Li–Fraumeni syndrome in adult patients with acute lymphoblastic leukemia

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Abstract

Background. Li–Fraumeni syndrome (LFS) is a rare, autosomal dominant, hereditary disorder that is characterized by an increased risk for certain types of cancer, acute lymphoblastic leukemia (ALL), particularly. Germline TP53 mutations are associated with LFS. Genetic counseling and follow-up is essential for patients with LFS and their relatives. Special therapeutic approaches are needed for treatment of oncological disease in these patients. The article presents a series of clinical cases of patients with ALL and SLF, considers general issues of diagnosis and treatment of adult patients with this hereditary genetic syndrome.

Aim. Describe clinical observations of patients with acute lymphoblastic leukemia (ALL) and LFS and consider general issues of diagnosis and treatment of adult patients with LFS and ALL.

Materials and methods. TP53 gene mutations were screened using Sanger sequencing in 180 de novo patients with Ph-negative (B- and T-cell) and Ph-positive ALL treated by Russian multicenter protocols (ALL-2009, ALL-2012, ALL-2016) at the National Research Center for Hematology, Moscow, Russia, and at the hematology departments of regional clinics of Russia (multicenter study participants).

Results. TP53 gene mutations were found in 7.8% (n=14) of de novo ALL patients. In patients, whose biological material was available TP53 gene mutational status was determined in non-tumor cells (bone marrow and peripheral blood during remission, bone marrow samples after allogeneic hematopoietic stem cells transplantation and in tissue of non-hematopoietic origin) for discriminating germline mutations. The analysis included 5 patients (out of 14 with TP53 mutations), whose non-tumor biological material was available for research. Germline status was confirmed in 4 out of 5 – B-cell ALL (n=3), T-cell ALL (n=1) – investigated patients.

Conclusion. Practical value of the research is the observation that the greater part of TP53 gene mutations in patients with Ph-negative B-cell ALL are germinal and associated with LFS.

About the authors

Kseniia I. Zarubina

National Research Center for Hematology

Author for correspondence.
Email: ksenijazarubina@mail.com
ORCID iD: 0000-0003-2947-6398

врач-гематолог отд-ния интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

Russian Federation, Moscow

Elena N. Parovichnikova

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0001-6177-3566

д-р мед. наук, проф., рук. отд. химиотерапии гемобластозов, депрессий кроветворения и ТКМ

Russian Federation, Moscow

Vadim L. Surin

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0002-1890-4492

и. о. рук. лаб. генной инженерии

Russian Federation, Moscow

Olesia S. Pshenichnikova

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0001-5752-8146

канд. биол. наук, ст. науч. сотр. лаб. генной инженерии

Russian Federation, Moscow

Olga A. Gavrilina

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0002-9969-8482

канд. мед. наук, врач-гематолог, ст. науч. сотр. отд-ния интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

Russian Federation, Moscow

Galina A. Isinova

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0003-2763-5391

канд. мед. наук, врач-гематолог отд-ния интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

Russian Federation, Moscow

Vera V. Troitskaya

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0002-4827-8947

канд. мед. наук, зав. отд-нием интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным стационаром

Russian Federation, Moscow

Andrei N. Sokolov

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0003-1494-7978

канд. мед. наук, ст. науч. сотр. отд-ния интенсивной высокодозной химиотерапии гемобластозов и депрессий кроветворения с круглосуточным и дневным стационаром

Russian Federation, Moscow

Irina V. Galtseva

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0002-8490-6066

канд. мед. наук, зав. лаб. иммунофенотипирования клеток крови и костного мозга

Russian Federation, Moscow

Nikolai M. Kapranov

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0002-6512-910X

мед. физик лаб. иммунофенотипирования клеток крови и костного мозга

Russian Federation, Moscow

Juliia O. Davydova

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0001-5932-0285

врач клинической лабораторной диагностики лаб. иммунофенотипирования клеток крови и костного мозга

Russian Federation, Moscow

Tatiana N. Obukhova

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0003-1613-652X

канд. мед. наук, зав. лаб. кариологии

Russian Federation, Moscow

Elena E. Nikulina

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0003-3914-8611

науч. сотр. лаб. молекулярной гематологии

Russian Federation, Moscow

Andrei B. Sudarikov

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0001-9463-9187

д-р биол. наук, зав. научно-клинической лаб. молекулярной гематологии

Russian Federation, Moscow

Valerii G. Savchenko

National Research Center for Hematology

Email: ksenijazarubina@mail.com
ORCID iD: 0000-0001-8188-5557

акад. РАН, д-р мед. наук, проф., ген. дир.

Russian Federation, Moscow

References

  1. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23(2):276-92. doi: 10.1200/JCO.2005.10.042
  2. Ngeow J, Liu C, Zhou K, et al. Detecting Germline PTEN Mutations Among At-Risk Patients With Cancer: An Age- and Sex-Specific Cost-Effectiveness Analysis. J Clin Oncol. 2015;33(23):2537-44. doi: 10.1200/JCO.2014.60.3456
  3. Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302-8. doi: 10.1038/nature12981
  4. Collopy LC, Walne AJ, Cardoso S, et al. Triallelic and epigenetic-like inheritance in human disorders of telomerase. Blood. 2015;126(2):176-84. doi: 10.1182/blood-2015-03-633388
  5. Steinke V, Engel C, Büttner R, et al. Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Dtsch Arztebl Int. 2013;110(3):32-8. doi: 10.3238/arztebl.2013.0032
  6. Lax SF. Hereditary breast and ovarian cancer. Pathologe. 2017;38(3):149-55. doi: 10.1007/s00292-017-0298-5
  7. DiNardo CD, Bannon SA, Routbort M, et al. Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC). Clin Lymphoma Myeloma Leuk. 2016;16(7):417-28.e2. doi: 10.1016/j.clml.2016.04.001
  8. Godley LA, Shimamura A. Genetic predisposition to hematologic malignancies: management and surveillance. Blood. 2017;130(4):424-32. doi: 10.1182/blood-2017-02-735290
  9. Bannon SA, DiNardo CD. Hereditary Predispositions to Myelodysplastic Syndrome. Int J Mol Sci. 2016;17(6):838. doi: 10.3390/ijms17060838
  10. Topka S, Vijai J, Walsh MF, et al. Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. PLoS Genet. 2015;11(6):e1005262. doi: 10.1371/journal.pgen.1005262
  11. Pippucci T, Savoia A, Perrotta S, et al. Mutations in the 5’ UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. Am J Hum Genet. 2011;88(1):115-20. doi: 10.1016/j.ajhg.2010.12.006
  12. Tawana K, Fitzgibbon J. Inherited DDX41 mutations: 11 genes and counting. Blood. 2016;127(8):960-1. doi: 10.1182/blood-2016-01-690909
  13. Maciejewski JP, Padgett RA, Brown AL, Müller-Tidow C. DDX41-related myeloid neoplasia. Semin Hematol. 2017;54(2):94-7. doi: 10.1053/j.seminhematol.2017.04.007
  14. Kanagal-Shamanna R, Loghavi S, DiNardo CD, et al. Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation. Haematologica. 2017;102(10):1661-70. doi: 10.3324/haematol.2017.167726
  15. Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127(11):1387-97. doi: 10.1182/blood-2015-09-669937
  16. Nickels EM, Soodalter J, Churpek JE, Godley LA. Recognizing familial myeloid leukemia in adults. Ther Adv Hematol. 2013;4(4):254-69. doi: 10.1177/2040620713487399
  17. Chompret A, Brugières L, Ronsin M, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000;82(12):1932-7. doi: 10.1054/bjoc.2000.1167
  18. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li–Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015;33(21):2345-52. doi: 10.1200/JCO.2014.59.5728
  19. Valdez JM, Nichols KE, Kesserwan C. Li–Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition. Br J Haematol. 2017;176(4):539-52. doi: 10.1111/bjh.14461
  20. Birch JM, Hartley AL, Marsden HB, et al. Excess risk of breast cancer in the mothers of children with soft tissue sarcomas. Br J Cancer. 1984;49(3):325-31. doi: 10.1038/bjc.1984.51
  21. Li FP, Fraumeni JFJr,, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48(18):5358-62
  22. Birch JM, Hartley AL, Blair V, et al. Identification of factors associated with high breast cancer risk in the mothers of children with soft tissue sarcoma. J Clin Oncol. 1990;8(4):583-90. doi: 10.1200/JCO.1990.8.4.583
  23. Swaminathan M, Bannon SA, Routbort M, et al. Hematologic malignancies and Li–Fraumeni syndrome. Cold Spring Harb Mol Case Stud. 2019;5(1):a003210. doi: 10.1101/mcs.a003210
  24. Varley JM, Evans DG, Birch JM. Li–Fraumeni syndrome--a molecular and clinical review. Br J Cancer. 1997;76(1):1-14. doi: 10.1038/bjc.1997.328
  25. McBride KA, Ballinger ML, Killick E, et al. Li–Fraumeni syndrome: cancer risk assessment and clinical management. Nat Rev Clin Oncol. 2014;11(5):260-71. doi: 10.1038/nrclinonc.2014.41
  26. Petitjean A, Mathe E, Kato S, et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. 2007;28(6):622-9. doi: 10.1002/humu.20495
  27. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405. doi: 10.1182/blood-2016-03-643544
  28. Hall TA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Oxford, 1999; p. 95-8.
  29. Зарубина К.И., Паровичникова Е.Н., Басхаева Г.А., и др. Трудности диагностики и терапии Ph-подобных острых лимфобластных лейкозов: описание 3 клинических случаев. Терапевтический архив. 2018;90(7):110-7 [Zarubina KI, Parovichnikova EN, Baskhaeva GA, et al. Diagnostics and Treatment Challenges of Ph-like Acute Lymphoblastic Leukemia: A Description of 3 Clinical Cases. Terapevticheskii Arkhiv (Ter. Arkh.). 2018;90(7):110-7 (in Russian)]. doi: 10.26442/terarkh2018907110-117
  30. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45(3):242-52. doi: 10.1038/ng.2532
  31. Hsiao MH, Yu AL, Yeargin J, et al. Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase. Blood. 1994;83(10):2922-30
  32. Comeaux EQ, Mullighan CG. TP53 Mutations in Hypodiploid Acute Lymphoblastic Leukemia. Cold Spring Harb Perspect Med. 2017;7(3):a026286. doi: 10.1101/cshperspect.a026286
  33. Correa H. Li–Fraumeni Syndrome. J Pediatr Genet. 2016;5(2):84-8. doi: 10.1055/s-0036-1579759
  34. Pepper C, Thomas A, Hoy T. Leukemic and non-leukemic lymphocytes from patients with Li–Fraumeni syndrome demonstrate loss of p53 function, Bcl-2 family dysregulation and intrinsic resistance to conventional chemotherapeutic drugs but not flavopiridol. Cell Cycle. 2003;2(1):53-8
  35. Akpan IJ, Osman AEG, Drazer MW, Godley LA. Hereditary Myelodysplastic Syndrome and Acute Myeloid Leukemia: Diagnosis, Questions, and Controversies. Curr Hematol Malig Rep. 2018;13(6):426-34. doi: 10.1007/s11899-018-0473-7
  36. University of Chicago Hematopoietic Malignancies Cancer Risk Team. How I diagnose and manage individuals at risk for inherited myeloid malignancies. Blood. 2016;128(14):1800-13. doi: 10.1182/blood-2016-05-670240

Supplementary files

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2. Fig. 1. Electropherograms of patients with TP53 mutations.

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3. Fig. 2. Detection of TP53 mutation in different stages of therapy in de novo B-cell acute lymphoblastic leukemia patient.

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