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Sequencing Study Uncovers Inherited Gene Variants with Ties to Childhood ALL Risk

NEW YORK (GenomeWeb) – Inherited germline variants — including a range of alterations in the transcriptional repressor-coding gene ETV6 genes — can contribute to the development of childhood acute lymphoblastic leukemia, according to a study published online last night in Lancet Oncology.

An international team led by investigators at St. Jude Children's Research Hospital did exome sequencing on a family that appeared particularly prone to ALL, uncovering a germline truncation in the ETV6 gene that seemed to coincide with ALL risk. And through targeted sequencing on thousands more children with ALL, they tracked down dozens more ALL-associated ETV6 variants.

"This is the latest example of the important role that genetic variation and inheritance plays in ALL risk," corresponding author Jun Yang, a pharmaceutical sciences researcher at St. Jude, said in a statement. "That has clear clinical implications and will help us understand the biology driving this cancer."

While childhood ALL is often attributed to somatic mutations, at least a few studies have shown that identical twins and other siblings of children with ALL are more likely to develop ALL themselves, the team explained, suggesting ALL susceptibility may have a heritable component.

That possibility has been explored to some extent in past studies, which have uncovered moderate risk variants in genes from lymphoid development and tumor suppressor pathways.

Higher risk variants in genes such as PAX5 and SH2B3 have been linked to ALL through studies of families frequently affected by ALL, the researchers noted, and a significant proportion of children with ALL carry germline TP53 mutations.

Together with the elevated risk of ALL in those with specific genetic conditions such as Down syndrome, such findings hint that additional germline variants may be at play in ALL development.

For the current study, the researchers began by using the Illumina TruSeq kit and HiSeq 2500 to do exome sequencing on a woman who had been successfully treated for ALL as a child, along with her two ALL-affected daughters, one unaffected daughter, and the children's unaffected father.

Among the suspicious variants detected in the children and their mother was a nonsense mutation in the transcriptional repressor gene ETV6, which is involved in red blood cell development.

The gene caught the team's attention, given the past detection of somatic ETV6 mutations in ALL tumors and the presence of ETV6 germline variants in some individuals with inherited thrombocytopenia and/or blood cancer susceptibility.

The same truncating mutation turned up in the mother and all three children, despite the lack of ALL in one of the children.

Four more nonsense mutations in ETV6, and 27 missense, slice site, or frameshift ETV6 mutations turned up in another 35 childhood ALL cases when the researchers did targeted gene sequencing on germline samples from 4,405 unrelated children with ALL who were treated through the Children's Oncology Group or St. Jude hospital ALL trials.

Interestingly, the ALL-associated variants tended to center on an ETV6 domain involved in erythroblast transformation, though the mechanism and degree of risk associated with such ETV6 alterations remains to be seen.

Nevertheless, the team's results so far suggest that the potentially risky ETV6 variants may be linked to particular ALL clinical features, including a slightly older age at diagnosis and an over-representation of ALL tumors with a hyper-diploid karyotype.