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Scientists Sequence ALL Clones to Track Mutations Driving Relapse

NEW YORK (GenomeWeb) – Scientists have used whole-exome sequencing to detail the genomic changes that drove relapse in patients with acute lymphoblastic leukemia (ALL).

Cancers such as leukemia are not a homogeneous disease, but a jumble of different dividing cancer cells, called clones, with distinctive sets of mutations. While chemotherapy might kill almost all the clones, some might escape therapy, leaving them to multiply and cause relapse.

Led by Charles Mullighan and Jinghui Zhang of the St. Jude Children's Research Hospital and Stephen Hunger of the Children's Hospital of Philadelphia, the scientists showed that most cases of relapse were driven by minor clones present at extremely low levels that managed to survive therapy.

"This finding was interesting, because most people think that the clone that has the most mutations is more likely to survive therapy and evolve, but that doesn't seem to be the case," Zhang said in a statement.

Of the relapsed tumors, 75 percent of them were descendants of minor subclones at the time of diagnosis, suggesting that in most cases the predominant clones were eradicated by therapy.

The researchers used deep whole-exome sequencing to analyze the cancer genome mutations in cell samples taken at three stages of ALL, diagnosis, remission, and relapse, allowing them to track mutations in clones. The samples were taken from 20 children who had ALL that returned following treatment. ALL is a leading cause of cancer deaths in children, with 15 percent of ALL patients relapsing, St. Jude said.

Their analysis showed great diversity in mutations at both diagnosis and relapse, suggesting that cancer cells mutate wildly throughout cancer progression. They identified seven specific genes in six pathways that were highly likely to be mutated in relapsed disease: NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1.

The findings have direct implications for the clinical management of ALL, the authors wrote. They suggested that there could be clinical utility to assaying for specific mutations that might predict relapse during the course of ALL treatment. Several mutations conferred resistance to therapeutics, they said, adding that a high frequency of mutations in epigenetic regulators suggested potential drug targets.

"When we are analyzing for the level of minimum residual disease in monitoring remission in patients, we should not only pay attention to the mutations in the predominant clone," Zhang, a co-senior author of the study, said. "We should also be tracking what kinds of mutations exist in the minor subclones."

Researchers at St. Jude and elsewhere are currently exploring the biological functions of the relapse-related genes.

In February, a team from St. Jude published a paper in the Journal of the American Medical Association detailing a genetic variant that was linked to a side effect of ALL treatment.