Genetic features of myelodysplastic syndrome and aplastic anemia in pediatric and young adult patients

The clinical and histopathological distinctions between inherited versus acquired bone marrow failure and myelodysplastic syndromes are challenging. The identification of inherited bone marrow failure/myelodysplastic syndromes is critical to inform appropriate clinical management. To investigate whether a subset of pediatric and young adults undergoing transplant for aplastic anemia or myelodysplastic syndrome have germline mutations in bone marrow failure/myelodysplastic syndrome genes, we performed a targeted genetic screen of samples obtained between 1990–2012 from children and young adults with aplastic anemia or myelodysplastic syndrome transplanted at the Fred Hutchinson Cancer Research Center. Mutations in inherited bone marrow failure/myelodysplastic syndrome genes were found in 5.1% (5/98) of aplastic anemia patients and 13.6% (15/110) of myelodysplastic syndrome patients. While the majority of mutations were constitutional, a RUNX1 mutation present in the peripheral blood at a 51% variant allele fraction was confirmed to be somatically acquired in one myelodysplastic syndrome patient. This highlights the importance of distinguishing germline versus somatic mutations by sequencing DNA from a second tissue or from parents. Pathological mutations were present in DKC1, MPL, and TP53 among the aplastic anemia cohort, and in FANCA, GATA2, MPL, RTEL1, RUNX1, SBDS, TERT, TINF2, and TP53 among the myelodysplastic syndrome cohort. Family history or physical examination failed to reliably predict the presence of germline mutations. This study shows that while any single specific bone marrow failure/myelodysplastic syndrome genetic disorder is rare, screening for these disorders in aggregate identifies a significant subset of patients with inherited bone marrow failure/myelodysplastic syndrome.

[1]  M. Wlodarski,et al.  Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. , 2016, Blood.

[2]  Li Ding,et al.  Germline Mutations in Predisposition Genes in Pediatric Cancer. , 2015, The New England journal of medicine.

[3]  J. Beyene,et al.  Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes , 2015, Journal of Medical Genetics.

[4]  Zhongming Zhao,et al.  Rare variants in RTEL1 are associated with familial interstitial pneumonia. , 2015, American journal of respiratory and critical care medicine.

[5]  Bale,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 , 2015, Genetics in Medicine.

[6]  David A. Williams,et al.  Genomic analysis of bone marrow failure and myelodysplastic syndromes reveals phenotypic and diagnostic complexity , 2015, Haematologica.

[7]  M. Nagasaki,et al.  Identification of acquired mutations by whole-genome sequencing in GATA-2 deficiency evolving into myelodysplasia and acute leukemia , 2014, Annals of Hematology.

[8]  J. Orange,et al.  GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. , 2014, Blood.

[9]  P. Hainaut,et al.  Li‐Fraumeni and Li‐Fraumeni—like syndrome among children diagnosed with pediatric cancer in Southern Brazil , 2013, Cancer.

[10]  N. Young,et al.  Current concepts in the pathophysiology and treatment of aplastic anemia. , 2013, Hematology. American Society of Hematology. Education Program.

[11]  J. Schug,et al.  Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome , 2013, Proceedings of the National Academy of Sciences.

[12]  P. Rosenberg,et al.  Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[13]  L. Siever,et al.  Spatial and Temporal Mapping of De Novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network , 2013, Cell.

[14]  K. Offit,et al.  A Recessive Founder Mutation in Regulator of Telomere Elongation Helicase 1, RTEL1, Underlies Severe Immunodeficiency and Features of Hoyeraal Hreidarsson Syndrome , 2013, PLoS genetics.

[15]  V. Plagnol,et al.  Constitutional Mutations in RTEL1 Cause Severe Dyskeratosis Congenita , 2013, American journal of human genetics.

[16]  P. Rohrlich,et al.  High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. , 2013, Blood.

[17]  K. Jacobs,et al.  Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita , 2013, Human Genetics.

[18]  V. Plagnol,et al.  Exome sequencing identifies MPL as a causative gene in familial aplastic anemia , 2012, Haematologica.

[19]  Franco Locatelli,et al.  Spliceosomal gene aberrations are rare, coexist with oncogenic mutations, and are unlikely to exert a driver effect in childhood MDS and JMML. , 2012, Blood.

[20]  J. Rosenfeld,et al.  Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. , 2012, Blood.

[21]  I. Baumann,et al.  Classification of childhood aplastic anemia and myelodysplastic syndrome. , 2011, Hematology. American Society of Hematology. Education Program.

[22]  Rochelle L. Garcia,et al.  Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing , 2011, Proceedings of the National Academy of Sciences.

[23]  D. Schindler,et al.  Fanconi Anemia Core Complex Gene Promoters Harbor Conserved Transcription Regulatory Elements , 2011, PloS one.

[24]  Anna L. Brown,et al.  Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia , 2011, Nature Genetics.

[25]  Tom Walsh,et al.  Accurate and exact CNV identification from targeted high-throughput sequence data , 2011, BMC Genomics.

[26]  N. Young,et al.  Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. , 2010, JAMA.

[27]  T. Walsh,et al.  Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing , 2010, Proceedings of the National Academy of Sciences.

[28]  B. Alter,et al.  Pathophysiology and management of inherited bone marrow failure syndromes. , 2010, Blood reviews.

[29]  Chieh-Yu Liu,et al.  AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. , 2009, Blood.

[30]  P. Rosenberg,et al.  Cancer in dyskeratosis congenita. , 2009, Blood.

[31]  C. Richler,et al.  Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome , 2009, PloS one.

[32]  C. Richards,et al.  Validation of Fanconi anemia complementation Group A assignment using molecular analysis , 2009, Genetics in Medicine.

[33]  J. Ivanovich,et al.  TERC and TERT gene mutations in patients with bone marrow failure and the significance of telomere length measurements. , 2009, Blood.

[34]  C. Voermans,et al.  Functional analysis of single amino‐acid mutations in the thrombopoietin‐receptor Mpl underlying congenital amegakaryocytic thrombocytopenia , 2008, British journal of haematology.

[35]  N. Orr,et al.  TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. , 2008, American journal of human genetics.

[36]  H. Du,et al.  Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene. , 2008, Blood.

[37]  M. McLellan,et al.  Low Frequency of Telomerase RNA Mutations Among Children With Aplastic Anemia or Myelodysplastic Syndrome , 2006, Journal of pediatric hematology/oncology.

[38]  A. Børresen-Dale,et al.  Acute myelogenous leukemia in a patient with Li–Fraumeni syndrome treated with valproic acid, theophyllamine and all-trans retinoic acid: a case report , 2006, Leukemia.

[39]  K. Ihara,et al.  Congenital amegakaryocytic thrombocytopenia in three siblings: molecular analysis of atypical clinical presentation. , 2005, Experimental hematology.

[40]  T. Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres , 2005 .

[41]  R. Takimoto,et al.  A patient with TP53 germline mutation developed Bowen's disease and myelodysplastic syndrome with myelofibrosis after chemotherapy against ovarian cancer. , 2005, Internal medicine.

[42]  S. Chanock,et al.  Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. , 2005, The New England journal of medicine.

[43]  S. Chanock,et al.  Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. , 2003, Blood.

[44]  S. Kato,et al.  Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  B. Alter,et al.  The CCC system: is it really the answer to pediatric MDS? , 2003, Journal of pediatric hematology/oncology.

[46]  I. Baumann,et al.  A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases , 2003, Leukemia.

[47]  A. D’Andrea,et al.  A novel diagnostic screen for defects in the Fanconi anemia pathway. , 2002, Blood.

[48]  I. Dokal,et al.  Dyskeratosis congenita in all its forms , 2000, British journal of haematology.

[49]  K. Collins,et al.  A telomerase component is defective in the human disease dyskeratosis congenita , 1999, Nature.

[50]  John M. Maris,et al.  Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia , 1999, Nature Genetics.

[51]  A. Poustka,et al.  X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. , 1999, American journal of human genetics.

[52]  M. Eguchi,et al.  Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[53]  D. Slater,et al.  The p53 gene in pediatric therapy-related leukemia and myelodysplasia. , 1996, Blood.

[54]  R. Berger,et al.  Bone Marrow Transplantation in Fanconi Anaemia , 1980, British journal of haematology.

[55]  P. Rohrlich,et al.  High frequency of GATA 2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome , myelodysplasia , and acute myeloid leukemia * , 2013 .

[56]  Claude-Alain H. Roten,et al.  Fast and accurate short read alignment with Burrows–Wheeler transform , 2009, Bioinform..

[57]  T. de Lange,et al.  Shelterin: the protein complex that shapes and safeguards human telomeres. , 2005, Genes & development.

[58]  Johanna M. Rommens,et al.  Mutations in SBDS are associated with Shwachman–Diamond syndrome , 2003, Nature Genetics.