early success in molecularly driven phase 1 and 2 studies [abstract]. Blood. 2018;132(Suppl 1):559. https://doi.org/10.1182/blood-2018-99-118494.
Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, et al. Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017;19(1):4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. https://doi.org/10.1038/gim.2015.30.
Schuurhuis GJ, Heuser M, Freeman S, Bene MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275–91. https://doi.org/10.1182/blood-2017-09-801498.
Hourigan CS, Karp JE. Minimal residual disease in acute myeloid leukaemia. Nat Rev Clin Oncol. 2013;10(8):460–71. https://doi.org/10.1038/nrclinonc.2013.100.
Bacher U, Dicker F, Haferlach C, Alpermann T, Rose D, Kern W, et al. Quantification of rare NPM1 mutation subtypes by digital PCR. Br J Haematol. 2014;167(5):710–4. https://doi.org/10.1111/bjh.13038.
Brunetti C, Anelli L, Zagaria A, Minervini A, Minervini CF, Casieri P, et al. Droplet digital PCR is a reliable tool for monitoring minimal residual disease in acute promyelocytic leukemia. J Mol Diagn. 2017;19(3):437–44. https://doi.org/10.1016/j.jmoldx.2017.01.004.
Mencia-Trinchant N, Hu Y, Alas MA, Ali F, Wouters BJ, Lee S, et al. Minimal residual disease monitoring of acute myeloid leukemia by massively multiplex digital PCR in patients with NPM1 mutations. J Mol Diagn. 2017;19(4):537–48. https://doi.org/10.1016/j.jmoldx.2017.03.005.
Zeijlemaker W, Gratama JW, Schuurhuis GJ. Tumor heterogeneity makes AML a “moving target” for detection of residual disease. Cytometry B Clin Cytom. 2013. https://doi.org/10.1002/cytob.21134.
Maurillo L, Buccisano F, Del Principe MI, Del Poeta G, Spagnoli A, Panetta P, et al. Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia. J Clin Oncol. 2008;26(30):4944–51. https://doi.org/10.1200/JCO.2007.15.9814.
Bacher U, Porret N, Joncourt R, Sanz J, Aliu N, Wiedemann G, et al. Pitfalls in the molecular follow up of NPM1 mutant acute myeloid leukemia. Haematologica. 2018;103(10):e486–8. https://doi.org/10.3324/haematol.2018.192104.
Hollein A, Meggendorfer M, Dicker F, Jeromin S, Nadarajah N, Kern W, et al. NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse. Blood Adv. 2018;2(22):3118–25. https://doi.org/10.1182/bloodadvances.2018023432.
Kihara R, Nagata Y, Kiyoi H, Kato T, Yamamoto E, Suzuki K, et al. Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. Leukemia. 2014;28(8):1586–95. https://doi.org/10.1038/leu.2014.55.
Jongen-Lavrencic M, Grob T, Hanekamp D, Kavelaars FG, Al Hinai A, Zeilemaker A, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018;378(13):1189–99. https://doi.org/10.1056/NEJMoa1716863.
Alonso CM, Llop M, Sargas C, Pedrola L, Panadero J, Hervas D, et al. Clinical utility of a next-generation sequencing panel for acute myeloid leukemia diagnostics. J Mol Diagn. 2019;21(2):228–40. https://doi.org/10.1016/j.jmoldx.2018.09.009.
Press RD, Eickelberg G, Froman A, Yang F, Stentz A, Flatley EM, et al. Next-generation sequencing-defined minimal residual disease before stem cell transplantation predicts acute myeloid leukemia relapse. Am J Hematol. 2019;94(8):902–12. https://doi.org/10.1002/ajh.25514.
Thol F, Gabdoulline R, Liebich A, Klement P, Schiller J, Kandziora C, et al. Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML. Blood. 2018;132(16):1703–13. https://doi.org/10.1182/blood-2018-02-829911.
Salk JJ, Schmitt MW, Loeb LA. Enhancing the accuracy of next-generation sequencing for detecting rare and subclonal mutations. Nat Rev Genet. 2018;19(5):269–85. https://doi.org/10.1038/nrg.2017.117.
Liggett LA, Sharma A, De S, DeGregori J. FERMI: a novel method for sensitive detection of rare mutations in somatic tissue. G3 (Bethesda). 2019;9(9):2977–87. https://doi.org/10.1534/g3.119.400438.
Klco JM, Miller CA, Griffith M, Petti A, Spencer DH, Ketkar-Kulkarni S, et al. Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia. JAMA. 2015;314(8):811–22. https://doi.org/10.1001/jama.2015.9643.
Hirsch P, Tang R, Abermil N, Flandrin P, Moatti H, Favale F, et al. Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia. Haematologica. 2017;102(7):1227–37. https://doi.org/10.3324/haematol.2016.159681.
Morita K, Kantarjian HM, Wang F, Yan Y, Bueso-Ramos C, Sasaki K, et al. Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia. J Clin Oncol. 2018;36(18):1788–97. https://doi.org/10.1200/JCO.2017.77.6757.
Malmberg EB, Stahlman S, Rehammar A, Samuelsson T, Alm SJ, Kristiansson E, et al. Patient-tailored analysis of minimal residual disease in acute myeloid leukemia using next-generation sequencing. Eur J Haematol. 2017;98(1):26–37. https://doi.org/10.1111/ejh.12780.
Kim T, Moon JH, Ahn JS, Kim YK, Lee SS, Ahn SY, et al. Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse. Blood. 2018;132(15):1604–13. https://doi.org/10.1182/blood-2018-04-848028.
Schroeder T, Rachlis E, Bug G, Stelljes M, Klein S, Steckel NK, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions—a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. 2015;21(4):653–60. https://doi.org/10.1016/j.bbmt.2014.12.016.
Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371(26):2477–87. https://doi.org/10.1056/NEJMoa1409405.
Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371(26):2488–98. https://doi.org/10.1056/NEJMoa1408617.
Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8. https://doi.org/10.1038/nm.3733.
Bhatnagar B, Eisfeld AK, Nicolet D, Mrozek K, Blachly JS, Orwick S, et al. Persistence of DNMT3A R882 mutations during remission does not adversely affect outcomes of patients with acute myeloid leukaemia. Br J Haematol. 2016;175(2):226–36. https://doi.org/10.1111/bjh.14254.
Debarri H, Lebon D, Roumier C, Cheok M, Marceau-Renaut A, Nibourel O, et al. IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the Acute Leukemia French Association. Oncotarget. 2015;6(39):42345–53. https://doi.org/10.18632/oncotarget.5645.
Rothenberg-Thurley M, Amler S, Goerlich D, Kohnke T, Konstandin NP, Schneider S, et al. Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia. Leukemia. 2017. https://doi.org/10.1038/leu.2017.350.
The University of Chicago Hematopoietic Malignancies Cancer Risk Team, Drazer MW, Feurstein S, West AH, Jones MF, Churpek JE, et al. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2016;128(14):1800–13. https://doi.org/10.1182/blood-2016-05-670240.
Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ, et al. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117(8):2469–75. https://doi.org/10.1182/blood-2010-09-307280.
Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26(31):5088–93. https://doi.org/10.1200/jco.2008.16.5563.
Wlodarski MW, Hirabayashi S, Pastor V, Stary J, Hasle H, Masetti R, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127(11):1387–97. https://doi.org/10.1182/blood-2015-09-669937(quiz 518).
Xiao H, Shi J, Luo Y, Tan Y, He J, Xie W, et al. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood. 2011;117(19):5257–60. https://doi.org/10.1182/blood-2010-12-326322.
Berger G, van den Berg E, Sikkema-Raddatz B, Abbott KM, Sinke RJ, Bungener LB, et al. Re-emergence of acute myeloid leukemia in donor cells following allogeneic transplantation in a family with a germline DDX41 mutation. Leukemia. 2017;31(2):520–2. https://doi.org/10.1038/leu.2016.310.
Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362(9396):1628–30. https://doi.org/10.1016/S0140-6736(03)14797-6.
Churpek JE, Nickels E, Marquez R, Rojek K, Liu B, Lorenz R, et al. Identifying familial myelodysplastic/acute leukemia predisposition syndromes through hematopoietic stem cell transplantation donors with thrombocytopenia. Blood. 2012;120(26):5247–9. https://doi.org/10.1182/blood-2012-09-457945.
Rosenberg PS, Alter BP, Ebell W. Cancer risks in Fanconi anemia: findings from the German Fanconi Anemia Registry. Haematologica. 2008;93(4):511–7. https://doi.org/10.3324/haematol.12234.
Dror Y, Freedman MH, Leaker M, Verbeek J, Armstrong CA, Saunders FE, et al. Low-intensity hematopoietic stem-cell transplantation across human leucocyte antigen barriers in dyskeratosis congenita. Bone Marrow Transplant. 2003;31(10):847–50. https://doi.org/10.1038/sj.bmt.1703931.
Dietz AC, Orchard PJ, Baker KS, Giller RH, Savage SA, Alter BP, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant. 2011;46(1):98–104. https://doi.org/10.1038/bmt.2010.65.
Nelson AS, Marsh RA, Myers KC, Davies SM, Jodele S, O’Brien TA, et al. A reduced-intensity conditioning regimen for patients with dyskeratosis congenita undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(5):884–8. https://doi.org/10.1016/j.bbmt.2016.01.026.
Guidugli L, Johnson AK, Alkorta-Aranburu G, Nelakuditi V, Arndt K, Churpek JE, et al. Clinical utility of gene panel-based testing for hereditary myelodysplastic syndrome/acute leukemia predisposition syndromes. Leukemia. 2017;31(5):1226–9. https://doi.org/10.1038/leu.2017.28.
Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015;373(24):2336–46. https://doi.org/10.1056/NEJMoa1508054.
Churpek JE, Pyrtel K, Kanchi KL, Shao J, Koboldt D, Miller CA, et al. Genomic analysis of germ line and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood. 2015;126(22):2484–90. https://doi.org/10.1182/blood-2015-04-641100.
Godley LA, Shimamura A. Genetic predisposition to hematologic malignancies: management and surveillance. Blood. 2017;130(4):424–32. https://doi.org/10.1182/blood-2017-02-735290.
Churpek JE, Lorenz R, Nedumgottil S, Onel K, Olopade OI, Sorrell A, et al. Proposal for the clinical detection and management of patients and their family members with familial myelodysplastic syndrome/acute leukemia predisposition syndromes. Leuk Lymphoma. 2013;54(1):28–35. https://doi.org/10.3109/10428194.2012.701738.
Mack EKM, Marquardt A, Langer D, Ross P, Ultsch A, Kiehl MG, et al. Comprehensive genetic diagnosis of acute myeloid leukemia by next-generation sequencing. Haematologica. 2019;104(2):277–87. https://doi.org/10.3324/haematol.2018.194258.
Hills RK, Ivey A, Grimwade D. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;375(6):e9. https://doi.org/10.1056/NEJMc1603847.
Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. https://doi.org/10.1056/NEJMoa1005143.
Liu X, Ye Q, Zhao XP, Zhang PB, Li S, Li RQ, et al. RAS mutations in acute myeloid leukaemia patients: a review and meta-analysis. Clin Chim Acta. 2019;489:254–60. https://doi.org/10.1016/j.cca.2018.08.040.
Dunna NR, Vuree S, Anuradha C, Sailaja K, Surekha D, Digumarti RR, et al. NRAS mutations in de novo acute leukemia: prevalence and clinical significance. Indian J Biochem Biophys. 2014;51(3):207–10.
Chou WC, Chou SC, Liu CY, Chen CY, Hou HA, Kuo YY, et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood. 2011;118(14):3803–10. https://doi.org/10.1182/blood-2011-02-339747.
Loh ML, Reynolds MG, Vattikuti S, Gerbing RB, Alonzo TA, Carlson E, et al. PTPN11 mutations in pediatric patients with acute myeloid leukemia: results from the Children’s Cancer Group. Leukemia. 2004;18(11):1831–4. https://doi.org/10.1038/sj.leu.2403492.
Hou HA, Chou WC, Lin LI, Chen CY, Tang JL, Tseng MH, et al. Characterization of acute myeloid leukemia with PTPN11 mutation: the mutation is closely associated with NPM1 mutation but inversely related to FLT3/ITD. Leukemia. 2008;22(5):1075–8. https://doi.org/10.1038/sj.leu.2405005.
Grosskopf S, Eckert C, Arkona C, Radetzki S, Bohm K, Heinemann U, et al. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem. 2015;10(5):815–26. https://doi.org/10.1002/cmdc.201500015.
Yu B, Liu W, Yu WM, Loh ML, Alter S, Guvench O, et al. Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies. Mol Cancer Ther. 2013;12(9):1738–48. https://doi.org/10.1158/1535-7163.Mct-13-0049-t.
Ahmad EI, Gawish HH, Al Azizi NM, Elhefni AM. The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine. Onco Targets Ther. 2011;4:115–21. https://doi.org/10.2147/ott.S12602.
Fasan A, Eder C, Haferlach C, Grossmann V, Kohlmann A, Dicker F, et al. GATA2 mutations are frequent in intermediate-risk karyotype AML with biallelic CEBPA mutations and are associated with favorable prognosis. Leukemia. 2013;27(2):482–5. https://doi.org/10.1038/leu.2012.174.
Weisberg E, Meng C, Case AE, Sattler M, Tiv HL, Gokhale PC, et al. Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU-285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies. Br J Haematol. 2019;187(4):488–501. https://doi.org/10.1111/bjh.16092.
Tsai CH, Hou HA, Tang JL, Kuo YY, Chiu YC, Lin CC, et al. Prognostic impacts and dynamic changes of cohesin complex gene mutations in de novo acute myeloid leukemia. Blood Cancer J. 2017;7(12):663. https://doi.org/10.1038/s41408-017-0022-y.
Cheah JJC, Hahn CN, Hiwase DK, Scott HS, Brown AL. Myeloid neoplasms with germline DDX41 mutation. Int J Hematol. 2017;106(2):163–74. https://doi.org/10.1007/s12185-017-2260-y.
Polprasert C, Schulze I, Sekeres MA, Makishima H, Przychodzen B, Hosono N, et al. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell. 2015;27(5):658–70. https://doi.org/10.1016/j.ccell.2015.03.017.
Eisfeld AK, Kohlschmidt J, Mrozek K, Mims A, Walker CJ, Blachly JS, et al. NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. Leukemia. 2018;32(12):2536–45. https://doi.org/10.1038/s41375-018-0147-4.
Saliba J, Saint-Martin C, Di Stefano A, Lenglet G, Marty C, Keren B, et al. Germline duplication of ATG2B and GSKIP predisposes to familial myeloid malignancies. Nat Genet. 2015;47(10):1131–40. https://doi.org/10.1038/ng.3380.
National Comprehensive Cancer Network. Myelodysplastic syndromes (version 2.2019). 2019. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed 22 Apr 2019.
Robles-Espinoza CD, Velasco-Herrera Mdel C, Hayward NK, Adams DJ. Telomere-regulating genes and the telomere interactome in familial cancers. Mol Cancer Res. 2015;13(2):211–22. https://doi.org/10.1158/1541-7786.Mcr-14-0305.
Borate U, et al. 373 Prevalence of inherited cancer predisposition mutations in a cohort of older AML patients enrolled on the beat AML master trial. https://ash.confex.com/ash/2019/webprogram/Paper131925.html.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
No external funding was used in the preparation of this manuscript.
Conflict of interest
Fei Yang, Tauangtham Anekpuritanang, and Richard D. Press declare that they have no conflicts of interest that might be relevant to the contents of this article.
Rights and permissions
About this article
Cite this article
Yang, F., Anekpuritanang, T. & Press, R.D. Clinical Utility of Next-Generation Sequencing in Acute Myeloid Leukemia. Mol Diagn Ther 24, 1–13 (2020). https://doi.org/10.1007/s40291-019-00443-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40291-019-00443-9