How I diagnose and manage individuals at risk for inherited myeloid malignancies

Abstract

Although inherited hematopoietic malignancies have been reported clinically since the early twentieth century, the molecular basis for these diseases has only recently begun to be elucidated. Growing utilization of next-generation sequencing technologies has facilitated the rapid discovery of an increasing number of recognizable heritable hematopoietic malignancy syndromes while also deepening the field’s understanding of the molecular mechanisms that underlie these syndromes. Because individuals with inherited hematopoietic malignancies continue to be underdiagnosed and are increasingly likely to be encountered in clinical practice, clinicians need to have a high index of suspicion and be aware of the described syndromes. Here, we present the methods we use to identify, test, and manage individuals and families suspected of having a hereditary myeloid malignancy syndrome. Finally, we address the areas of ongoing research in the field and encourage clinicians and researchers to contribute and collaborate.

Clinical Assessment and Diagnosis of Germline Predisposition to Hematopoietic Malignancies: The University of Chicago Experience

“…As we have discussed in previous reviews ( 1 , 20 , 21 ), we recommend clinical testing for the presence of a germline syndrome in individuals with: (i) multiple cancer diagnoses; (ii) hematopoietic malignancies diagnosed in two individuals within a 3-generation pedigree; (iii) relatives with cytopenias, hematopoietic abnormality such as macrocytosis/dysplasia, and/or poor stem cell mobilization; and (iv) relatives with other physical findings associated with a known germline predisposition syndrome (Table 1 ). Once genetic counseling has been performed, and an individual wants to proceed with clinical testing, an appropriate sample must be obtained.…”

“…A detailed past medical history, family history, and physical examination, as well as a review of key laboratory findings, are critical to identify patients with genetic predisposition for hematopoietic malignancies (Table 1 ). Findings such as dysmorphic features, short stature, cytopenias, immunodeficiency, specific histopathology, or toxicity out of proportion to that typically seen after chemotherapy or radiation, may indicate an underlying cancer predisposition syndrome ( 1 , 16 , 26 – 29 ). In the era of precision medicine and identification of new prognostic biomarkers, referral to our Hematopoietic Malignancies Cancer Risk Team is also driven by the use of next generation sequencing panels that are designed for use for diagnosis and prognostication, but when performed on DNA derived from affected tissue, cannot distinguish somatic from germline variants.…”

“…As health-care professionals consider the diagnosis of inherited predisposition to hematopoietic malignancies increasingly in patients with a strong personal and family history ( 1 ), coordination between pediatric and adult care teams is critical for optimal assessment of all family members across the age spectrum. Communication and coordination between pediatric and adult hematology/medical oncology groups are the hallmarks of the approach utilized by The University of Chicago Hematopoietic Malignancies Cancer Risk Team.…”

Familial myelodysplastic syndrome/acute myeloid leukemia

“…The genes implicated are diverse, including well-known hematopoietic transcription factors such as CEBPA, GATA2, and RUNX1 as well as genes such as BRCA1 and MSH6 , more traditionally thought of as solid tumor risk genes [10]. The most recently identified genes, DDX41, SAMD9 and SAMD9L , are revealing novel pathways involved in leukemogenesis and deepening our understanding of the basic biology of MDS/AML [11–13].…”

“…From a clinical perspective, understanding when and how to suspect germ line predisposition in a patient being evaluated for cytopenias and/or MDS/AML is critical for optimal care of the patient and his/her family [10]. Incorporating specific personal medical and family history questions about chronic cytopenias, aplastic anemia, MDS/AML, a bleeding propensity, or specific organ system features such as pulmonary fibrosis or immunodeficiency are key components for clinical detection.…”