Germline Genetic Predisposition to Hematologic Malignancy

Abstract

Development of hematologic malignancies is driven by mutations that may be somatic or germline. Availability of next-generation DNA sequencing technologies has facilitated the development of individualized diagnostic evaluations and tailored treatment strategies. Until now, such personalized medical approaches have largely centered on prognostic stratification and treatment strategies informed by acquired somatic mutations. The role of germline mutations in children and adults with hematologic malignancies was previously underappreciated. Diagnosis of an inherited predisposition to hematologic malignancy informs choice of therapy, risk of treatment-related complications, donor selection for hematopoietic stem cell transplantation, evaluation of comorbidities, and surveillance strategies to improve clinical outcomes. The recognition that patients with inherited hematologic malignancy syndromes may present without classic clinical stigmata or suspicious family history has led to increased reliance on genetic testing, which, in turn, has raised new diagnostic challenges. Genomic testing is a rapidly evolving field with an increasing number of choices for testing for the practicing clinician to navigate. This review will discuss general approaches to diagnosis and management of patients with germline predisposition to hematology malignancies and will consider applications and limitations of genomic testing in clinical practice.

Neutropenia in the age of genetic testing: Advances and challenges

“…Table (adapted from Reference ) lists testing considerations of the various testing platforms. The advantages and disadvantages of each approach must be considered when selecting a testing methodology.…”

When should transplant physicians think about familial blood cancers?

“…The awareness of hereditary hematologic malignancies (HHMs) has grown significantly following the discovery of germline RUNX1 mutations as the cause of familial platelet disorder with predisposition to myeloid malignancies (FPDMMs) in 1999 . Since that time, mutations in a growing list of other genes, such as ANKRD26, CEBPA, DDX41, ETV6, GATA2, SAMD9, SAMD9L , and others, have been found to predispose to hematologic malignancies (HMs), such as myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and lymphoid malignancies . The penetrance of these germline aberrations is significant, from 35% to 40% for pathogenic RUNX1 variants to ~100% for 5’ CEBPA mutations .…”

Next-Generation Sequencing (NGS)-Based Clinical Testing is Recommended for the Detection of Gene Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia Predisposition Syndromes

“…Similarly, a study of individuals from 17 families with two or more biological relatives with MDS/AML detected a pathogenic germline variant in five of the families (29%) [5]. Familial MDS/AML may occur in the context of bone marrow failure diseases such as GATA2 spectrum disorders, Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenital/telomere biology disorders, as well as in association with germ line mutations in the ANKRD26, CEBPA, DDX41, ELANE, ETV6, HAX1, RUNX1, SAMD9, SAMD9L, SRP72, and TP53 genes (Table 1) [6,7].…”