Research highlight

Hyper-mutation in pediatric brain tumors

Nature Genetics

February 3, 2015

The genetic mutations responsible for a hyper-mutated form of childhood brain tumor are reported in a study published online this week in Nature Genetics. The authors suggest that the rapid accumulation of mutations in these tumors could be exploited for the development of new treatments by identifying drugs that will push the cancer cells over the upper limit of mutations compatible with life.

Children who inherit two mutated copies of one of the key DNA repair genes are at high risk of pediatric cancers. This rare syndrome, known as biallelic mismatch repair deficiency (bMMRD), predisposes the child to many different types of cancer, among which blood cancers and brain tumors are the most common. However, not all children with bMMRD will develop cancer.

Adam Shlien and colleagues studied brain tumors from 12 bMMRD patients, 10 of which had aggressive brain tumors. When compared to each patient’s normal tissue, they discovered that the aggressive brain tumors were hyper-mutated, with an average of nearly 8,000 protein-altering mutations. In comparison, most other pediatric cancers have approximately 19 such mutations. The authors found that all hyper-mutated brain tumors carried mutations in one of two genes, POLE or POLD, which are DNA repair genes from a different pathway than the ones responsible for bMMRD. The results explain why these tumors progress so rapidly.

doi: 10.1038/ng.3202

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