Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes

被引：43

作者：

Musa, Julian ^{[1
]}

Cidre-Aranaz, Florencia ^{[1
]}

Aynaud, Marie-Ming ^{[2
]}

Orth, Martin F. ^{[1
]}

Knott, Maximilian M. L. ^{[1
,3
]}

Mirabeau, Olivier ^{[2
]}

Mazor, Gal ^{[4
]}

Varon, Mor ^{[4
]}

Hoelting, Tilman L. B. ^{[1
]}

Grossetete, Sandrine ^{[2
]}

Gartlgruber, Moritz ^{[5
]}

Surdez, Didier ^{[2
]}

Gerke, Julia S. ^{[1
]}

Ohmura, Shunya ^{[1
]}

Marchetto, Aruna ^{[1
]}

Dallmayer, Marlene ^{[1
]}

Baldauf, Michaela C. ^{[1
]}

Stein, Stefanie ^{[1
]}

Sannino, Giuseppina ^{[1
]}

Li, Jing ^{[1
]}

Romero-Perez, Laura ^{[1
]}

Westermann, Frank ^{[5
]}

Hartmann, Wolfgang ^{[6
]}

Dirksen, Uta ^{[7
]}

Gymrek, Melissa ^{[8
,9
]}

Anderson, Nathaniel D. ^{[10
,11
]}

Shlien, Adam ^{[10
,11
,12
]}

Rotblat, Barak ^{[4
]}

Kirchner, Thomas ^{[3
,13
,14
]}

Delattre, Olivier ^{[2
]}

Gruenewald, Thomas G. P. ^{[1
,3
,13
,14
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Fac Med, Inst Pathol, Max Eder Res Grp Pediat Sarcoma Biol, Munich, Germany

[2] PSL Res Univ, Equipe Labellisee LNCC Genet & Biol Pediat Canc, INSERM, SIREDO Oncol Ctr,Inst Curie Res Ctr,U830, Paris, France

[3] Ludwig Maximilians Univ Munchen, Fac Med, Inst Pathol, Munich, Germany

[4] Ben Gurion Univ Negev, Dept Life Sci, Beer Sheva, Israel

[5] German Canc Res Ctr, Neuroblastoma Genom, Heidelberg, Germany

[6] Univ Hosp Munster, Gerhard Domagk Inst Pathol, Div Translat Pathol, Munster, Germany

[7] Univ Hosp Essen, Dept Pediat Hematol & Oncol, Essen, Germany

[8] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA

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

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

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

[13] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany

[14] German Canc Res Ctr, Heidelberg, Germany

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

EWING SARCOMA; GENOMIC LANDSCAPE; READ ALIGNMENT; B-MYB; ONCOLOGY; ELEMENTS; SUSCEPTIBILITY; IDENTIFICATION; POLYMORPHISM; CHROMATIN;

D O I：

10.1038/s41467-019-12071-2

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：

Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, patient survival and drug response. Binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancerlike DNA element controls expression of the transcription factor MYBL2 mediating these phenotypes. Whole-genome and RNA sequencing reveals that variability at this locus is inherited via the germline and is associated with variable inter-tumoral MYBL2 expression. High MYBL2 levels sensitize EwS cells for inhibition of its upstream activating kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a putative biomarker for anti-CDK2-therapy. Collectively, we establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and highlight the importance of integrating the regulatory genome in precision medicine.

引用

页数：10

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