Mutations in Minor Subclones Lead to Leukemia Relapse After Chemotherapy

Cancer researchers monitored changes in the genomic composition of acute lymphoblastic leukemia (ALL) cells in all stages of cancer progression in order to determine why some cells survived chemotherapy to proliferate and eventually cause the death of the patient.

ALL is a leading cause of cancer deaths in children, with 15% of ALL patients relapsing with poor prognosis for survival. However, there is incomplete understanding of genetic heterogeneity and clonal evolution during progression of the disease.

Investigators at St. Jude Children's Research Hospital (Memphis, TN, USA) used deep whole-exome sequencing technology (which determines the DNA sequence of the exons, or protein-coding regions, of tens of thousands of genes simultaneously) to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukemias from diagnosis to relapse.

They reported that clonal diversity was comparable at diagnosis and relapse and that clonal survival from diagnosis to relapse was not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS, and IKZF1 mutations enriched at relapse.

Half of the leukemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone.

“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 does not seem to be the case,” said senior author Dr. Jinghui Zhang, professor of computational biology at St. Jude Children's Research Hospital. “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. We should also be tracking what kinds of mutations exist in the minor subclones.”

The study was published in the March 19, 2015, online edition of the journal Nature Communications.

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