Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia

ABSTRACT

Introduction: Historically, the majority of childhood cancers, including acute lymphoblastic leukemia (ALL), were not thought to have a hereditary basis. However, recent germline genomic studies have revealed that at least 5 – 10% of children with cancer (and approximately 3 – 4% of children with ALL) develop the disease due to an underlying genetic predisposition.

Areas covered: This review discusses several recently identified ALL predisposing conditions and provides updates on other more well-established syndromes. It also covers topics related to the evaluation and management of children and family members at increased ALL risk.

Expert opinion: Germline predisposition is gaining recognition as an important risk factor underlying the development of pediatric ALL. The challenge now lies in how best to capitalize on germline genetic information to improve ALL diagnosis, treatment, and perhaps even prevention.

KEYWORDS:

• Acute lymphoblastic leukemia (ALL)
• familial studies
• genetic predisposition
• genome wide association studies (GWAS)
• hematologic malignancy
• transcription factors

Article highlights

• Recent family-based and large scale high-throughput sequencing studies have uncovered several novel genetic conditions predisposing to acute lymphoblastic leukemia (ALL).

• The genes associated with these ALL predisposing conditions are often the same as those targeted by somatic mutations in ALL blasts (e.g. PAX5, IKZF1, ETV6, PTPN11).

• For some conditions, such as those caused by germline alterations affecting PAX5, IKZF1, and ETV6, affected individuals are primarily predisposed to develop ALL.

• For others, such as Noonan syndrome (NS), Neurofibromatosis 1 (NF1), Li-Fraumeni syndrome (LFS), and Constitutional mismatch repair deficiency (CMMRD), affected individuals are at risk for ALL as well as other hematologic malignancies and/or solid tumors.

• Examination of the genetic status of leukemic blasts can provide clues to the underlying ALL predisposing condition. For example, blasts in LFS commonly exhibit a low hypodiploid karyotype, while blasts in CMMRD have a hypermutator phenotype.

• Knowledge of an underlying ALL predisposing condition informs leukemia treatment through avoidance of carcinogenic therapies. It also enables the initiation of screening programs for the early detection and treatment of second primary or therapy-associated cancers.

• When considering genetic testing in a child with ALL, it is important to choose the appropriate germline tissue; cultured skin fibroblasts are the preferred source of germline DNA.

• Pre-emptive allogeneic hematopoietic stem cell transplantation before the overt development of leukemia is a consideration for some individuals with ALL predisposing conditions.

• Continued efforts are warranted to better define the spectrum and penetrance of known ALL predisposing conditions, discover new genes and germline variants associated with ALL risk, elucidate the interactions between germline genetic variation and environmental exposures in the development of ALL, and optimize clinical care based on germline genetic information.

Acknowledgments

The authors wish to thank Joshua Stokes and colleagues in Biomedical Communications at St. Jude for their assistance in preparing the figure.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was funded in part by the American Lebanese Syrian Associated Charities and St. Jude Children’s Research Hospital.