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Newly identified DNA repair defect linked to increased risk of leukemia relapse
Date:9/26/2011

r work from the laboratory of Evans and others that linked a deficit of MSH2 with an increased risk of certain cancers and resistance to mercaptopurine, a drug that is the backbone of leukemia treatment.

In this study, scientists found that 11 percent of 90 newly diagnosed pediatric ALL patients had low or undetectable levels of the MSH2 protein.

Ten years after an ALL diagnosis, children with low MSH2 protein levels were less likely to be alive and four times more likely to have suffered relapses. The comparison included 97 patients treated in a St. Jude study called Total XV, which ended in 2007. Sixteen patients had leukemia with low MSH2 levels. The analysis took other factors into account, including a patient's age and early treatment response, which are associated with high-risk ALL. The results suggest MSH2 protein levels might help identify a new group of high-risk patients.

Further work revealed no evidence of problems in the MSH2 gene itself, so scientists expanded their search for why some patients had low MSH2 levels in their leukemia cells. Researchers looked for changes in the makeup of eight genes known or suspected of playing a role in the breakdown of MSH2. To do that, they screened DNA from 69 of the 90 newly diagnosed ALL patients at nearly 1 million spots in the genome.

The research showed each patient was missing at least one of the four genes that regulate MSH2 degradation. "MSH2 was still made, but the system to protect it from destruction had been impaired or eliminated, leading to more rapid breakdown of MSH2 and a crippled system for fixing DNA," Evans said. The missing genes were FRAP1, HERC1, PRKCZ and PIK3C2B.

A check of leukemia cells from another group of St. Jude ALL patients found that about 12 percent, or 21 of the 170 children, were missing at least one of the same genes. A search of public databases found one or more of the same genes deleted in 13.5 percent of sporadic colorectal canc
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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