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 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.

Roland Arnold | Richard G Grundy | Daniele Merico | Uri Tabori | Shlomi Constantini | Richard de Borja | Abolfazl Heidari | Patrick S Tarpey | Peter J Campbell | Michael R Stratton | Jordan Lerner-Ellis | Eric Bouffet | Peter Van Loo | Stephen W Scherer | Peter Dirks | Cynthia Hawkins | Manasa Ramakrishna | Steven Gallinger | Moritz Gerstung | Annie Huang | Adam Shlien | Paul Coupland | S. Scherer | D. Merico | P. Nathan | M. Stratton | P. Futreal | P. Campbell | P. Tarpey | D. Wedge | M. Gerstung | P. Van Loo | L. Alexandrov | S. Behjati | Manasa Ramakrishna | C. Hawkins | P. Coupland | A. Pollett | Roland Arnold | Z. Pursell | B. Campbell | A. Shlien | A. Gartner | S. Gallinger | R. Elhasid | C. E. Pearson | S. Constantini | M. Meyn | M. Remke | P. Dirks | Michael D. Taylor | A. Huang | D. Malkin | S. Ben-Shachar | S. Alexander | R. Grundy | B. Meier | G. Charames | S. Ling | U. Tabori | E. Bouffet | D. Merino | R. Dvir | Shriya Deshmukh | K. Hodel | M. Aronson | J. Lerner-Ellis | Marc Remke | Michael D Taylor | Anton Gartner | P Andrew Futreal | Aaron Pollett | Christopher E Pearson | C. Durno | David Malkin | R. de Borja | Sam Behjati | N. Avitzur | M Stephen Meyn | Paul C Nathan | Simon C Ling | Bettina Meier | Ludmil B Alexandrov | Erin E Henninger | A Yasemin Göksenin | Zachary F Pursell | H. Druker | Shay Ben-Shachar | Brittany B Campbell | David Wedge | Tatiana Lipman | Shriya Deshmukh | Na'ama Avitzur | Ye Hong | Diana M Merino | Gagan B Panigrahi | Neha P Thakkar | Karl P Hodel | Doua Bakry | George S Charames | Harriet Druker | Matthew Mistry | Rina Dvir | Ronald Grant | Ronit Elhasid | Roula Farah | Glenn P Taylor | Sarah Alexander | Carol Durno | Melyssa Aronson | M. Mistry | R. Grant | A. Heidari | Erin E. Henninger | R. Farah | T. Lipman | G. Panigrahi | Neha Thakkar | D. Bakry | S. Ling | A. Y. Göksenin | Ye Hong | Richard de Borja | M. Meyn | Michael R. Stratton | Glenn P. Taylor | M. Stratton

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