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Precision medicine encompasses all approaches that use patient- and disease-specific information to prevent, diagnose, and treat a disease, and applying its principles to hematologic diseases is a priority for ASH. The use of genome sequencing and genomic profiling is expanding at a rapid pace, significantly improving the diagnoses and treatment of hematologic diseases by identifying unique variants that can be targeted with gene-based targeted therapeutic approaches.

The ASH Task Force on Precision Medicine is central to ASH’s activities around this priority area, and for the past three years, a central piece of the puzzle has been the Society’s partnership with the National Institutes of Health–funded Clinical Genome Resource (ClinGen). Two expert review panels, co-led by Drs. Lucy Godley and David Wu, and by Drs. Jorge Di Paola and Wolfgang Bergmeier have focused on hereditary predisposition to myeloid malignancies and hereditary platelet disorders, respectively.

The expert review panel focusing on germline variants implicated in myeloid malignancies made significant strides recently, publishing two papers on curation rules for RUNX1. The first (Luo X, et al. Blood Adv. 2019;3:2962-2979) gives details on the curation rules, and the second (Wu D, et al. Haematologica. 2020;105:870-887) shows how those rules are applied in the curation process. The panel deposited RUNX1 variant data curations into ClinVar, with the recognition of the U.S. Food and Drug Administration and is beginning the development of curation rules for GATA2, which started with adding experts on GATA2 deficiency to the panel. “The panel quickly realized,” said Dr. Godley, “that we need a detailed description of the GATA2 deficiency phenotype, which did not exist, so our panel is now working to define that.” The group also applied for NIH funding for the Myeloid Malignancy Variant Curation Expert Panel. In the year ahead, Dr. Godley remarked that the panel is looking forward to still more in the area of variant curation, including, “defining the GATA2 deficiency phenotype with data from patients across the world, finalizing GATA2 curation rules; curating RUNX1 and GATA2 variants in ClinVar, and starting to develop curation rules for more genes!”

Likewise, the expert review panel focusing on germline variants implicated in platelet disorders also had a successful year, zeroing in on Glanzmann thrombasthenia in the curation process. The group was given the task to curate germline variants in platelet disorder genes, in partnership with ClinGen, more than 2 years ago. In that time, they convened a working group of more than 25 members including clinicians, basic and translational scientists, genetic counselors, and professional curators that met at least monthly. “This group is highly diverse and represents many countries of the world,” said Dr. Di Paola. “We decided to start the curation process with Glanzmann thrombasthenia as it is caused by mutations in two genes (ITGA2B and ITGB3), is mostly inherited in a recessive manner, and has been extensively studied.” After they determined the rule specification for both genes — a nontrivial task that took more than a year to complete — and received approval from the ClinGen Steering Committee, the panel started the pilot curation process and assigned pathogenicity (or not) to 70 variants. These findings are being submitted for publication. “We are proud of this work as we have set up the basis not only for the curation of all variants reported in these genes, but also for other genes involved in platelet disorders,” Dr. Di Paola remarked. “In the long term we hope that these efforts will help hematologists to better interpret clinical genetic panels and therefore improve diagnosis and treatment of platelet disorders.”

The task force’s Somatic Working Group has also made progress in 2020 with the development of an interactive table of somatic gene variants, which is available on the ASH website. As Dr. Torsten Haferlach shared, today’s information is delivered by techniques such as next-generation sequencing. And as these techniques gain importance in diagnosis, prognostication, and treatment guidance, variant data have to be interpreted in order to be useful. “This is a tedious procedure as manual work is typically required to sift through multiple sources, thus quickly presenting a bottleneck,” said Dr. Haferlach. “Not all variants in a genome are pathogenic. Some are single-nucleotide polymorphisms…and some are classified as ’variant of unknown significance…’”

The Somatic Working Group, an interdisciplinary team from six institutions, was formed to create a reliable resource for next-generation sequencing diagnostics in a systematic review process, and to make their consensus classification available to the wider hematology community. “We anticipate that this will lead to more homogeneity in molecular testing reports for patients undergoing evaluation of myeloid and lymphoid malignancies,” said Dr. Haferlach, noting that regular updates to the variant table will help hematologists use next-generation sequencing in their daily patient care routine. “It is mandatory that hematologists understand these new methods, increase the use of precision medicine approaches, and explore all options to patient care as soon as possible.”

To learn more the programs and activities supporting this research priority, visit the ASH website or email ashprecisionmedicine@hematology.org.

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