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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 ×
Campbell, Brittany B
de Borja, Richard
Alexandrov, Ludmil B
Merico, Daniele
Wedge, David
Van Loo, Peter
Tarpey, Patrick S
Coupland, Paul
Behjati, Sam
Pollett, Aaron
Lipman, Tatiana
Heidari, Abolfazl
Deshmukh, Shriya
Avitzur, Na'ama
Meier, Bettina
Gerstung, Moritz
Hong, Ye
Merino, Diana M
Ramakrishna, Manasa
Remke, Marc
Arnold, Roland
Panigrahi, Gagan B
Thakkar, Neha P
Hodel, Karl P
Henninger, Erin E
Göksenin, A Yasemin
Bakry, Doua
Charames, George S
Druker, Harriet
Lerner-Ellis, Jordan
Mistry, Matthew
Dvir, Rina
Grant, Ronald
Elhasid, Ronit
Farah, Roula
Taylor, Glenn P
Nathan, Paul C
Alexander, Sarah
Ben-Shachar, Shay
Ling, Simon C
Gallinger, Steven
Constantini, Shlomi
Dirks, Peter
Huang, Annie
Scherer, Stephen W
Grundy, Richard G
Durno, Carol
Aronson, Melyssa
Gartner, Anton
Meyn, M Stephen
Taylor, Michael D
Pursell, Zachary F
Pearson, Christopher E
Malkin, David
Futreal, P Andrew
Stratton, Michael R
Bouffet, Eric
Hawkins, Cynthia
Campbell, Peter J
Tabori, Uri #
Issue Date: Mar-2015
Publisher: Nature Publishing Group
Series Title: Nature Genetics vol:47 issue:3 pages:257-62
Article number: 10.1038/ng.3202
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.
URI: 
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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