Germline ETV6 Variations as Basis of Novel Genetic Syndrome Associated With Childhood Acute Lymphoblastic Leukemia


Key Points

  • ETV6 variants potentially associated with ALL predisposition were found in 1% of cases.
  • A hyperdiploid leukemia karyotype was identified in 64% of ALL cases harboring germline ETV6 risk variants compared with 27% of cases with wild-type ETV6.

In a systematic genetic study reported in The Lancet Oncology, Moriyama et al found that germline ETV6 variations identified in a small proportion of children with acute lymphoblastic leukemia (ALL) were associated with a novel syndrome predisposing carriers to disease. Recent data indicated that germline ETV6 variations were associated with familial clustering of hematologic malignancies, suggesting that ETV6 could be an important determinant for ALL susceptibility.

Study Details

In the study, whole-exome sequencing was performed in an index family with several cases of ALL to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was performed in children from the Children’s Oncology Group and St Jude Children’s Research Hospital front-line ALL trials. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants.

ETV6 Variants

A novel nonsense ETV6 variant (p.Arg359X) with high penetrance was indentified in an index family. Targeted sequencing of ETV6 in 4,405 childhood cases of ALL identified 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frameshift variants) potentially related to ALL risk in 35 cases (1%). Of 31 ALL-related ETV6 variants, 15 were clustered in the erythroblast transformation specific domain and predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at diagnosis of ALL (10.2 vs 4.7 years, P = .017), and the hyperdiploid leukemia karyotype was identified in 9 (64%) of 14 ALL cases harboring germline ETV6 risk variants compared with 538 (27%) of 2,007 cases with wild-type ETV6 (P = .0050).

The investigators concluded: “Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants is needed.”

The study was supported by the U.S. National Institutes of Health and American Lebanese Syrian Associated Charities.

Jun J. Yang, PhD, of St Jude Children’s Research Hospital, is the corresponding author of The Lancet Oncology article.

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