Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

Adam Shlien, et. al., Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers, Nature Genetics 47, 257-262 (2015)

High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed).

Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (~600 mutations/cell division), reaching but not exceeding ~20,000 exonic mutations in <6 month. This implies a threshold compatible with cancer-cell survival.

Ultra-hypermutated bMMRD cancers contained an even distribution of mutations throughout the genome and displayed other features distinct from other sequenced tumors: they were almost completely devoid of the copy number alterations typically observed in childhood brain cancers and were microsatellite stable.

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