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Fanconi Anemia germline variants as susceptibility factors in aplastic anemia, MDS and AML

Bartlomiej Przychodzen1, Hideki Makishima1, Mikkael A Sekeres1

  • 1Department of Translational Hematology and Oncology Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.

Oncotarget
|February 9, 2018
PubMed

Insights

Germline Fanconi Anemia (FA) gene mutations are more common in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients. Telomerase gene mutations were not linked to increased disease risk in bone marrow failure (BMF) conditions.

Area of Science:

  • Genetics
  • Hematology
  • Oncology

Background:

  • Bone marrow failure (BMF) encompasses a spectrum of hematologic disorders.
  • Germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes are implicated in BMF pathogenesis.
  • Understanding genetic predispositions is crucial for diagnosing and managing BMF.

Purpose of the Study:

  • To investigate the frequency of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes in a large cohort of bone marrow failure (BMF) patients.
  • To determine the association between these germline alterations and specific BMF subtypes, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and aplastic anemia (AA).

Main Methods:

  • Systematic analysis of germline (GL) DNA using next-generation sequencing.
  • A cohort of 489 patients with BMF, MDS, AML, and AA was studied.
  • Comparison with large control cohorts to assess variant frequencies.

Main Results:

  • An increased frequency of heterozygous FA gene mutations was observed in patients with MDS and, to a lesser extent, AML.
  • Heterozygous FA mutations may have a long latency period and are not fully compensated by a normal allele.
  • Germline (GL) telomerase gene mutations were not associated with an increased risk of BMF, and no increased frequency of damaging variants was found in telomerase complex genes compared to controls.

Conclusions:

  • Germline (GL) FA alterations can be associated with MDS, suggesting a role beyond typical FA complementation group disorders.
  • Low penetrance and delayed disease onset can complicate the identification of genetic predisposition factors in BMF.
  • The study did not find an association between germline telomerase gene mutations and increased BMF risk.
Keywords:
AMLFanconi AnemiaMDSgermline

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