Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma

被引：75

作者：

Smida, Jan ^{[1
,2
,3
,4
]}

Xu, Hongen ^{[5
]}

Zhang, Yanping ^{[5
]}

Baumhoer, Daniel ^{[6
]}

Ribi, Sebastian ^{[6
]}

Kovac, Michal ^{[6
]}

von Luettichau, Irene ^{[3
,4
]}

Bielack, Stefan ^{[7
]}

O'Leary, Valerie B. ^{[1
]}

Leib-Moesch, Christine ^{[8
]}

Frishman, Dmitrij ^{[5
,9
,10
]}

Nathrath, Michaela ^{[2
,3
,4
,11
]}

机构：

[1] German Res Ctr Environm Hlth, Helmholtz Zentrum Munich, Inst Radiat Biol, Neuherberg, Germany

[2] Helmholtz Zentrum Munich, German Res Ctr Environm Hlth, Clin Cooperat Grp Osteosarcoma, Neuherberg, Germany

[3] Tech Univ Munich, Dept Pediat, Pediat Oncol Ctr, Munich, Germany

[4] Comprehens Canc Ctr, Munich, Germany

[5] Tech Univ Munich, Dept Bioinformat, Wissensch Zentrum Weihenstephan, Freising Weihenstephan, Germany

[6] Univ Hosp Basel, Inst Pathol, Bone Tumour Reference Ctr, Basel, Switzerland

[7] Klinikum Stuttgart Olgahosp, Pediat Oncol Hematol Immunol 5, Stuttgart, Germany

[8] Helmholtz Zentrum Munich, German Res Ctr Environm Hlth, Inst Virol, Neuherberg, Germany

[9] Helmholtz Zentrum Munich, German Res Ctr Environm Hlth, Inst Bioinformat & Syst Biol, Neuherberg, Germany

[10] St Petersburg State Polytech Univ, St Petersburg, Russia

[11] Klinikum Kassel, Dept Pediat Hematol & Oncol, Kassel, Germany

来源：

INTERNATIONAL JOURNAL OF CANCER | 2017年 / 141卷 / 04期

关键词：

osteosarcoma; SCNAs; driver genes; chromosomal breakage pattern; chromothripsis; HIDDEN MARKOV MODEL; FRAGILE SITE FRA16D; STRUCTURAL VARIATIONS; PROTEIN EXPRESSION; TUMOR-SUPPRESSOR; CANCER; CHROMOTHRIPSIS; DNA; WWOX; INSTABILITY;

D O I：

10.1002/ijc.30778

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS-specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole-genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well-known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. Certain genomic features, such as transposable elements and non-B DNA-forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage patternchromothripsishas been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS-specific fragility pattern provides novel clues for understanding the biology of OS. What's new? Osteosarcoma (OS) is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS-specific characteristics in localization and frequencies of chromosomal breakages implicate a specific set of responsible driver genes or specific mechanism of fragility induction. Here, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples. Breakage analysis revealed OS specific unstable regions in which well-known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. A complex breakage pattern-chromothripsis-was suggested as a widespread phenomenon in OS and found to be predictive of patient clinical outcome.

引用

页码：816 / 828

页数：13

共 68 条

[1]

[Anonymous], BIOPROTOCOL

[2] The common fragile site FRA16D gene product WWOX: roles in tumor suppression and genomic stability [J].

Aqeilan, Rami I. ;

Abu-Remaileh, Muhannad ;

Abu-Odeh, Mohammad .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2014, 71 (23) :4589-4599

[3] Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas [J].

Bayani, J ;

Zielenska, M ;

Pandita, A ;

Al-Romaih, K ;

Karaskova, J ;

Harrison, K ;

Bridge, JA ;

Sorensen, P ;

Thorner, P ;

Squire, JA .

GENES CHROMOSOMES & CANCER, 2003, 36 (01) :7-16

[4] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[5] Prognostic factors in high-grade osteosarcoma of the extremities or trunk:: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols [J].

Bielack, SS ;

Kempf-Bielack, B ;

Delling, G ;

Exner, GU ;

Flege, S ;

Helmke, K ;

Kotz, R ;

Salzer-Kuntschik, M ;

Werner, M ;

Winkelmann, W ;

Zoubek, A ;

Jürgens, H ;

Winkler, K .

JOURNAL OF CLINICAL ONCOLOGY, 2002, 20 (03) :776-790

[6] Second and Subsequent Recurrences of Osteosarcoma: Presentation, Treatment, and Outcomes of 249 Consecutive Cooperative Osteosarcoma Study Group Patients [J].

Bielack, Stefan S. ;

Kempf-Bielack, Beate ;

Branscheid, Detlev ;

Carrle, Dorothe ;

Friedel, Godehard ;

Helmke, Knut ;

Kevric, Matthias ;

Jundt, Gernot ;

Kuehne, Thomas ;

Maas, Rainer ;

Schwarz, Rudolf ;

Zoubek, Andreas ;

Juergens, Heribert .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (04) :557-565

[7] Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens [J].

Cai, Haoyang ;

Kumar, Nitin ;

Bagheri, Homayoun C. ;

von Mering, Christian ;

Robinson, Mark D. ;

Baudis, Michael .

BMC GENOMICS, 2014, 15

[8] Non-B DB v2.0: a database of predicted non-B DNA-forming motifs and its associated tools [J].

Cer, Regina Z. ;

Donohue, Duncan E. ;

Mudunuri, Uma S. ;

Temiz, Nuri A. ;

Loss, Michael A. ;

Starner, Nathan J. ;

Halusa, Goran N. ;

Volfovsky, Natalia ;

Yi, Ming ;

Luke, Brian T. ;

Bacolla, Albino ;

Collins, Jack R. ;

Stephens, Robert M. .

NUCLEIC ACIDS RESEARCH, 2013, 41 (D1) :D94-D100

[9] Recurrent Somatic Structural Variations Contribute to Tumorigenesis in Pediatric Osteosarcoma [J].

Chen, Xiang ;

Bahrami, Armita ;

Pappo, Alberto ;

Easton, John ;

Dalton, James ;

Hedlund, Erin ;

Ellison, David ;

Shurtleff, Sheila ;

Wu, Gang ;

Wei, Lei ;

Parker, Matthew ;

Rusch, Michael ;

Nagahawatte, Panduka ;

Wu, Jianrong ;

Mao, Shenghua ;

Boggs, Kristy ;

Mulder, Heather ;

Yergeau, Donald ;

Lu, Charles ;

Ding, Li ;

Edmonson, Michael ;

Qu, Chunxu ;

Wang, Jianmin ;

Li, Yongjin ;

Navid, Fariba ;

Daw, Najat C. ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Downing, James R. ;

Zhang, Jinghui ;

Dyer, Michael A. .

CELL REPORTS, 2014, 7 (01) :104-112

[10] DNA breaks and chromosome pulverization from errors in mitosis [J].

Crasta, Karen ;

Ganem, Neil J. ;

Dagher, Regina ;

Lantermann, Alexandra B. ;

Ivanova, Elena V. ;

Pan, Yunfeng ;

Nezi, Luigi ;

Protopopov, Alexei ;

Chowdhury, Dipanjan ;

Pellman, David .

NATURE, 2012, 482 (7383) :53-U70

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