The Hematologist

January-February 2020, Volume 17, Issue 1

Germline Predisposition to Childhood Leukemia: T-ALL Risk Variants Uncovered in GWAS

Suzanne P. MacFarland, MD Attending Physician, Division of Oncology and Cancer Predisposition Program
Children's Hospital of Philadelphia, Philadelphia, PA
David T. Teachey, MD Associate Professor of Pediatrics
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Published on: January 08, 2020

For many years, most childhood cancers, including leukemias have been largely considered unfortunate infrequent events that are not inherited. Numerous rare syndromes have been demonstrated to predispose children to leukemia, including Li-Fraumeni syndrome (LFS), constitutional mismatch repair deficiency (CMMRD), Fanconi anemia, Bloom syndrome, ataxia-telangiectasia, neurofibromatosis type 1, and Noonan syndrome.1 The mechanisms for tumorigenesis are different with each of these disorders, leading to disease-specific screening guidelines for affected patients.2,3 Moreover, most of these predisposition syndromes have comorbid disease manifestations and/or family histories with high cancer penetrance. The three-year-old with a history of frequent life-threatening infections who develops leukemia is observed differently than the three-year-old with no significant past medical or family history.

As we have entered a genomic age that includes more frequent sequencing of tumor and germline DNA, it has become apparent that genetic predisposition to childhood cancer is more common than previously realized. For example, several single-gene disorders have been recognized as the cause of variably penetrant acute lymphoblastic leukemia (ALL) predisposition syndromes. These include germline mutations in ETV6, IKZF1, and PAX5, among others.2,3 While the prevalence of these syndromes is individually rare, screening is often recommended to include interval complete blood counts and/or bone marrow (BM) biopsy, and these patients are recommended to follow with a cancer predisposition or BM failure program for surveillance.1

Additionally, throughout the past decade, genome-wide association studies (GWAS) have shed some light on constitutional cancer predisposition to childhood ALL, identifying further regions of germline variation. Studies identified and confirmed susceptibility loci in ARID5B, IZKF1, CEBPE, BMI1, and CDKN2A/2B.4-9 In addition to confirmation of some of the aforementioned predisposition genes and loci, novel predisposing loci were uncovered in several more recent GWAS, such as 17q21 (including IKZF3) and 8q24.21.10,11 Certain variants also segregate to specific subtypes of ALL, such as TP63 in ETV6-RUNX1 fusion-positive B-cell ALL (B-ALL) and PIPK2A in hyperdiploid B-ALL.6,11,12 While some of these polymorphisms create leukemia risk in all patients, others, such as ARID5B, have increased prevalence in certain racial and/or ethnic groups.13

ALL can be subdivided into two major immunophenotypes, B- and T-cell ALL (T-ALL), and most of the predisposition studies have been performed in B-ALL patient cohorts. The germline contributors to T-ALL risk are not as well described. Enter the recent GWAS published by Dr. Maoxiang Qian and colleagues. This research identified strong associations that were distinct from those previously identified in B-ALL.14 By analyzing single-nucleotide polymorphisms (SNPs) in 1,191 T-ALL germline samplesfor susceptibility loci, investigators discovered results distinct from those previously identified in B-ALL or larger pan-ALL cohorts. This was particularly true for transcription factor genes associated with B-ALL risk such as GATA3, and less so for tumor suppressors such as CDKN2B.

Notably, the GWAS of Dr. Qian and colleagues identified the USP7 locus as a novel risk factor in African-American patients with T-ALL; it was also noted to segregate with TAL1 somatic changes, with a germline or somatic change in USP7 occurring in more than half of TAL1 T-ALL cases. The USP7 locus has been previously identified as somatically mutated in 12 percent of T-ALL cases.15 Of the identified SNPs, half clustered to the transcription start site, overlapping with histone modification sites and open chromatin segments, and the other half were intronic, suggesting changes in transcriptional regulation at the root of the increased leukemia risk. When cases of B-ALL were included in analysis of this GWAS data, USP7 was the only risk allele specific to T-ALL, whereas CDKN2A/B, ARID5B, IKZF3, PIP4K2A, and 8q24.21 were specific to neither B-ALL nor T-ALL (Figure). Although further study with a larger sample size is needed, this study by Dr. Qian and colleagues points to lineage-specific leukemia predisposing loci.

While these GWAS results point to certain susceptibility loci that increase risk for childhood leukemia, it is more difficult to translate this into practical application for individual patients, especially given the low penetrance of some of these variants and the lack of understanding of mechanism of cancer susceptibility in most cases. As germline testing for low penetrance variants has thus far been limited to the research setting, it is important to conduct further studies into the germline incidence of these changes in the pediatric leukemia population.

Germline predisposition for childhood leukemia has been increasingly recognized as an inciting factor in many childhood malignancies. Large GWAS of germline changes in these patients contribute to the field by providing a better understanding of the germline landscape of these disorders, including low-penetrance, higher-prevalence genetic variants that contribute to risk. Moving forward, further defining the prevalence and pathogenesis of these variants will be crucial to risk-stratifying children and conducting appropriate leukemia surveillance. A major question is whether this is just the tip of the iceberg. The effects of variants in the epigenome and in noncoding areas of the genome on predisposition have yet to be rigorously studied. Also, some academic centers are now performing more comprehensive genomic profiling on tumor and germline DNA in newly diagnosed patients with cancer. This practice will become more commonplace as technologies continue to improve and cost continues to drop, raising ethical and genetic counseling concerns regarding the impact of identifying novel or poorly defined variants on patients and their families. Finally, a better understanding of the mechanism(s) of leukemia predisposition of variants and risk loci will advance our understanding of overall leukemogenesis, raising the hope of not only better cures but also preventative strategies.

References

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Conflict of Interests

Dr. MacFarland and Dr. Teachey indicated no relevant conflicts of interest. back to top