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ETV6 variations may predict predisposition to childhood ALL
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Germline variations to transcriptional repressor ETV6 may predict a predisposition to childhood acute lymphoblastic leukemia, according to the results of a systematic genetic study.
As such, recommendations for clinical interventions and surveillance of individuals harboring ETV6 variations are needed, according to the researchers.
ALL is the most common childhood cancer and can be cured with risk-adapted chemotherapy, according to study background. However, little research has been conducted into hereditary predisposition for the disease.
However, recent reports of germline variations to ETV6 appeared associated with substantial familial clustering of hematologic malignancies, suggesting the gene may serve as a genetic determinant for ALL susceptibility.
Jun J. Yang
Thus, Jun J. Yang, PhD, associate member of the department of pharmaceutical sciences at St. Jude Children’s Research Hospital, and colleagues sought to comprehensively identify ALL predisposition variants in ETV6, as well as to determine the extent to which these variants contributed to the overall risk for pediatric ALL.
Yang and colleagues identified an index family of European descent (n = 5) with several recorded cases of childhood ALL and performed whole-exome sequencing to identify causal variants for ALL predisposition. Further, the researchers performed targeted sequencing in 4,405 children enrolled in frontline ALL trials from the Children’s Oncology Group and at St. Jude.
In the index family, the researchers identified a novel non-sense ETV6 variant (p.Arg359X) with a strong penetrance.
Among the 4,405 childhood samples of ALL available, subsequent targeted sequencing found 31 exonic variants (non-sense, n =4; missense, n = 21; splice site, n =1; frameshift, n = 5) that potentially related to ALL risk in 1% of patients (n = 35).
Forty-eight percent (n = 15) of these variants clustered in the erythroblast transformation specific domain, which the researchers predicted to be highly deleterious.
The researchers found that children with ALL-related ETV6 mutations tended to be significantly older at time of diagnosis compared with those without mutations (median, 10.2 years vs. 4.7 years; P = .017).
Further, the hyperdiploid leukemia karyotype appeared highly overrepresented in patients with ALL harboring germline ETV6 risk variants compared with wild-type patients (64% vs. 27%; P = .005).
“Future longitudinal family studies are needed to better define the penetrance, age-specific leukemia incidence, and clinical features that are characteristic of ALL in patients with ETV6 germline variants,” Yang and colleagues wrote. “These clinical and mechanistic studies are absolutely crucial for the development of recommendations for clinical interventions in the future for individuals harboring ALL-related ETV6 variants.”
In an accompanying editorial, Torsten Haferlach, MD, CEO of MLL Munich Leukemia Laboratory in Germany, noted that these results suggest that family history should play an important role in the diagnosis of childhood ALL.
“A comprehensive family history has to be included by clinicians as part of a standard approach to the diagnosis and workup of not only pediatric ALL but in all cases of malignant or premalignant stages in hematopoietic disorders,” Haferlach wrote. “Furthermore, recommendations for counselling and genetic testing of family members, who might also be carriers of predisposing germline variants, have to be devised.” – by Cameron Kelsall
Disclosure: The researchers and Haferlach report no relevant financial disclosures.
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