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

被引：281

作者：

Shlien, Adam ^{[1
,2
,3
]}

Campbell, Brittany B. ^{[1
,4
,5
]}

de Borja, Richard ^{[1
]}

Alexandrov, Ludmil B. ^{[6
]}

Merico, Daniele ^{[1
,7
]}

Wedge, David ^{[6
]}

Van Loo, Peter ^{[6
,8
]}

Tarpey, Patrick S. ^{[6
]}

Coupland, Paul ^{[9
]}

Behjati, Sam ^{[6
]}

Pollett, Aaron ^{[10
]}

Lipman, Tatiana ^{[1
,4
]}

Heidari, Abolfazl ^{[1
,4
]}

Deshmukh, Shriya ^{[1
,4
]}

Avitzur, Na'ama ^{[1
,4
]}

Meier, Bettina ^{[11
]}

Gerstung, Moritz ^{[6
]}

Hong, Ye ^{[11
]}

Merino, Diana M. ^{[1
]}

Ramakrishna, Manasa ^{[6
]}

Remke, Marc ^{[4
]}

Arnold, Roland ^{[1
]}

Panigrahi, Gagan B. ^{[1
]}

Thakkar, Neha P. ^{[1
,12
]}

Hodel, Karl P. ^{[13
]}

Henninger, Erin E. ^{[13
]}

Goeksenin, A. Yasemin ^{[13
]}

Bakry, Doua ^{[14
,15
]}

Charames, George S. ^{[3
,10
]}

Druker, Harriet ^{[12
,14
]}

Lerner-Ellis, Jordan ^{[3
,10
,16
]}

Mistry, Matthew ^{[1
,4
,5
]}

Dvir, Rina ^{[17
]}

Grant, Ronald ^{[14
,15
]}

Elhasid, Ronit ^{[17
]}

Farah, Roula ^{[18
]}

Taylor, Glenn P. ^{[19
]}

Nathan, Paul C. ^{[14
,15
]}

Alexander, Sarah ^{[14
,15
]}

Ben-Shachar, Shay ^{[20
]}

Ling, Simon C. ^{[15
,21
]}

Gallinger, Steven ^{[22
,23
]}

Constantini, Shlomi ^{[24
]}

Dirks, Peter ^{[4
,25
]}

Huang, Annie ^{[4
,14
,15
]}

Scherer, Stephen W. ^{[1
,7
,12
,26
]}

Grundy, Richard G. ^{[27
]}

Durno, Carol ^{[21
,22
]}

Aronson, Melyssa ^{[22
]}

Gartner, Anton ^{[11
]}

机构：

[1] Hosp Sick Children, Program Genet & Genome Biol, Toronto, ON M5G 1X8, Canada

[2] Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON M5G 1X8, Canada

[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada

[4] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1X8, Canada

[5] Univ Toronto, Fac Med, Inst Med Sci, Toronto, ON, Canada

[6] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton, Cambs, England

[7] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada

[8] Univ Leuven, Dept Human Genet, Leuven, Belgium

[9] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[10] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada

[11] Univ Dundee, Ctr Gene Regulat & Express, Dundee, Scotland

[12] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[13] Tulane Univ, Sch Med, Tulane Canc Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA

[14] Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada

[15] Univ Toronto, Dept Pediat, Toronto, ON, Canada

[16] Ontario Inst Canc Res, Toronto, ON, Canada

[17] Tel Aviv Med Ctr & Sch Med, Dept Pediat Hematooncol, Tel Aviv, Israel

[18] St George Hosp Univ Med Ctr, Beirut, Lebanon

[19] Univ Toronto, Hosp Sick Children, Div Pathol, Toronto, ON M5G 1X8, Canada

[20] Tel Aviv Med Ctr & Sch Med, Gilbert Israeli Neurofibromatosis Ctr, Tel Aviv, Israel

[21] Univ Toronto, Hosp Sick Children, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Toronto, ON M5G 1X8, Canada

[22] Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Familial Gastrointestinal Canc Registry, Toronto, ON M5G 1X5, Canada

[23] Mt Sinai Hosp, Dept Surg, Toronto, ON M5G 1X5, Canada

[24] Tel Aviv Med Ctr & Sch Med, Dana Childrens Hosp, Dept Pediat Neurosurg, IL-64239 Tel Aviv, Israel

[25] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[26] Univ Toronto, McLaughlin Ctr, Toronto, ON, Canada

[27] Univ Nottingham, Childrens Brain Tumour Res Ctr, Nottingham NG7 2RD, England

[28] Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[29] Univ Cambridge, Dept Haematol, Cambridge, England

来源：

NATURE GENETICS | 2015年 / 47卷 / 03期

基金：

英国惠康基金;

关键词：

DNA-POLYMERASE EPSILON; SEQUENCING DATA; ACTIVE-SITE; HUMAN COLON; FIDELITY; INSTABILITY; ALIGNMENT; TISSUES; FORK;

D O I：

10.1038/ng.3202

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 epsilon or delta. 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 (similar to 600 mutations/cell division), reaching but not exceeding similar to 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.

引用

页码：257 / +

页数：8

共 29 条

[1] 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-+

[2] Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium [J].

Bakry, Doua ;

Aronson, Melyssa ;

Durno, Carol ;

Rimawi, Hala ;

Farah, Roula ;

Alharbi, Qasim Kholaif ;

Alharbi, Musa ;

Shamvil, Ashraf ;

Ben-Shachar, Shay ;

Mistry, Matthew ;

Constantini, Shlomi ;

Dvir, Rina ;

Qaddoumi, Ibrahim ;

Gallinger, Steven ;

Lerner-Ellis, Jordan ;

Pollett, Aaron ;

Stephens, Derek ;

Kelies, Steve ;

Chao, Elizabeth ;

Malkin, David ;

Bouffet, Eric ;

Hawkins, Cynthia ;

Tabori, Uri .

EUROPEAN JOURNAL OF CANCER, 2014, 50 (05) :987-996

[3]

Bebenek K, 1995, METHOD ENZYMOL, V262, P217

[4] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

[5] Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred [J].

Durno, Carol A. ;

Aronson, Melyssa ;

Tabori, Uri ;

Malkin, David ;

Gallinger, Steven ;

Chan, Helen S. L. .

PEDIATRIC BLOOD & CANCER, 2012, 59 (04) :652-656

[6] Integrated genomic characterization of endometrial carcinoma [J].

Getz, Gad ;

Gabriel, Stacey B. ;

Cibulskis, Kristian ;

Lander, Eric ;

Sivachenko, Andrey ;

Sougnez, Carrie ;

Lawrence, Mike ;

Kandoth, Cyriac ;

Dooling, David ;

Fulton, Robert ;

Fulton, Lucinda ;

Kalicki-Veizer, Joelle ;

McLellan, Michael D. ;

O'Laughlin, Michelle ;

Schmidt, Heather ;

Wilson, Richard K. ;

Ye, Kai ;

Ding, Li ;

Mardis, Elaine R. ;

Ally, Adrian ;

Balasundaram, Miruna ;

Birol, Inanc ;

Butterfield, Yaron S. N. ;

Carlsen, Rebecca ;

Carter, Candace ;

Chu, Andy ;

Chuah, Eric ;

Chun, Hye-Jung E. ;

Dhalla, Noreen ;

Guin, Ranabir ;

Hirst, Carrie ;

Holt, Robert A. ;

Jones, Steven J. M. ;

Lee, Darlene ;

Li, Haiyan I. ;

Marra, Marco A. ;

Mayo, Michael ;

Moore, Richard A. ;

Mungall, Andrew J. ;

Plettner, Patrick ;

Schein, Jacqueline E. ;

Sipahimalani, Payal ;

Tam, Angela ;

Varhol, Richard J. ;

Robertson, A. Gordon ;

Pashtan, Itai ;

Saksena, Gordon ;

Onofrio, Robert C. ;

Schumacher, Steven E. ;

Tabak, Barbara .

NATURE, 2013, 497 (7447) :67-73

[7] Phenotypic characterization of missense polymerase-δ mutations using an inducible protein-replacement system [J].

Ghodgaonkar, Medini Manohar ;

Kehl, Patrick ;

Ventura, Ilenia ;

Hu, Liyan ;

Bignami, Margherita ;

Jiricny, Josef .

NATURE COMMUNICATIONS, 2014, 5

[8] DNA Polymerase ε and Its Roles in Genome Stability [J].

Henninger, Erin E. ;

Pursell, Zachary F. .

IUBMB LIFE, 2014, 66 (05) :339-351

[9] Improved variant discovery through local re-alignment of short-read next-generation sequencing data using SRMA [J].

Homer, Nils ;

Nelson, Stanley F. .

GENOME BIOLOGY, 2010, 11 (10)

[10] Comparative lesion sequencing provides insights into tumor evolution [J].

Jones, Sian ;

Chen, Wei-dong ;

Parmigiani, Giovanni ;

Diehl, Frank ;

Beerenwinkel, Niko ;

Antal, Tibor ;

Traulsen, Arne ;

Nowak, Martin A. ;

Siegel, Christopher ;

Velculescu, Victor E. ;

Kinzler, Kenneth W. ;

Vogelstein, Bert ;

Willis, Joseph ;

Markowitz, Sanford D. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (11) :4283-4288

← 1 2 3 →