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

DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutational 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) – higher than all childhood and most cancers (>7000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerases epsilon or delta. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germline bMMRD (p<10e-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. Thus implying 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.

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Dataset ID Description Technology Samples
EGAD00001001217 15
EGAD00001001218 10
Publications Citations
Comprehensive Analysis of Hypermutation in Human Cancer.
Cell 171: 2017 1042-1056.e10
Nucleosome positioning stability is a modulator of germline mutation rate variation across the human genome.
Nat Commun 11: 2020 1363
DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.
Cancer Discov 11: 2021 1176-1191
Mutations in the RAS/MAPK Pathway Drive Replication Repair-Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition.
Cancer Discov 11: 2021 1454-1467