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Genetic basis of high-risk childhood cancer points to possible new drug treatment strategy
Date:1/20/2013

were in remission. The study included whole-genome sequencing of the entire cancer and normal genomes of 20 patients with near haploid or low hypodiploid subtypes. For another 20 patients, investigators deciphered just DNA involved in protein production. Researchers also screened cancer cells from 117 adult ALL patients, including 11 with the low hypodiploid subtype.

The whole genome sequencing was done in conjunction with the St. Jude Children's Research Hospital Washington University Pediatric Cancer Genome Project. The project has sequenced the complete normal and cancer genomes of more than 600 children and adolescents with some of the most aggressive and least understood cancers.

Near haploid ALL was characterized by alterations in six genes and increased activity in key pathways that help regulate cell division and development. Disruption of these pathways, known as Ras and PI3K, has been linked to other cancers. The changes were found in 71 percent of near haploid ALL patients and included deletion of the NF1 gene. The gene had not previously been linked to high-risk leukemia. Other alterations involved the genes NRAS, KRAS, MAPK1, FLT3 and PTPN11.

Low hypodiploid ALL in both adults and children was linked to mutations in the TP53 tumor suppressor gene. The gene was altered in 91 percent of pediatric patients with the ALL subtype and in 10 of the 11 adults with low hypodiploid ALL included in the study. Other common alterations involved RB1, another tumor suppressor gene.

About 38 percent of children with low hypodiploid ALL also carried TP53 abnormalities in non-cancerous blood cells. The mutations included many previously linked to Li-Fraumeni syndrome, which is characterized by changes in TP53.

Further evidence linking low hypodiploid ALL to Li-Fraumeni syndrome came when researchers found the same TP53 mutation in two generations of the same family. The father was 31 years old when he was found to have a brai
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Contact: Carrie Strehlau
media@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

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