Germline Predisposition to Hematopoietic Malignancies

Inherited predisposition to hematopoietic malignancies due to deleterious germline variants is being recognized in an increasing number of genes due to the increasing availability of next generation sequencing (NGS). With greater numbers of genes and mutation types identified, the complexity of clinical testing also increases, challenging busy practitioners to diagnose patients accurately. Recognition of germline cancer predisposition has important health implications for the management of the index patient and his/her family members and complicates planning for allogeneic stem cell transplantation in which relatives are often the preferred donors. Challenges to diagnosis of these conditions include: (i) the idea that these syndromes are rare; (ii) the idea that germline variants only pertain to people presenting at young ages; (iii) busy clinics that make it difficult to take comprehensive personal and family histories from patients and carefully review available molecular profiling data; (iv) complicated syndromes in which presentations are more varied than classic descriptions; (v) obtaining comprehensive testing that includes assessment of single nucleotide and copy number variants in all of the genes that can confer risk; (vi) obtaining true germline tissue in quantities that allow comprehensive testing; and (vi) a lack of data regarding the natural history of these disorders. Key features of the initial clinical presentation that signal a likelihood of having germline predisposition include: personal history of two or more cancers; personal history of a hematopoietic malignancy along with a family history of another hematopoietic malignancy/prolonged cytopenia/or other hematologic abnormality such as macrocytosis or onset of a nonhematopoietic tumor at an age < 50 years old within two generations of the proband; and/or molecular testing of hematopoietic cells showing a deleterious variant in a gene known to confer a hereditary hematopoietic malignancy, especially one that persists despite change in disease status (i.e., persists from diagnosis through remission). I will discuss how to prioritize patients for germline testing; how to perform rigorous and comprehensive germline testing, and how positive results impact treatment plans for the index patient and cancer surveillance strategies for the individual and their family members who share the deleterious variant.

Originally published on March 28, 2024

Lecture Presenter

Lucy A. Godley, MD, PhD Section of Hematology/Oncology, Departments of Medicine and Human Genetics The University of Chicago

Dr. Godley began her scientific career in several laboratories: Sally/Vincent Marchesi (Yale), Don Wiley (Harvard), and Harold Varmus (UCSF/NIH). She completed her medical training at Northwestern followed by an Internal Medicine/Hematology-Oncology residency/fellowship at the University of Chicago, where she joined the faculty in 2003. As a physician-scientist with research and clinical responsibilities, Dr. Godley seeks to understand disease on a molecular basis and is able to bring that perspective to the care of her patients. Her laboratory studies inherited hematopoietic malignancies and the control of differentiation potential in cancer cells by modified cytosines.

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Objectives

After this presentation, participants will be able to:

• Recognize patients at high risk for having a germline predisposition allele
• Evaluate what constitutes comprehensive testing for hereditary hematopoietic malignancies
• Describe specific management strategies for patients with specific germline predisposition disorders

Sponsored by:

University of Utah School of Medicine, Department of Pathology, and ARUP Laboratories