DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells

被引：62

作者：

Chung, Jiil ^{[1
,2
,3
]}

Maruvka, Yosef E. ^{[4
,5
]}

Sudhaman, Sumedha ^{[1
,2
]}

Kelly, Jacalyn ^{[1
,2
]}

Haradhvala, Nicholas J. ^{[4
,5
,6
]}

Bianchi, Vanessa ^{[1
]}

Edwards, Melissa ^{[1
]}

Forster, Victoria J. ^{[1
,2
]}

Nunes, Nuno M. ^{[1
,2
]}

Galati, Melissa A. ^{[1
,2
,3
]}

Komosa, Martin ^{[1
]}

Deshmukh, Shriya ^{[7
,8
]}

Cabric, Vanja ^{[9
]}

Davidson, Scott ^{[1
,10
]}

Zatzman, Matthew ^{[1
,11
]}

Light, Nicholas ^{[1
,3
,11
]}

Hayes, Reid ^{[1
,10
]}

Brunga, Ledia ^{[1
,10
]}

Anderson, Nathaniel D. ^{[1
,11
]}

Ho, Ben ^{[11
]}

Hodel, Karl P. ^{[12
]}

Siddaway, Robert ^{[2
]}

Morrissy, A. Sorana ^{[13
,14
,15
]}

Bowers, Daniel C. ^{[16
,17
]}

Larouche, Valerie ^{[18
]}

Bronsema, Annika ^{[19
]}

Osborn, Michael ^{[20
]}

Cole, Kristina A. ^{[21
,22
]}

Opocher, Enrico ^{[23
]}

Mason, Gary ^{[24
]}

Thomas, Gregory A. ^{[25
]}

Ben George ^{[26
]}

Ziegler, David S. ^{[27
,28
]}

Lindhorst, Scott ^{[29
,30
]}

Vanan, Magimairajan ^{[31
]}

Yalon-Oren, Michal ^{[32
]}

Reddy, Alyssa T. ^{[33
]}

Massimino, Maura ^{[34
]}

Tomboc, Patrick ^{[35
]}

Van Damme, An ^{[36
]}

Lossos, Alexander ^{[37
]}

Durno, Carol ^{[38
,39
]}

Aronson, Melyssa ^{[38
]}

Morgenstern, Daniel A. ^{[40
,41
]}

Bouffet, Eric ^{[42
]}

Huang, Annie ^{[2
,11
,42
]}

Taylor, Michael D. ^{[2
,43
]}

Villani, Anita ^{[42
]}

Malkin, David ^{[42
]}

Hawkins, Cynthia E. ^{[2
,10
,11
,44
]}

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, Fac Med, Inst Med Sci, Toronto, ON, Canada

[4] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA

[5] Broad Inst Harvard & MIT, Cambridge, MA USA

[6] Harvard Univ, Harvard Grad Program Biophys, Cambridge, MA 02138 USA

[7] McGill Univ, Dept Expt Med, Montreal, PQ, Canada

[8] McGill Univ, Res Inst, Hlth Ctr, Montreal, PQ, Canada

[9] Univ Toronto, Dept Paediat, Toronto, ON, Canada

[10] Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON, Canada

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

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

[13] Univ Calgary, Cumming Sch Med, Calgary, AB, Canada

[14] Charbonneau Canc Inst, Calgary, AB, Canada

[15] Alberta Childrens Prov Gen Hosp, Res Inst, Calgary, AB, Canada

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

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

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

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

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

[21] Childrens Hosp Philadelphia, Div Oncol & Ctr Childhood Canc Res, Philadelphia, PA 19104 USA

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

[23] Univ Padua, Pediat Oncol & Hematol, Azienda Osped, Padua, Italy

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

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

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

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

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

[29] Med Univ South Carolina, Dept Neurosurg, Neuro Oncol, Charleston, SC 29425 USA

[30] Med Univ South Carolina, Dept Med, Div Hematol Med Oncol, Charleston, SC 29425 USA

[31] Univ Manitoba, Canc Care Manitoba Res Inst Oncol & Hematol RIOH, Dept Pediat Hematol Oncol, Winnipeg, MB, Canada

[32] Tel Aviv Univ, Edmond & Lilly Safra Childrens Hosp, Sheba Med Ctr, Tel Hashomer Sackler Sch Med,Canc Res Ctr, Tel Aviv, Israel

[33] Univ Alabama Birmingham, Dept Pediat, Div Pediat Hematol & Oncol, Birmingham, AL USA

[34] Fdn IRCCS Ist Nazl Tumori INT, Pediat Unit, Milan, Italy

[35] WVU Med Childrens, Dept Pediat, Sect Hematol Oncol, Morgantown, WV USA

[36] Clin Univ St Luc, Div Hematol & Oncol, Dept Pediat, Brussels, Belgium

[37] Hadassah Hebrew Univ, Agnes Ginges Ctr Human Neurogenet, Dept Neurol, Med Ctr, Jerusalem, Israel

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

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

[40] Hosp Sick Children, Dept Paediat, Toronto, ON, Canada

[41] Univ Toronto, Toronto, ON, Canada

[42] Hosp Sick Children, Dept Hematol Oncol, Toronto, ON, Canada

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

[44] Hosp Sick Children, Peter Gilgan Ctr Res & Learning, Program Cell Biol, Toronto, ON, Canada

[45] NIH, NIEHS, Genome Integr Struct Biol Lab, Durham, NC USA

[46] Harvard Med Sch, Boston, MA 02115 USA

[47] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

来源：

CANCER DISCOVERY | 2021年 / 11卷 / 05期

基金：

芬兰科学院;

关键词：

LYNCH-SYNDROME; DEFICIENCY; REPLICATION; HEREDITARY; EPSILON; DELTA; MUTATIONS; TUMORS; RECOMMENDATIONS; RECONSTITUTION;

D O I：

10.1158/2159-8290.CD-20-0790

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.

引用

页码：1176 / 1191

页数：16

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