Photo courtesy of
St. Jude/Seth Dixon
Germline variations in the ETV6 gene are associated with an increased risk of developing pediatric acute lymphoblastic leukemia (ALL), according to research published in The Lancet Oncology.
Researchers said the magnitude of the risk must still be determined, as well as how the variants identified may promote ALL.
The evidence suggests that ETV6 variation alone is not sufficient to cause ALL but may play a significant role in inherited predisposition to childhood ALL.
The researchers discovered the association between the ETV6 variants and childhood ALL by sequencing the whole exome of a family in which the mother and 2 of the 3 children have a history of pediatric ALL.
All were treated at St. Jude Children’s Research Hospital in Memphis, Tennessee, and are now cancer-free.
The researchers identified a novel non-sense ETV6 variant (p.Arg359X) in this mother and her 3 children, including a daughter who has not been diagnosed with cancer. The father does not have the variant.
This variant is predicted to result in the production of a shortened ETV6 protein that cannot fulfill its normal function of binding to DNA and regulating the expression of other genes.
The researchers screened an additional 4405 children with ALL and found 31 ETV6 exonic variants—21 missense, 5 frameshift, 4 non-sense, and 1 splice site—that are potentially related to leukemia risk in 35 patients, or almost 1% of the patients screened.
The variants identified were unique to ALL patients or extremely rare in the general population, the researchers said.
Patients with the variants tended to be older when diagnosed with ALL (10.2 years vs 4.7 years; P=0.017) and were more likely to have hyperdiploid leukemia. Sixty-four percent of ALL cases with germline ETV6 variants were hyperdiploid, compared to 27% of ALL cases without the variants (P=0.0050).
The variants were not associated with a particular ethnicity or with the outcome of ALL therapy.
The researchers also noted that almost half of the ETV6 variants identified (n=15) clustered in the erythroblast transformation specific domain.
“That suggests the loss or alteration of this DNA-binding function of ETV6 may be critical to cancer promotion,” said study author Jun J. Yang, PhD, of St. Jude.
“This is the latest example of the important role that genetic variation and inheritance plays in ALL risk. That has clear clinical implications and will help us understand the biology driving this cancer.”
These findings build on previous work that revealed an association between inherited ETV6 variations and thrombocytopenia in families with a susceptibility to hematologic malignancies. The researchers said this new study further solidifies the association between ETV6 and pediatric ALL.
