Tissue-specific mutation accumulation in human adult stem cells during life

被引:671
作者
Blokzijl, Francis [1 ,2 ,3 ]
de Ligt, Joep [1 ,2 ,3 ]
Jager, Myrthe [1 ,2 ,3 ]
Sasselli, Valentina [2 ,3 ]
Roerink, Sophie [4 ]
Sasaki, Nobuo [2 ,3 ]
Huch, Meritxell [2 ,3 ]
Boymans, Sander [1 ,2 ,3 ]
Kuijk, Ewart [1 ,2 ,3 ]
Prins, Pjotr [2 ,3 ]
Nijman, Isaac J. [2 ,3 ]
Martincorena, Inigo [3 ,4 ]
Mokry, Michal [5 ]
Wiegerinck, Caroline L. [5 ]
Middendorp, Sabine [5 ]
Sato, Toshiro [2 ,3 ]
Schwank, Gerald [2 ,3 ]
Nieuwenhuis, Edward E. S. [5 ]
Verstegen, Monique M. A. [6 ]
van der Laan, Luc J. W. [6 ]
de Jonge, Jeroen [6 ]
IJzermans, Jan N. M. [6 ]
Vries, Robert G. [7 ]
van de Wetering, Marc [2 ,3 ]
Stratton, Michael R. [4 ]
Clevers, Hans [2 ,3 ]
Cuppen, Edwin [1 ,2 ,3 ]
van Boxtel, Ruben [1 ,2 ,3 ]
机构
[1] Univ Med Ctr Utrecht, Ctr Mol Med, Canc Genom Netherlands, Dept Genet, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands
[2] KNAW, Hubrecht Inst Dev Biol & Stem Cell Res, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands
[3] Univ Med Ctr Utrecht, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands
[4] Wellcome Trust Sanger Inst, Canc Genome Project, Wellcome Trust Genome Campus, Hinxton CB10 1SA, Cambs, England
[5] Univ Med Ctr Utrecht, Dept Pediat, Lundlaan 6, NL-3584 EA Utrecht, Netherlands
[6] Erasmus MC Univ Med Ctr, Dept Surg, Postbus 2040, NL-3000 CA Rotterdam, Netherlands
[7] Fdn Hubrecht Organoid Technol HUB, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands
关键词
SOMATIC MUTATIONS; CLONAL HEMATOPOIESIS; CANCER-RISK; AGE; DATABASE; POPULATION; SIGNATURES; DISCOVERY; EXPANSION; ALIGNMENT;
D O I
10.1038/nature19768
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer(1,2). Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication(1). However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells(3-5). Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues(1). Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.
引用
收藏
页码:260 / +
页数:17
相关论文
共 43 条
[1]   CNVnator: An approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing [J].
Abyzov, Alexej ;
Urban, Alexander E. ;
Snyder, Michael ;
Gerstein, Mark .
GENOME RESEARCH, 2011, 21 (06) :974-984
[2]   Clock-like mutational processes in human somatic cells [J].
Alexandrov, Ludmil B. ;
Jones, Philip H. ;
Wedge, David C. ;
Sale, Julian E. ;
Campbell, Peter J. ;
Nik-Zainal, Serena ;
Stratton, Michael R. .
NATURE GENETICS, 2015, 47 (12) :1402-+
[3]   Signatures of mutational processes in human cancer [J].
Alexandrov, Ludmil B. ;
Nik-Zainal, Serena ;
Wedge, David C. ;
Aparicio, Samuel A. J. R. ;
Behjati, Sam ;
Biankin, Andrew V. ;
Bignell, Graham R. ;
Bolli, Niccolo ;
Borg, Ake ;
Borresen-Dale, Anne-Lise ;
Boyault, Sandrine ;
Burkhardt, Birgit ;
Butler, Adam P. ;
Caldas, Carlos ;
Davies, Helen R. ;
Desmedt, Christine ;
Eils, Roland ;
Eyfjord, Jorunn Erla ;
Foekens, John A. ;
Greaves, Mel ;
Hosoda, Fumie ;
Hutter, Barbara ;
Ilicic, Tomislav ;
Imbeaud, Sandrine ;
Imielinsk, Marcin ;
Jaeger, Natalie ;
Jones, David T. W. ;
Jones, David ;
Knappskog, Stian ;
Kool, Marcel ;
Lakhani, Sunil R. ;
Lopez-Otin, Carlos ;
Martin, Sancha ;
Munshi, Nikhil C. ;
Nakamura, Hiromi ;
Northcott, Paul A. ;
Pajic, Marina ;
Papaemmanuil, Elli ;
Paradiso, Angelo ;
Pearson, John V. ;
Puente, Xose S. ;
Raine, Keiran ;
Ramakrishna, Manasa ;
Richardson, Andrea L. ;
Richter, Julia ;
Rosenstiel, Philip ;
Schlesner, Matthias ;
Schumacher, Ton N. ;
Span, Paul N. ;
Teague, Jon W. .
NATURE, 2013, 500 (7463) :415-+
[4]   Deciphering Signatures of Mutational Processes Operative in Human Cancer [J].
Alexandrov, Ludmil B. ;
Nik-Zainal, Serena ;
Wedge, David C. ;
Campbell, Peter J. ;
Stratton, Michael R. .
CELL REPORTS, 2013, 3 (01) :246-259
[5]   Crypt stem cells as the cells-of-origin of intestinal cancer [J].
Barker, Nick ;
Ridgway, Rachel A. ;
van Es, Johan H. ;
van de Wetering, Marc ;
Begthel, Harry ;
van den Born, Maaike ;
Danenberg, Esther ;
Clarke, Alan R. ;
Sansom, Owen J. ;
Clevers, Hans .
NATURE, 2009, 457 (7229) :608-U119
[6]   Genome sequencing of normal cells reveals developmental lineages and mutational processes [J].
Behjati, Sam ;
Huch, Meritxell ;
van Boxtel, Ruben ;
Karthaus, Wouter ;
Wedge, David C. ;
Tamuri, Asif U. ;
Martincorena, Inigo ;
Petljak, Mia ;
Alexandrov, Ludmil B. ;
Gundem, Gunes ;
Tarpey, Patrick S. ;
Roerink, Sophie ;
Blokker, Joyce ;
Maddison, Mark ;
Mudie, Laura ;
Robinson, Ben ;
Nik-Zainal, Serena ;
Campbell, Peter ;
Goldman, Nick ;
van de Wetering, Marc ;
Cuppen, Edwin ;
Clevers, Hans ;
Stratton, Michael R. .
NATURE, 2014, 513 (7518) :422-+
[7]   Control-FREEC: a tool for assessing copy number and allelic content using next-generation sequencing data [J].
Boeva, Valentina ;
Popova, Tatiana ;
Bleakley, Kevin ;
Chiche, Pierre ;
Cappo, Julie ;
Schleiermacher, Gudrun ;
Janoueix-Lerosey, Isabelle ;
Delattre, Olivier ;
Barillot, Emmanuel .
BIOINFORMATICS, 2012, 28 (03) :423-425
[8]   Ensembl 2015 [J].
Cunningham, Fiona ;
Amode, M. Ridwan ;
Barrell, Daniel ;
Beal, Kathryn ;
Billis, Konstantinos ;
Brent, Simon ;
Carvalho-Silva, Denise ;
Clapham, Peter ;
Coates, Guy ;
Fitzgerald, Stephen ;
Gil, Laurent ;
Giron, Carlos Garcia ;
Gordon, Leo ;
Hourlier, Thibaut ;
Hunt, Sarah E. ;
Janacek, Sophie H. ;
Johnson, Nathan ;
Juettemann, Thomas ;
Kaehaeri, Andreas K. ;
Keenan, Stephen ;
Martin, Fergal J. ;
Maurel, Thomas ;
McLaren, William ;
Murphy, Daniel N. ;
Nag, Rishi ;
Overduin, Bert ;
Parker, Anne ;
Patricio, Mateus ;
Perry, Emily ;
Pignatelli, Miguel ;
Riat, Harpreet Singh ;
Sheppard, Daniel ;
Taylor, Kieron ;
Thormann, Anja ;
Vullo, Alessandro ;
Wilder, Steven P. ;
Zadissa, Amonida ;
Aken, Bronwen L. ;
Birney, Ewan ;
Harrow, Jennifer ;
Kinsella, Rhoda ;
Muffato, Matthieu ;
Ruffier, Magali ;
Searle, Stephen M. J. ;
Spudich, Giulietta ;
Trevanion, Stephen J. ;
Yates, Andy ;
Zerbino, Daniel R. ;
Flicek, Paul .
NUCLEIC ACIDS RESEARCH, 2015, 43 (D1) :D662-D669
[9]   A framework for variation discovery and genotyping using next-generation DNA sequencing data [J].
DePristo, Mark A. ;
Banks, Eric ;
Poplin, Ryan ;
Garimella, Kiran V. ;
Maguire, Jared R. ;
Hartl, Christopher ;
Philippakis, Anthony A. ;
del Angel, Guillermo ;
Rivas, Manuel A. ;
Hanna, Matt ;
McKenna, Aaron ;
Fennell, Tim J. ;
Kernytsky, Andrew M. ;
Sivachenko, Andrey Y. ;
Cibulskis, Kristian ;
Gabriel, Stacey B. ;
Altshuler, David ;
Daly, Mark J. .
NATURE GENETICS, 2011, 43 (05) :491-+
[10]   Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine [J].
Dollé, MET ;
Snyder, WK ;
Gossen, JA ;
Lohman, PHM ;
Vijg, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (15) :8403-8408