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- Title
Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.
- Authors
Shlien, Adam; Meier, Bettina; Hong, Ye; Gartner, Anton; Remke, Marc; Thakkar, Neha P; Pearson, Christopher E; Hodel, Karl P; Henninger, Erin E; Göksenin, A Yasemin; Pursell, Zachary F; Bakry, Doua; Grant, Ronald; Nathan, Paul C; Alexander, Sarah; Charames, George S; Druker, Harriet; Lerner-Ellis, Jordan; Dvir, Rina; Elhasid, Ronit
- Abstract
DNA replication−associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). 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). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10−13). 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 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.
- Subjects
SOMATIC mutation; DNA replication; POLYMERASES; GENOMES; BRAIN tumors; CANCER
- Publication
Nature Genetics, 2015, Vol 47, Issue 3, p257
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.3202