Germline Mutations Associated with Leukemia in Childhood: New Discoveries and Emerging Phenotypes

Abstract

Acute leukemia is the most common cancer of childhood. The pathogenesis of childhood leukemia is multifactorial, and most cases occur sporadically. Although the majority of genetic changes are acquired somatic mutations, recent discoveries have revealed that inherited germline mutations are present in an increasing proportion of children, predisposing them to leukemia. Recently described germline mutations in ETV6, SH2B3, and PAX5 have been associated with increased risks of acute lymphoblastic leukemia (ALL). A high incidence of germline mutations in GATA2 is seen in pediatric myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Susceptibility genes for adult leukemia are found at increased incidence in children with MDS/AML. Recent findings have broadened the phenotype of inherited bone marrow failure syndromes, with a decreased emphasis on phenotypic abnormalities. Newly identified germline susceptibilities to hematologic malignancies are emerging at a rapid pace with the advent of next-generation sequencing approaches. A higher incidence of germline mutations accounts for childhood leukemia more than previously thought, and affected children do not necessarily fit into previously described syndromic presentations; therefore, careful clinical consideration is required for accurate diagnosis. Furthermore, children with inherited predisposition require a multidisciplinary approach to ensure proper evaluation and treatment, including but not limited to genetic counseling for the patient and family members and close management by a hematologist and oncologist, plus evaluations by a psychologist, as well as by a stem cell transplantation specialist.