November 2019: Hiding in Plain Sight: Identifying Myeloid Neoplasms with Germline Predisposition


David R. Czuchlewski, M.D., M.Ed.
Professor of Pathology, University of New Mexico
Medical Director, Genetics and Cytometry, TriCore Reference Laboratories

Brief overview
Myeloid neoplasms with germline predisposition are important to recognize, yet challenging to the diagnostic pathologist and laboratorian on a number of levels. This webinar will present practical tips for the recognition and workup of germline genetic etiologies in myeloid neoplasms.

Learning objectives

  • Describe key clues to identify myeloid neoplasms with germline predisposition.
  • Enact a logical testing strategy for detecting germline etiology in suspect .
  • Avoid common diagnostic pitfalls associated with these neoplasms.

Watch the Webinar

Answers to Questions from Live Webinar

Below is a list of questions received from the live webinar attendees. Click on any question to reveal the speaker's response.

The WHO classification does specifically include cases of AML and MDS arising from bone marrow failure disorders (including Fanconi anemia and Shwachman-Diamond syndrome) as “Myeloid neoplasms with germline predisposition.” There are definitely germline variants in MPL and JAK2 that are associated with hereditary thrombocytosis, but we need to be very cautious about carefully separating those from true myeloid neoplasms. Perhaps the strongest evidence for a germline variant leading to a true MPN predisposition would be very rare families identified with duplications of ATG2B and GSKIP at 14q32.2.

In addition to the individualized, case-by-case approaches covered in the webinar, there is indeed some discussion about the possibility of more universal screening. I would refer you to the discussion here:

Tawana K, Drazer MW, Churpek JE. Universal genetic testing for inherited susceptibility in children and adults with myelodysplastic syndrome and acute myeloid leukemia: are we there yet? Leukemia 2018; 32: 1482-92.

However, this would not be considered as a standard-of-care approach at this point.

Thanks for the question for clarification. In relation to the flow cytometric signature of germline GATA2 mutation, I would not strongly suspect that unless I saw very significant decreases across the board in multiple of the cell subsets I listed (monocytes, hematogones, B-cells, NK cells; dendritic cells are also decreased, but we don’t typically assess those). To your point, it would be quite common, for example, to see an isolated decrease in hematogones in a case of routine de novo MDS. But if mature B cells and monocytes, for example, were also essentially absent, I might get curious. So I would not look at any of those subsets in isolation for purposes of possible GATA2 cases.

The WHO revised 4th edition suggests in several places that this needs to be a concern. “Patients with biallelic CEBPA mutations should be evaluated for a familial syndrome” (144) and “the identification of biallelic CEBPA mutations within leukemic cells should prompt evaluation for germline inheritance of one of the alleles” (124). As I discussed, the most definitive option would be CEBPA sequencing using a uniform culture of skin fibroblasts. In practice, the assessment would also take into account family history; and absence of the mutations in a post-remission (and non-transplanted) blood or bone marrow specimen would be taken as evidence against a germline mutation (keeping in mind the caveats I mention regarding this specimen type re clonal hematopoiesis).

The challenge with some of these emerging genetic etiologies is their rarity, which makes it difficult to fully document their connection to myeloid neoplasia and to describe their natural history. I do think most people would agree that SAMD9 and SAMD9L germline mutation will clearly deserve some degree of formal recognition, as it is an important cause of MDS in childhood. However, as an illustration of how difficult it is to define the “true” parameters of germline predisposition, check out this recent letter looking at SAMD9 and SAMD9L in the context of adult MDS in Blood: