Comprehensive Analysis of Hypermutation in Human Cancer

被引：610

作者：

Campbell, Brittany B. ^{[1
,2
,3
]}

Light, Nicholas ^{[1
,3
]}

Fabrizio, David ^{[4
]}

Zatzman, Matthew ^{[1
,54
]}

Fuligni, Fabio ^{[1
]}

de Borja, Richard ^{[1
]}

Davidson, Scott ^{[1
,53
]}

Edwards, Melissa ^{[1
]}

Elvin, Julia A. ^{[4
]}

Hodel, Karl P. ^{[5
]}

Zahurancik, Walter J. ^{[6
,7
]}

Suo, Zucai ^{[6
,7
]}

Lipman, Tatiana ^{[1
]}

Wimmer, Katharina ^{[8
]}

Kratz, Christian P. ^{[9
]}

Bowers, Daniel C. ^{[10
,11
,12
]}

Laetsch, Theodore W. ^{[10
,11
,12
]}

Dunn, Gavin P. ^{[13
]}

Johanns, Tanner M. ^{[13
,14
]}

Grimmer, Matthew R. ^{[14
]}

Smirnov, Ivan V. ^{[15
,16
]}

Larouche, Valerie ^{[17
]}

Samuel, David ^{[18
]}

Bronsema, Annika ^{[19
]}

Osborn, Michael ^{[20
]}

Stearns, Duncan ^{[21
]}

Raman, Pichai ^{[22
,23
,24
]}

Cole, Kristina A. ^{[22
,23
,24
]}

Storm, Phillip B. ^{[25
]}

Yalon, Michal ^{[26
]}

Opocher, Enrico ^{[27
]}

Mason, Gary ^{[28
]}

Thomas, Gregory A. ^{[29
]}

Sabel, Magnus ^{[30
,31
]}

George, Ben ^{[32
]}

Ziegler, David S. ^{[33
,34
,45
]}

Lindhorst, Scott ^{[35
,36
]}

Issai, Vanan Magimairajan ^{[37
,38
]}

Constantini, Shlomi ^{[39
]}

Toledano, Helen ^{[39
]}

Elhasid, Ronit ^{[42
]}

Farah, Roula ^{[43
]}

Dvir, Rina ^{[40
,41
]}

Dirks, Peter ^{[44
]}

Huang, Annie ^{[2
,45
,54
]}

Galati, Melissa A. ^{[1
]}

Chung, Jiil ^{[1
]}

Ramaswamy, Vijay ^{[45
]}

Irwin, Meredith S. ^{[45
]}

Aronson, Melyssa ^{[46
]}

机构：

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

[2] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada

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

[4] Fdn Med Inc, Cambridge, MA USA

[5] Tulane Univ, Sch Med, Tulane Canc Ctr, Dept Biochem & Mol Biol, 1430 Tulane Ave, New Orleans, LA 70112 USA

[6] Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA

[7] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA

[8] Med Univ Innsbruck, Div Human Genet, Innsbruck, Austria

[9] Hannover Med Sch, Pediat Hematol & Oncol, Hannover, Germany

[10] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA

[11] Univ Texas Southwestern Med Ctr Dallas, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA

[12] Childrens Hlth, Pauline Allen Gill Ctr Canc & Blood Disorders, Dallas, TX USA

[13] Washington Univ, Sch Med, Dept Neurol Surg, Ctr Human Immunol & Immunotherapy Programs, St Louis, MO USA

[14] Washington Univ, Sch Med, Dept Med, Div Oncol, St Louis, MO 63110 USA

[15] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA

[16] Univ Calif San Francisco, Dept Neurol Surg, Div Neuroepidemiol, San Francisco, CA 94143 USA

[17] Univ Laval, Dept Pediat, CRCHU Quebec, Ctr Mere Enfant Soleil CHU Quebec, Quebec City, PQ, Canada

[18] Valley Childrens Hosp, Dept Hematol Oncol, Madera, CA USA

[19] Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany

[20] Womens & Childrens Hosp, Dept Haematol & Oncol, Adelaide, SA, Australia

[21] UH Rainbow Babies & Childrens Hosp, Dept Pediatrics Hematol & Oncol, Cleveland, OH USA

[22] Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA

[23] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

[24] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[25] Childrens Hosp Philadelphia, Div Neurosurg, Philadelphia, PA USA

[26] Sheba Med Ctr, Dept Pediat Hematol Oncol, Tel Hashomer, Israel

[27] Azienda Osped Univ Studi Padova, Pediatr Oncol & Hematol, Via Giustiniani N1, Padua, Italy

[28] UPMC, Childrens Hosp Pittsburgh, Dept Pediat Hematol Oncol, Pittsburgh, PA USA

[29] Oregon Hlth & Sci Univ, Div Pediat Hematol Oncol, Portland, OR 97201 USA

[30] Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Pediat, Gothenburg, Sweden

[31] Sahlgrens Univ Hosp, Queen Silvia Childrens Hosp, Gothenburg, Sweden

[32] Med Coll Wisconsin, Div Hematol & Oncol, Milwaukee, WI 53226 USA

[33] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia

[34] Univ New South Wales, Childrens Canc Inst, Lowy Canc Res Ctr, Randwick, NSW, Australia

[35] Med Univ South Carolina, Dept Neurosurg, Neurooncol, Charleston, SC USA

[36] Med Univ South Carolina, Dept Med, Div Hematol Med Oncol, Charleston, SC USA

[37] Canc Care Manitoba, Dept Pediat Hematol Oncol, Winnipeg, MB, Canada

[38] Univ Manitoba, RIOH, Winnipeg, MB, Canada

[39] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Pediat Neurosurg, Tel Aviv, Israel

[40] Schneider Childrens Med Ctr Israel, Dept Pediat Hematol Oncol, Petah Tiqwa, Israel

[41] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel

[42] Tel Aviv Sourasky Med Ctr, Dept Hematol Oncol, Tel Aviv, Israel

[43] Univ Ctr Med, Dept Pediat, St George Hosp, Beirut, Lebanon

[44] Hosp Sick Children, Dept Neurosurg, Toronto, ON, Canada

[45] Hosp Sick Children, Div Hematol Oncol, Toronto, ON, Canada

[46] Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Toronto, ON, Canada

[47] Hosp Sick Children, Div Gastroenterol Hepatol Nutr, Toronto, ON, Canada

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

[49] Univ Wisconsin, Ctr Human Genom & Precis Med, Madison, WI USA

[50] Sheba Med Ctr, Canc Res Ctr, Ramat Gan, Israel

来源：

CELL | 2017年 / 171卷 / 05期

关键词：

MISMATCH REPAIR DEFICIENCY; DNA-POLYMERASE EPSILON; CELL LUNG-CANCER; MUTATIONAL PROCESSES; SOMATIC MUTATIONS; MOLECULAR CHARACTERIZATION; CTLA-4; BLOCKADE; GRADE GLIOMAS; PD-1; LANDSCAPE;

D O I：

10.1016/j.cell.2017.09.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replicationrepair- associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

引用

页码：1042 / +

页数：25

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