Genetic predispositions to childhood leukemia

Abstract

While the majority of leukemia cases occur in the absence of any known predisposing factor, there are germline mutations that significantly increase the risk of developing hematopoietic malignancies in childhood. In this review article, we describe a number of these mutations and their clinical features. These predispositions can be broadly classified as those leading to bone marrow failure, those involving tumor suppressor genes, DNA repair defects, immunodeficiencies or other congenital syndromes associated with transient myeloid disorders. While leukemia can develop as a secondary event in the aforementioned syndromes, there are also several syndromes that specifically lead to the development of leukemia as their primary phenotype. Many of the genes discussed in this review can also be somatically mutated in other cancers, highlighting the importance of understanding shared alterations and mechanisms underpinning syndromic and sporadic leukemia.

Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics

“…The underlying aetiologies of most cases of childhood ALL remain largely unknown, although various environmental, ethnic, immunological, infectious, socioeconomic and other epidemiological factors have been rigorously evaluated as potential contributors to leukaemogenesis (Wiemels, ). Childhood ALL is also associated with uncommon constitutional leukaemia predisposition syndromes, such as trisomy 21 and TP53 mutations (Li‐Fraumeni syndrome) (Stieglitz & Loh, ). Rare germline ETV6 and PAX5 mutations and ARID5B , CEBPE , GATA3 , and IKZF1 polymorphisms have also been linked to increased ALL occurrence (Shah et al , ; Perez‐Andreu et al , ; Zhang et al , ).…”

AML presenting with a preleukemic episode and acquired heterochromia in a child with macrosomia

“…Genetic syndromes associated with overgrowth and cancer predisposition include Beckwith–Wiedemann, Sotos, Gorlin, Proteus, and hemihyperplasia; these are primarily associated with solid tumors . Other than macrosomia, there was no developmental delay, craniofacial abnormalities, or other evidence of syndromic disease in our patient.…”

Applying molecular epidemiology in pediatric leukemia

“…As reported previously, many of these can be grouped into one of the following remaining categories: cell cycle/differentiation syndromes, bone marrow failure syndromes, telomere maintenance syndromes, immunodeficiency syndromes, and transcription factor syndromes with pure familial leukemia. A comprehensive description of these other syndromes with associated leukemia risk is beyond the scope of the current report, but the reader is directed to the 2 following reviews by Seif (2011)7 and Stieglitz and Loh (2013)88 for an excellent summary of leukemia predisposition. Understanding the genetic risk for childhood leukemia is very important to identify children, and their family members, who may be at risk for hereditary cancer predisposition 89.…”