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Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms
  1. Eduard Schulz1,
  2. Angelika Valentin1,
  3. Peter Ulz2,
  4. Christine Beham-Schmid3,
  5. Karin Lind1,
  6. Verena Rupp2,
  7. Herwig Lackner4,
  8. Albert Wölfler1,
  9. Armin Zebisch1,
  10. Werner Olipitz5,
  11. Jochen Geigl2,
  12. Andrea Berghold6,
  13. Michael R Speicher2,
  14. Heinz Sill1
  1. 1Division of Hematology, Medical University of Graz, Austria
  2. 2Institute of Human Genetics, Medical University of Graz, Austria
  3. 3Institute of Pathology, Medical University of Graz, Austria
  4. 4Division of Pediatric Hematology and Oncology, Medical University of Graz, Austria
  5. 5Department of Medicine III, Ludwig-Maximilian University of Munich, Germany
  6. 6Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Austria
  1. Correspondence to Dr Heinz Sill, Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 Graz, Austria; heinz.sill{at}


Background Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes.

Methods The study systematically evaluated pedigrees of patients with t-MNs for cancer incidences and the possibility of a hereditary cancer predisposition syndrome. In addition, mutational analyses were performed using constitutional DNA from index patients, and deleterious heterozygous germline mutations were assessed for loss of heterozygosity in sorted leukaemic cells by single nucleotide polymorphism array.

Results A nuclear pedigree was obtained in 51/53 patients with t-MNs resulting in a total of 828 individuals analysed. With a standardised incidence ratio of 1.03 (95% CI 0.74 to 1.39), the tumour incidence of first- degree relatives was not increased. However, six pedigrees were suggestive for a hereditary breast and ovarian cancer syndrome, three of a Li-Fraumeni like syndrome, and three index patients showed multiple primary neoplasms. Mutational analysis revealed two BRCA1 (c.3112G→T, c.5251C→T), one BRCA2 (c.4027A→G), two BARD1 (C557S) and four TP53 germline mutations (g.18508_18761delinsGCC, c.847C→T, c.845_848dupGGCG, c.1146delA) in nine of 53 (17%) index patients with t-MNs. Loss of heterozygosity in leukaemic cells was demonstrated for the BRCA1c.3112G→T and TP53c.845_848dupGGCG mutations, respectively.

Conclusion It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.

  • Therapy-related myeloid neoplasms
  • cancer predisposition syndromes
  • BRCA1/2
  • BARD1
  • TP53
  • haematology (incl blood transfusion)
  • genetics
  • epigenetics
  • microRNA
  • oncology
  • molecular genetics
  • cancer: breast
  • genetic epidemiology
  • genetics
  • leukaemia

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  • Funding Funding for this study was provided by “Jubiläumsfonds” of the Austrian National Bank (Nr.13918), Land Steiermark and Leukämiehilfe Steiermark. ES is supported by the PhD program “Molecular Medicine” at Medical University of Graz, Austria.

  • Competing interests None.

  • Ethics approval The study was performed according to the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the Medical University of Graz, Austria, and written informed consent was obtained from all individuals.

  • Provenance and peer review Not commissioned; externally peer reviewed.