Complete Loss of Replication Repair Drives Ultra-Hypermutated Cancers

Mutations that occur during DNA replication are repaired by DNA polymerase proofreading and mismatch repair (MMR), and failure of each of these repair pathways results in the persistence of mutations that can lead to cancer. Sporadic cancers contain various mutations in DNA repair pathways and accumulate multiple types of mutations over many years, whereas inherited DNA-repair deficiencies result in early-onset cancers and allow for the study of secondary pathways that drive carcinogenesis. Shlien and colleagues sequenced tumor samples from children with inherited biallelic mismatch repair deficiency (bMMRD) and found that all malignant bMMRD brain tumors analyzed harbored a much higher number of point mutations (249 mutations/Mb) relative to other pediatric cancers (0.61 mutations/Mb). These “ultra-hypermutated cancers” were unique in that the mutations were evenly distributed across the genome, lacked copy-number alterations, and were microsatellite stable. In contrast, non-neoplastic samples from bMMRD patients did not exhibit excessive mutations, suggesting that ultra-hypermutation requires secondary mutations. Indeed, ultra-hypermutated cancers acquired somatic mutations in genes encoding the DNA proofreading polymerases ϵ (POLE) or δ (POLD1), which were not present in nonmalignant tissue or non–ultra-hypermutated bMMRD cancers. POLE and POLD1 mutations affected conserved residues, resulting in impaired intrinsic proofreading activity, loss of replication fidelity, and a substantial increase (230-fold) in exonic mutation load compared with that of bMMRD tumors. bMMRD/polymerase-mutant cancers were characterized by distinct mutational signatures that occurred early in tumorigenesis and were also present in sporadic cancers with somatic MMR and POLE mutations. In addition, serial analysis of tumor samples indicated that bMMRD/polymerase-mutant cancers simultaneously accumulated sufficient driver mutations in less than 6 months and continuously mutated until reaching a threshold. These studies suggest a novel mechanism of carcinogenesis in which complete loss of DNA replication repair leads to massive accumulation of point mutations and rapid cancer initiation.

Shlien A, Campbell BB, de Borja R, Alexandrov LB, Merico D, Wedge D, et al. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nat Genet 2015 Feb 2 [Epub ahead of print].

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