Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults

Abstract

Myelodysplastic syndrome (MDS) is a clonal blood disorder characterized by ineffective hematopoiesis, cytopenias, dysplasia and an increased risk of acute myeloid leukemia (AML). With the growing availability of clinical genetic testing, there is an increasing appreciation that a number of genetic predisposition syndromes may underlie apparent de novo presentations of MDS/AML, particularly in children and young adults. Recent findings of clonal hematopoiesis in acquired aplastic anemia add another facet to our understanding of the mechanisms of MDS/AML predisposition. As more predisposition syndromes are recognized, it is becoming increasingly important for hematologists and oncologists to have familiarity with the common as well as emerging syndromes, and to have a systematic approach to diagnosis and screening of at risk patient populations. Here, we provide a practical algorithm for approaching a patient with a suspected MDS/AML predisposition, and provide an in-depth review of the established and emerging familial MDS/AML syndromes caused by mutations in the ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, SRP72 genes. Finally, we discuss recent data on the role of somatic mutations in malignant transformation in acquired aplastic anemia, and review the practical aspects of MDS/AML management in patients and families with predisposition syndromes.

Keywords: aplastic anemia; bone marrow failure; clonal hematopoiesis; familial MDS/AML; genetic predisposition.

Figure 1. Incidence and Characteristics of Myelodysplastic Syndrome by Age at Diagnosis

A. Incidence of Myelodysplastic Syndrome by Age at Diagnosis. Histogram plot depicts the incidence rates of MDS stratified by age-group, as reported by the United States Surveillance, Epidemiology, and End Results (SEER) database analysis through 2011[14]. Overlying line plot depicts the percentage of individuals without a diagnosis of hematologic malignancy who have detectable clonal hematopoiesis with somatic mutations [–4]. B. Characteristics of MDS in children and young adults, compared to MDS in older adults (age > 60 years). The solid black line separates childhood and young adult MDS (left) from older adults and the elderly (right). Clinical, cytogenetic and molecular features that occur at a higher frequency in a particular age group are listed above the corresponding age categories.

Figure 2. Classification of Childhood and Young Adult MDS

A. Childhood MDS has been historically classified into the categories of de novo or primary MDS, and “secondary” MDS, defined as therapy-related MDS following exposure to cytotoxic therapies, or MDS secondary to well-described inherited bone marrow failure (BMF) syndromes or acquired BMF [1]. B. Proposed revised classification of childhood and young adult MDS: 1) therapy-related MDS, 2) MDS secondary to acquired BMF, and 3) MDS secondary to inherited predisposition syndromes, including classical BMF syndromes as well as emerging MDS/AML predisposition syndromes.

Figure 3. Proposed Evaluation Algorithm for an MDS/AML Predisposition Syndrome

The complete evaluation for underlying predisposition should include metaphase cytogenetic analysis, and, in appropriate cases, single nucleotide polymorphism array (SNP-A) and fluorescent in situ hybridization (FISH) to evaluate for smaller copy number changes beyond the resolution of metaphase karyotyping. Ancillary functional testing should include chromosomal breakage and lymphocyte telomere length measurements to screen for Fanconi Anemia and Dyskeratosis Congenita, respectively. Flow cytometry for paroxysmal nocturnal hemoglobinuria (PNH) can help screen for acquired bone marrow failure, with the presence of a PNH clone suggesting absence of inherited BMF. For most cases, we recommend genetic testing with next-generation sequencing (NGS) technology to screen for known familial MDS/AML syndromes, with any additional BMF testing or gene-specific testing as guided by the patient’s history.

Figure 4. Hematologic Malignancy-Associated Somatic Mutations As Detected in Targeted Sequencing Studies of Patients with Acquired Aplastic Anemia

A histogram summarizing published targeted sequencing studies of patients with acquired aplastic anemia. Individual studies are listed along the Y-axis, with the number of patients included in each study is plotted along the X-axis. The dark gray bar shows the corresponding number of patients without detected somatic mutations in targeted genes; light colored bar shows the number of patients with identified somatic mutations, with the corresponding percentage of patients with mutations stated to the right of each bar plot. An embedded table depicts salient characteristics of each study, if available: Age, age at diagnosis in years, median (range); MDS, whether patients with post-AA MDS were included or excluded from the study; Sensitivity, minimal % mutant allele frequency detected in each study. n/a: not available; *, the listed age corresponds to a larger patient cohort; **, age at sequencing.