1005 – GERMLINE PREDISPOSITION TO HEMATOPOIETIC MALIGNANCIES

• Published in: Experimental hematology Vol. 100; p. S19
• Main Authors: Godley, Lucy, none, none
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2021
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2021.12.004

Familial predisposition to hematopoietic malignancies is more common than generally appreciated. Genes encoding components of pathways involving DNA repair, especially homologous recombination, telomere biology, and ribosomopathies are among the most frequently identified. Deleterious variants in additional genes involved in immune recognition and immunodeficiencies are also emerging as important risk factors. Recent studies of young patients with myelodysplastic syndrome and aplastic anemia have revealed a high frequency of causative germline alleles in those diagnosed at or under age 40, and future work may reveal whether germline risk is confined to the young extends across the entire age spectrum. Individuals prioritized for germline testing include those diagnosed with a hematopoietic malignancy at a much younger age than those in the general population; with multiple cancers themselves; with other close relatives with hematopoietic malignancies and/or other hematopoietic abnormalities and/or young onset solid tumors; or with tumor profiling showing a deleterious variant in a gene known to confer germline risk. Our robust clinical testing pipeline consists of an augmented whole exome sequencing platform that covers the non-coding loci where germline variants confer risk and a custom bioinformatic pipeline that can identify single nucleotide variants as well as copy number variants. 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.