LUCY GODLEY (CHICAGO)
GERMLINE PREDISPOSITION TO AML
The University of Chicago, Chicago, USA
Familial predisposition to hematopoietic malignancies is likely more common than generally
appreciated. Currently, we know most about predisposition syndromes that confer risk for myeloid
malignancies, but familial predisposition to lymphoid malignancies has also been described and ripe
for discovery. Accurate diagnosis of the germline basis for patients with hematopoietic malignancies
is critical for their clinical management, especially when considering allogeneic stem cell
transplantation using a related donor. Recognition of germline predisposition to myelodysplastic
syndrome (MDS)/AML is important for clinical management, since allogeneic hematopoietic stem
cell transplantation (HSCT) is the only potential cure for MDS patients, and family members are the
preferred source for donor hematopoietic stem/progenitor cells (HSPCs). However, we lack
comprehensive studies that analyze the frequency of germline mutations throughout the entire life
span. This information could reveal whether germline mutations cause MDS/AML at a consistent
frequency across the ages, which would require assessment for germline mutations in MDS
patients/their HLA-matched relatives in anyone being considered for allogeneic HSCT; or if the
frequency decreases across the age spectrum, suggesting that germline assessment could be
restricted to patients diagnosed younger than a particular age. Such data could be used to develop
clinical recommendations for germline testing of MDS patients and their HLA-matched relatives who
could serve as HSCT donors. Preliminary data from our group demonstrate that 19% of patients with
MDS diagnosed from 18 to 40 years old have germline mutations, commonly in telomere biology
genes and those comprising the BRCA pathway. In older MDS/AML patients, germline DDX41
mutations are associated with myeloid malignancies. These frequencies are much higher than
suspected previously and suggest that many MDS patients could have a deleterious inherited
mutation driving disease development.
We have established a comprehensive approach to patient evaluation, including
documentation of a complete family and bleeding history, consultation with a certified genetic
counselor familiar with inherited hematopoietic predisposition syndromes, and testing using DNA
derived from cultured skin fibroblasts to ensure testing of germline material. We are also able to
predict which patients are likely to have a germline genetic mutation based on serial molecular
profiling of leukemia/bone marrow cells throughout treatment. Our robust clinical testing pipeline
includes next-generation sequencing to identify point mutations as well as array-based methods to
assess for genomic rearrangements. We are able to identify a germline mutation in about 20% of
individuals/families presenting with familial clustering of myeloid malignancies.
Patients who test negative for the known predisposition syndromes are offered participation
in research to allow discovery of new syndromes. Although widespread application of next-generation
sequencing makes screening relatively straightforward, the relative rarity of families with
germline mutations means that new gene discovery is likely to require the cooperative effort of
groups throughout the world.