Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

被引：66

作者：

Ratnaparkhe, Manasi ^{[1
,2
]}

Wong, John K. L. ^{[1
]}

Wei, Pei-Chi ^{[3
,4
]}

Hlevnjak, Mario ^{[1
]}

Kolb, Thorsten ^{[1
]}

Simovic, Milena ^{[1
,2
]}

Haag, Daniel ^{[5
]}

Paul, Yashna ^{[1
]}

Devens, Frauke ^{[1
]}

Northcott, Paul ^{[6
,7
]}

Jones, David T. W. ^{[5
]}

Kool, Marcel ^{[5
]}

Jauch, Anna ^{[8
]}

Pastorczak, Agata ^{[9
]}

Mlynarski, Wojciech ^{[9
]}

Korshunov, Andrey ^{[10
,11
]}

Kumar, Rajiv ^{[12
,13
]}

Downing, Susanna M. ^{[14
]}

Pfister, Stefan M. ^{[5
]}

Zapatka, Marc ^{[1
]}

McKinnon, Peter J. ^{[14
]}

Alt, Frederick W. ^{[3
,4
]}

Lichter, Peter ^{[1
]}

Ernst, Aurelie ^{[1
]}

机构：

[1] German Canc Res Ctr, Div Mol Genet, German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[2] Heidelberg Univ, Fac Biosci, D-69120 Heidelberg, Germany

[3] Harvard Med Sch, Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA

[4] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[5] NCT Heidelberg KiTZ, Hopp Childrens Canc Ctr, D-69120 Heidelberg, Germany

[6] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[7] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

[8] Heidelberg Univ, Inst Human Genet, D-69120 Heidelberg, Germany

[9] Med Univ Lodz, Dept Pediat Oncol Hematol & Diabetol, PL-91738 Lodz, Poland

[10] Heidelberg Univ Hosp, German Canc Res Ctr DKFZ, Clin Cooperat Unit Neuropathol, Dept Neuropathol, D-69120 Heidelberg, Germany

[11] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[12] Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany

[13] German Canc Res Ctr, German Consortium Translat Canc Res DKTK, D-69120 Heidelberg, Germany

[14] St Jude Childrens Res Hosp, Dept Genet, Memphis, TN 38105 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

关键词：

STRUCTURAL VARIATION; MEDULLOBLASTOMA; CHROMOTHRIPSIS; MUTATIONS; HYBRIDIZATION; LANDSCAPE; CELLS;

D O I：

10.1038/s41467-018-06925-4

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：

Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n =16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumors with complex genomic rearrangements.

引用

页数：13

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