“A horror story,” said my mentor, beginning his teaching point with a warning. We were about to see a patient with dyskeratosis congenita and pancytopenia. It was a story about a young adult with newly diagnosed acute myeloid leukemia (AML) with history of sclerodactyly and oral cancer, who unfortunately died during induction chemotherapy.
As an adult hematologist, I do not routinely see patients with congenital syndromes, but since then, I research every unfamiliar gene that is mutated on next-generation sequencing (NGS) to ensure I am not missing a germline mutation with predisposition to a blood cancer. Awareness of congenital syndromes and a high index of suspicion are critical for adult hematologists.
This year’s ASH-EHA Joint Symposium on Sunday, December 11, from 12:30 p.m. to 1:30 p.m. Central time (Ernest N. Morial Convention Center, Hall E), will host Dr. Charlotte M. Niemeyer from Albert-Ludwigs-Universitat Freiburg and Dr. Lucy A. Godley from University of Chicago Medical Center to discuss hereditary hematopoietic neoplasia.
An increasing number of patients with myelodysplastic syndrome (MDS) and AML are found to have germline pathogenic variants on routine NGS testing that are associated with the development of myeloid disease. In fact, an estimated 5 to 15 percent of adults and 4 to 13 percent of children harbor mutations associated with hereditary MDS/AML.1 Many implicated genes, including GATA2, ETV6, DDX41, CEBPA, RUNXN, are also involved in the pathogenesis of de novo MDS/AML, necessitating the need for germline testing in cases with suspected hereditary myeloid neoplasm.2 Accordingly, in 2016, the World Health Organization recognized the entity myeloid neoplasm with germline predisposition. Guidelines are available for recognized syndromes such as Fanconi anemia, Diamond-Blackfan anemia, Schwachman-Diamond syndrome, dyskeratosis congenita, and short telomere syndromes,3 but are not formally established for disorders associated with recently discovered genetic alterations.
The Nordic MDS Study Group created a working group between Sweden, Norway, Finland, and Denmark to compile and study rare cases of germline predisposition syndromes in myeloid malignancies and provide an initial set of guidelines.1 They propose germline testing in patients with MDS/AML and a suggestive personal or family history, presence of a gene variant on somatic testing that may be germline, and age younger than 50 years with abnormalities of chromosome 7. Additionally, they recommend obtaining germline tissue, preferably fibroblasts, or alternatively blood if the myeloid neoplasm is in remission, and highlight the importance of genetic counseling at the time of germline testing.
This phenomenon, however, is not unique to myeloid neoplasms. Germline mutations in IKZF1, SH2B3, and PAX5 have been identified in familial acute lymphoblastic leukemia, while mutations in KDM1A/LSD1 are associated with familial multiple myeloma.2
Knowledge about the genetic basis of blood cancers is of utmost importance. First, it sheds light on a question asked by patients and doctors alike — “how did this cancer start?” It also has direct clinical implications. The presence of these variants may inform the frequency and intensity of screening for other cancers. In addition, awareness about a patient’s germline variants may guide other family members in decision-making about screening. Last but not least, the transplant conditioning regimen is carefully selected based on the underlying syndrome, and matched related donors should be vigilantly screened to ensure the donor does not carry the germline pathogenic mutation.
As our understanding of the genetic basis of hereditary hematologic malignancies evolves, so will our understanding of the pathogenesis of these diseases. In the molecular era, these advances will hopefully lead to new targeted treatments and even gene .
To dive further into hereditary hematologic malignancies, we also recommend the oral abstract session on Bone Marrow Failure and Cancer Predisposition Syndromes on Sunday, December 11 from 9:30 a.m. to 11:00 a.m. (Ernest N. Morial Convention Center, Room 260-262), and the Scientific Workshop on Germline Predisposition to Hematopoietic Malignancies and Bone Marrow Failure available on demand through December 16, 2022.
- Baliakas P, Tesi B, Wartiovaara-Kautto U, et al. Nordic guidelines for germline predisposition to myeloid neoplasms in adults: recommendations for genetic diagnosis, clinical management and follow-up. Hemasphere. 2019;3(6):e321.
- Geyer JT. Myeloid Neoplasms with Germline Predisposition. Pathobiology. 2019;86(1):53-61.
- Godley LA, Shimamura A. Genetic predisposition to hematologic malignancies: management and surveillance. Blood. 2017;130(4):424-432.
Dr. Kumar and Dr. Jeong indicated no relevant conflicts of interest.
