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 Ramakrishna; Marc 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

doi:10.1038/ng.3202

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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

211 Citations (Scopus)

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.

Original language	English
Pages (from-to)	257-262
Number of pages	6
Journal	Nature Genetics
Volume	47
Issue number	3
DOIs	https://doi.org/10.1038/ng.3202
Publication status	Published - 2 Feb 2015

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Shlien, A., Campbell, B. B., de Borja, R., Alexandrov, L. B., Merico, D., Wedge, D., Van Loo, P., Tarpey, P. S., Coupland, P., Behjati, S., Pollett, A., Lipman, T., Heidari, A., Deshmukh, S., Avitzur, N., Meier, B., Gerstung, M., Hong, Y., Merino, D. M., ... Biallelic Mismatch Repair Deficiency Consortium (2015). Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers. Nature Genetics, 47(3), 257-262. https://doi.org/10.1038/ng.3202

@article{3a72270e0bf944b59612529c9b5a9cbd,

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

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. ",

keywords = "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",

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

year = "2015",

month = feb,

day = "2",

doi = "10.1038/ng.3202",

language = "English",

volume = "47",

pages = "257--262",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "3",

}

Shlien, A, Campbell, BB, de Borja, R, Alexandrov, LB, Merico, D, Wedge, D, Van Loo, P, Tarpey, PS, Coupland, P, Behjati, S, Pollett, A, Lipman, T, Heidari, A, Deshmukh, S, Avitzur, N, Meier, B, Gerstung, M, Hong, Y, Merino, DM, Ramakrishna, M, Remke, M, Arnold, R, Panigrahi, GB, Thakkar, NP, Hodel, KP, Henninger, EE, Göksenin, AY, Bakry, D, Charames, GS, Druker, H, Lerner-Ellis, J, Mistry, M, Dvir, R, Grant, R, Elhasid, R, Farah, R, Taylor, GP, Nathan, PC, Alexander, S, Ben-Shachar, S, Ling, SC, Gallinger, S, Constantini, S, Dirks, P, Huang, A, Scherer, SW, Grundy, RG, Durno, C, Aronson, M, Gartner, A & Biallelic Mismatch Repair Deficiency Consortium 2015, 'Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers', Nature Genetics, vol. 47, no. 3, pp. 257-262. https://doi.org/10.1038/ng.3202

TY - JOUR

T1 - Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

AU - Shlien, Adam

AU - Campbell, Brittany B.

AU - de Borja, Richard

AU - Alexandrov, Ludmil B.

AU - Merico, Daniele

AU - Wedge, David

AU - Van Loo, Peter

AU - Tarpey, Patrick S.

AU - Coupland, Paul

AU - Behjati, Sam

AU - Pollett, Aaron

AU - Lipman, Tatiana

AU - Heidari, Abolfazl

AU - Deshmukh, Shriya

AU - Avitzur, Na'ama

AU - Meier, Bettina

AU - Gerstung, Moritz

AU - Hong, Ye

AU - Merino, Diana M.

AU - Ramakrishna, Manasa

AU - Remke, Marc

AU - Arnold, Roland

AU - Panigrahi, Gagan B.

AU - Thakkar, Neha P.

AU - Hodel, Karl P.

AU - Henninger, Erin E.

AU - Göksenin, A. Yasemin

AU - Bakry, Doua

AU - Charames, George S.

AU - Druker, Harriet

AU - Lerner-Ellis, Jordan

AU - Mistry, Matthew

AU - Dvir, Rina

AU - Grant, Ronald

AU - Elhasid, Ronit

AU - Farah, Roula

AU - Taylor, Glenn P.

AU - Nathan, Paul C.

AU - Alexander, Sarah

AU - Ben-Shachar, Shay

AU - Ling, Simon C.

AU - Gallinger, Steven

AU - Constantini, Shlomi

AU - Dirks, Peter

AU - Huang, Annie

AU - Scherer, Stephen W.

AU - Grundy, Richard G.

AU - Durno, Carol

AU - Aronson, Melyssa

AU - Gartner, Anton

AU - Biallelic Mismatch Repair Deficiency Consortium

PY - 2015/2/2

Y1 - 2015/2/2

N2 - 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.

AB - 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.

KW - Base Pair Mismatch

KW - Brain Neoplasms

KW - DNA Mismatch Repair

KW - DNA Repair

KW - DNA Replication

KW - DNA-Directed DNA Polymerase

KW - Exons

KW - Germ-Line Mutation

KW - Humans

KW - Microsatellite Instability

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ng.3202

DO - 10.1038/ng.3202

M3 - Article

C2 - 25642631

SN - 1061-4036

VL - 47

SP - 257

EP - 262

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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