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Researchers identify inherited gene variation linked to greater acute lymphoblastic leukemia risk.

ALL is identified in about 3,000 individuals each year aged 19 or younger in the U.S., making it the most common childhood cancer. While the cause remains largely unknown, only a small fraction of childhood leukemia is believed to involve an inherited genetic predisposition. However, findings suggest that the inherited risk for ALL may be much greater than what is thought previously.  Now, researchers at St. Jude Children’s Research Hospital studying two generations of a family affected by pediatric acute lymphoblastic leukemia (ALL) have identified an inherited variation in the ETV6 gene that is associated with an increased risk of developing the disease.  The team state that evidence from this study suggests that the ETV6 variations alone are not sufficient to cause cancer, however, they may play a significant role in inherited predisposition to childhood leukemia.  The study is published in the journal Lancet Oncology.

Previous studies show that ETV6 plays an important role in the blood system, particularly production of the platelets that help prevent bleeding. The gene works by binding to DNA and regulating the expression of other genes. An abnormal gene created by the fusion of ETV6 and the RUNX1 gene is one of the most common alterations in childhood ALL and is found in the leukemic cells of 20 to 25 percent of pediatric ALL.  The current study shows that almost half of the ETV6 variants identified in this study occurred in the region of the gene responsible for binding to DNA, which suggests the loss or alteration of this DNA-binding function of ETV6 may be critical to cancer promotion

The current study identified the association between ETV6 and childhood ALL by sequencing the whole exome of a family in which the mother and two of the three children have a history of pediatric ALL.  Results show that the mother and her children, including a daughter who does not have a cancer diagnosis, have an alteration in one of the two copies of ETV6; the father does not have the variant.  Data findings show that the alteration 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 lab also validated this finding via the analysis of another 4,405 children with ALL and found 31 ETV6 variations that are potentially related to leukemia risk in 35 patients screened. Data findings show that the variations were unique to ALL patients or extremely rare in the general population.  It was also observed that patients with the variant tended to be older when their cancer was identified and more likely to have extra chromosomes; the variants, however, were not associated with a particular ethnicity or outcome of ALL therapy.

The researchers note that the family in this study has received genetic counseling through the St. Jude Cancer Predisposition Program to understand the risk and the need for continued monitoring, particularly of the currently cancer-free child with the ETV6 variation. They go on to add that no additional blood cancers have been reported in the extended family, with the identification of these variations helping the family to better understand why their children developed cancer and to plan for the future; all were treated at St. Jude and are now cancer free.

The team surmise that this is the latest example of the important role that genetic variation and inheritance plays in ALL risk, which has clear clinical implications to raise the understanding of the biology driving this cancer.  For the future, the researchers state that additional research is needed to understand the biological effects of the ETV6 variants and to develop recommendations for monitoring and treatment, with the magnitude of the risk still needing to be determined.

Source: St. Jude Children’s Research Hospital


Acute Lymphoblastic Leukemia.  Credit: Blausen Medical | Medical Animations.
Acute Lymphoblastic Leukemia. Credit: Blausen Medical | Medical Animations.

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