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

Adam Shlien, Brittany B. Campbell, Richard de Borja, Ludmil B. Alexandrov, Daniele Merico, David Wedge, Peter Van Loo, Patrick S. Tarpey, Paul Coupland, Sam Behjati, Aaron Pollett, Tatiana Lipman, Abolfazl Heidari, Shriya Deshmukh, Na'ama Avitzur, Bettina Meier, Moritz Gerstung, Ye Hong, Diana M. Merino, Manasa RamakrishnaMarc Remke, Roland Arnold, Gagan B. Panigrahi, Neha P. Thakkar, Karl P. Hodel, Erin E. Henninger, A. Yasemin Göksenin, Doua Bakry, George S. Charames, Harriet Druker, Jordan Lerner-Ellis, Matthew Mistry, Rina Dvir, Ronald Grant, Ronit Elhasid, Roula Farah, Glenn P. Taylor, Paul C. Nathan, Sarah Alexander, Shay Ben-Shachar, Simon C. Ling, Steven Gallinger, Shlomi Constantini, Peter Dirks, Annie Huang, Stephen W. Scherer, Richard G. Grundy, Carol Durno, Melyssa Aronson, Anton Gartner, Biallelic Mismatch Repair Deficiency Consortium

Research output: Contribution to journalArticlepeer-review

211 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)257-262
Number of pages6
JournalNature Genetics
Issue number3
Publication statusPublished - 2 Feb 2015


  • Base Pair Mismatch
  • Brain Neoplasms
  • DNA Mismatch Repair
  • DNA Repair
  • DNA Replication
  • DNA-Directed DNA Polymerase
  • Exons
  • Germ-Line Mutation
  • Humans
  • Microsatellite Instability
  • Journal Article
  • Research Support, Non-U.S. Gov't


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