Journal Article
. 2020 Jan; 56(2):522-530.
doi: 10.3892/ijo.2019.4950.

Comprehensive identification and characterization of somatic copy number alterations in triple‑negative breast cancer

Zaibing Li 1 Xiao Zhang 2 Chenxin Hou 3 Yuqing Zhou 3 Junli Chen 1 Haoyang Cai 4 Yifeng Ye 2 Jinping Liu 2 Ning Huang 1 
  • PMID: 31894314
  •     68 References
  •     3 citations


Triple‑negative breast cancer (TNBC) accounts for ~15% of all breast cancer diagnoses each year. Patients with TNBC tend to have a higher risk for early relapse and a worse prognosis. TNBC is characterized by extensive somatic copy number alterations (CNAs). However, the DNA CNA profile of TNBC remains to be extensively investigated. The present study assessed the genomic profile of CNAs in 201 TNBC samples, aiming to identify recurrent CNAs that may drive the pathogenesis of TNBC. In total, 123 regions of significant amplification and deletion were detected using the Genomic Identification of Significant Targets in Cancer algorithm, and potential driver genes for TNBC were identified. A total of 31 samples exhibited signs of chromothripsis and revealed chromosome pulverization hotspot regions. The present study further determined 199 genomic locations that were significantly enriched for breakpoints, which indicated TNBC‑specific genomic instability regions. Unsupervised hierarchical clustering of tumors resulted in three main subgroups that exhibited distinct CNA profiles, which may reveal the heterogeneity of molecular mechanisms in TNBC subgroups. These results will extend the molecular understanding of TNBC and will facilitate the discovery of therapeutic and diagnostic target candidates.

Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study.
Ines Vaz-Luis, Rebecca A Ottesen, +10 authors, Nancy U Lin.
J Clin Oncol, 2014 Jun 04; 32(20). PMID: 24888816    Free PMC article.
Dissecting the heterogeneity of triple-negative breast cancer.
Otto Metzger-Filho, Andrew Tutt, +11 authors, Martine Piccart-Gebhart.
J Clin Oncol, 2012 Mar 29; 30(15). PMID: 22454417
Highly Cited. Review.
Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.
Katia Nones, Nicola Waddell, +41 authors, Andrew P Barbour.
Nat Commun, 2014 Oct 30; 5. PMID: 25351503    Free PMC article.
Highly Cited.
Subtypes of familial breast tumours revealed by expression and copy number profiling.
Nic Waddell, Jeremy Arnold, +22 authors, Georgia Chenevix-Trench.
Breast Cancer Res Treat, 2009 Dec 05; 123(3). PMID: 19960244
Bioinformatic analysis of the human DHRS4 gene cluster and a proposed mechanism for its transcriptional regulation.
Zhong-Jing Su, Qiao-Xia Zhang, +7 authors, Dong-Yang Huang.
BMC Mol Biol, 2010 Jun 08; 11. PMID: 20525226    Free PMC article.
Criteria for inference of chromothripsis in cancer genomes.
Jan O Korbel, Peter J Campbell.
Cell, 2013 Mar 19; 152(6). PMID: 23498933
Highly Cited. Review.
Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.
Brian D Lehmann, Joshua A Bauer, +4 authors, Jennifer A Pietenpol.
J Clin Invest, 2011 Jun 03; 121(7). PMID: 21633166    Free PMC article.
Highly Cited.
Combined genomic and gene expression microarray profiling identifies ECOP as an upregulated gene in squamous cell carcinomas independent of DNA amplification.
A Baras, Y Yu, +2 authors, C A Moskaluk.
Oncogene, 2009 Jun 16; 28(32). PMID: 19525979
ChromothripsisDB: a curated database of chromothripsis.
Jian Yang, Gaofeng Deng, Haoyang Cai.
Bioinformatics, 2016 Jan 02; 32(9). PMID: 26722116
Epidermal growth factor receptor-coamplified and overexpressed protein (VOPP1) is a putative oncogene in gastric cancer.
Caiping Gao, Minghui Pang, +7 authors, Liangping Li.
Clin Exp Med, 2014 Nov 16; 15(4). PMID: 25398664
Complex landscapes of somatic rearrangement in human breast cancer genomes.
Philip J Stephens, David J McBride, +30 authors, Michael R Stratton.
Nature, 2009 Dec 25; 462(7276). PMID: 20033038    Free PMC article.
Highly Cited.
Molecular cytogenetic identification of subgroups of grade III invasive ductal breast carcinomas with different clinical outcomes.
Chris Jones, Emily Ford, +6 authors, Sunil R Lakhani.
Clin Cancer Res, 2004 Sep 28; 10(18 Pt 1). PMID: 15447982
Punctuated copy number evolution and clonal stasis in triple-negative breast cancer.
Ruli Gao, Alexander Davis, +10 authors, Nicholas E Navin.
Nat Genet, 2016 Aug 16; 48(10). PMID: 27526321    Free PMC article.
Highly Cited.
COSMIC: exploring the world's knowledge of somatic mutations in human cancer.
Simon A Forbes, David Beare, +14 authors, Peter J Campbell.
Nucleic Acids Res, 2014 Oct 31; 43(Database issue). PMID: 25355519    Free PMC article.
Highly Cited.
Hallmarks of cancer: the next generation.
Douglas Hanahan, Robert A Weinberg.
Cell, 2011 Mar 08; 144(5). PMID: 21376230
Highly Cited. Review.
GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers.
Craig H Mermel, Steven E Schumacher, +3 authors, Gad Getz.
Genome Biol, 2011 Apr 30; 12(4). PMID: 21527027    Free PMC article.
Highly Cited.
Role of epidermal growth factor receptor in breast cancer.
Hiroko Masuda, Dongwei Zhang, +3 authors, Naoto T Ueno.
Breast Cancer Res Treat, 2012 Oct 18; 136(2). PMID: 23073759    Free PMC article.
Highly Cited. Review.
Constitutional and somatic rearrangement of chromosome 21 in acute lymphoblastic leukaemia.
Yilong Li, Claire Schwab, +30 authors, Christine J Harrison.
Nature, 2014 Mar 29; 508(7494). PMID: 24670643    Free PMC article.
Highly Cited.
arrayMap 2014: an updated cancer genome resource.
Haoyang Cai, Saumya Gupta, +2 authors, Michael Baudis.
Nucleic Acids Res, 2014 Nov 28; 43(Database issue). PMID: 25428357    Free PMC article.
High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer.
Suet F Chin, Andrew E Teschendorff, +13 authors, Carlos Caldas.
Genome Biol, 2007 Oct 11; 8(10). PMID: 17925008    Free PMC article.
Highly Cited.
Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes.
Tae-Min Kim, Ruibin Xi, +3 authors, Peter J Park.
Genome Res, 2012 Nov 08; 23(2). PMID: 23132910    Free PMC article.
The UCSC Genome Browser database: 2015 update.
Kate R Rosenbloom, Joel Armstrong, +26 authors, W James Kent.
Nucleic Acids Res, 2014 Nov 28; 43(Database issue). PMID: 25428374    Free PMC article.
Highly Cited.
A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival.
Siyuan Zheng, Jun Fu, +15 authors, Roel G W Verhaak.
Genes Dev, 2013 Jun 26; 27(13). PMID: 23796897    Free PMC article.
Triple-negative breast cancer: disease entity or title of convenience?
Lisa Carey, Eric Winer, +2 authors, Luca Gianni.
Nat Rev Clin Oncol, 2010 Sep 30; 7(12). PMID: 20877296
Highly Cited. Review.
Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms.
Wigard P Kloosterman, Masoumeh Tavakoli-Yaraki, +19 authors, Edwin Cuppen.
Cell Rep, 2012 Jul 21; 1(6). PMID: 22813740
Highly Cited.
Chromothripsis is a common mechanism driving genomic rearrangements in primary and metastatic colorectal cancer.
Wigard P Kloosterman, Marlous Hoogstraat, +13 authors, Edwin Cuppen.
Genome Biol, 2011 Oct 22; 12(10). PMID: 22014273    Free PMC article.
The complex nature of fragile site plasticity and its importance in cancer.
Dan Sarni, Batsheva Kerem.
Curr Opin Cell Biol, 2016 Apr 12; 40. PMID: 27062332
Chromothripsis and cancer: causes and consequences of chromosome shattering.
Josep V Forment, Abderrahmane Kaidi, Stephen P Jackson.
Nat Rev Cancer, 2012 Sep 14; 12(10). PMID: 22972457
Highly Cited. Review.
Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer.
Matthew D Burstein, Anna Tsimelzon, +10 authors, Powel H Brown.
Clin Cancer Res, 2014 Sep 12; 21(7). PMID: 25208879    Free PMC article.
Highly Cited.
Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death.
Gabriel Ichim, Jonathan Lopez, +17 authors, Stephen W G Tait.
Mol Cell, 2015 Feb 24; 57(5). PMID: 25702873    Free PMC article.
Highly Cited.
Marker chromosomes can arise from chromothripsis and predict adverse prognosis in acute myeloid leukemia.
Tilmann Bochtler, Martin Granzow, +17 authors, Study Alliance Leukemia Investigators.
Blood, 2017 Jan 26; 129(10). PMID: 28119329
Progenetix: 12 years of oncogenomic data curation.
Haoyang Cai, Nitin Kumar, +3 authors, Michael Baudis.
Nucleic Acids Res, 2013 Nov 15; 42(Database issue). PMID: 24225322    Free PMC article.
Sequence analysis of mutations and translocations across breast cancer subtypes.
Shantanu Banerji, Kristian Cibulskis, +44 authors, Matthew Meyerson.
Nature, 2012 Jun 23; 486(7403). PMID: 22722202    Free PMC article.
Highly Cited.
Emerging landscape of oncogenic signatures across human cancers.
Giovanni Ciriello, Martin L Miller, +3 authors, Chris Sander.
Nat Genet, 2013 Sep 28; 45(10). PMID: 24071851    Free PMC article.
Highly Cited.
A single-array preprocessing method for estimating full-resolution raw copy numbers from all Affymetrix genotyping arrays including GenomeWideSNP 5 & 6.
Henrik Bengtsson, Pratyaksha Wirapati, Terence P Speed.
Bioinformatics, 2009 Jun 19; 25(17). PMID: 19535535    Free PMC article.
A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome?
Arkarachai Fungtammasan, Erin Walsh, +2 authors, Kateryna D Makova.
Genome Res, 2012 Mar 30; 22(6). PMID: 22456607    Free PMC article.
Highly Cited.
NCBI GEO: archive for functional genomics data sets--update.
Tanya Barrett, Stephen E Wilhite, +14 authors, Alexandra Soboleva.
Nucleic Acids Res, 2012 Nov 30; 41(Database issue). PMID: 23193258    Free PMC article.
Highly Cited.
Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing.
Charissa Kim, Ruli Gao, +6 authors, Nicholas E Navin.
Cell, 2018 Apr 24; 173(4). PMID: 29681456    Free PMC article.
Highly Cited.
The landscape of somatic copy-number alteration across human cancers.
Rameen Beroukhim, Craig H Mermel, +59 authors, Matthew Meyerson.
Nature, 2010 Feb 19; 463(7283). PMID: 20164920    Free PMC article.
Highly Cited.
Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
Philip J Stephens, Chris D Greenman, +29 authors, Peter J Campbell.
Cell, 2011 Jan 11; 144(1). PMID: 21215367    Free PMC article.
Highly Cited.
Intracellular localization of GASP/ECOP/VOPP1.
Alexander Baras, Christopher A Moskaluk.
J Mol Histol, 2010 Jun 24; 41(2-3). PMID: 20571887
A chromosomal region 7p11.2 transcript map: its development and application to the study of EGFR amplicons in glioblastoma.
Greg D Eley, Jill L Reiter, +4 authors, C David James.
Neuro Oncol, 2002 Mar 28; 4(2). PMID: 11916499    Free PMC article.
Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
Jan J Molenaar, Jan Koster, +19 authors, Rogier Versteeg.
Nature, 2012 Mar 01; 483(7391). PMID: 22367537
Highly Cited.
The cancer genome.
Michael R Stratton, Peter J Campbell, P Andrew Futreal.
Nature, 2009 Apr 11; 458(7239). PMID: 19360079    Free PMC article.
Highly Cited. Review.
Chromosome fragile sites.
Sandra G Durkin, Thomas W Glover.
Annu Rev Genet, 2007 Jul 05; 41. PMID: 17608616
Highly Cited. Review.
Triple-negative breast cancer.
William D Foulkes, Ian E Smith, Jorge S Reis-Filho.
N Engl J Med, 2010 Nov 12; 363(20). PMID: 21067385
Highly Cited. Review.
A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions.
Wen Xue, Thomas Kitzing, +15 authors, Scott W Lowe.
Proc Natl Acad Sci U S A, 2012 May 09; 109(21). PMID: 22566646    Free PMC article.
VOPP1 promotes breast tumorigenesis by interacting with the tumor suppressor WWOX.
Florian Bonin, Karim Taouis, +16 authors, Keltouma Driouch.
BMC Biol, 2018 Oct 05; 16(1). PMID: 30285739    Free PMC article.
Circular binary segmentation for the analysis of array-based DNA copy number data.
Adam B Olshen, E S Venkatraman, Robert Lucito, Michael Wigler.
Biostatistics, 2004 Oct 12; 5(4). PMID: 15475419
Highly Cited.
Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes.
L Melchor, E Honrado, +5 authors, J Benítez.
Oncogene, 2007 Dec 12; 27(22). PMID: 18071313
Cancer: When catastrophe strikes a cell.
Jose M C Tubio, Xavier Estivill.
Nature, 2011 Feb 26; 470(7335). PMID: 21350479
Pan-cancer patterns of somatic copy number alteration.
Travis I Zack, Stephen E Schumacher, +15 authors, Rameen Beroukhim.
Nat Genet, 2013 Sep 28; 45(10). PMID: 24071852    Free PMC article.
Highly Cited.
The Cancer Genome Atlas Pan-Cancer analysis project.
Cancer Genome Atlas Research Network, John N Weinstein, +7 authors, Joshua M Stuart.
Nat Genet, 2013 Sep 28; 45(10). PMID: 24071849    Free PMC article.
Highly Cited.
Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.
Pengfei Liu, Ayelet Erez, +28 authors, Weimin Bi.
Cell, 2011 Sep 20; 146(6). PMID: 21925314    Free PMC article.
Highly Cited.
Chromothripsis: breakage-fusion-bridge over and over again.
Carlos Oscar Sánchez Sorzano, Alberto Pascual-Montano, +2 authors, Karel H M van Wely.
Cell Cycle, 2013 Jun 14; 12(13). PMID: 23759584    Free PMC article.
Alternative transcription initiation and splicing variants of the DHRS4 gene cluster.
Qiaoxia Zhang, Yifan Li, +9 authors, Dongyang Huang.
Biosci Rep, 2008 Aug 30; 29(1). PMID: 18754758
Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes.
Emad A Rakha, Somaia E Elsheikh, +12 authors, Ian O Ellis.
Clin Cancer Res, 2009 Mar 26; 15(7). PMID: 19318481
Highly Cited.
Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens.
Haoyang Cai, Nitin Kumar, +3 authors, Michael Baudis.
BMC Genomics, 2014 Jan 31; 15. PMID: 24476156    Free PMC article.
Comprehensive genomic characterization of squamous cell lung cancers.
Cancer Genome Atlas Research Network.
Nature, 2012 Sep 11; 489(7417). PMID: 22960745    Free PMC article.
Highly Cited.
DNA breaks and chromosome pulverization from errors in mitosis.
Karen Crasta, Neil J Ganem, +7 authors, David Pellman.
Nature, 2012 Jan 20; 482(7383). PMID: 22258507    Free PMC article.
Highly Cited.
Genomic and transcriptional aberrations linked to breast cancer pathophysiologies.
Koei Chin, Sandy DeVries, +21 authors, Joe W Gray.
Cancer Cell, 2006 Dec 13; 10(6). PMID: 17157792
Highly Cited.
The International HapMap Project.
International HapMap Consortium.
Nature, 2003 Dec 20; 426(6968). PMID: 14685227
Highly Cited.
Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma.
Jan Smida, Hongen Xu, +9 authors, Michaela Nathrath.
Int J Cancer, 2017 May 12; 141(4). PMID: 28494505
Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.
Tobias Rausch, David T W Jones, +48 authors, Jan O Korbel.
Cell, 2012 Jan 24; 148(1-2). PMID: 22265402    Free PMC article.
Highly Cited.
Chromothripsis from DNA damage in micronuclei.
Cheng-Zhong Zhang, Alexander Spektor, +5 authors, David Pellman.
Nature, 2015 May 29; 522(7555). PMID: 26017310    Free PMC article.
Highly Cited.
Cancer genomes evolve by pulverizing single chromosomes.
Matthew Meyerson, David Pellman.
Cell, 2011 Jan 11; 144(1). PMID: 21215363
CpG island evolution in the mammalian DHRS4 gene cluster and its role in the regulation of gene transcription.
Z Su, G Liu, +3 authors, D Huang.
Genet Mol Res, 2016 Jun 21; 15(2). PMID: 27323117
CTLPScanner: a web server for chromothripsis-like pattern detection.
Jian Yang, Jixiang Liu, +3 authors, Haoyang Cai.
Nucleic Acids Res, 2016 May 18; 44(W1). PMID: 27185889    Free PMC article.
Triple-Negative Breast Cancer Comparison With Canine Mammary Tumors From Light Microscopy to Molecular Pathology.
Asadoor Amirkhani Namagerdi, Danila d'Angelo, +5 authors, Antonio Giordano.
Front Oncol, 2020 Dec 08; 10. PMID: 33282730    Free PMC article.
Survival outcomes are associated with genomic instability in luminal breast cancers.
Lydia King, Andrew Flaus, Emma Holian, Aaron Golden.
PLoS One, 2021 Feb 04; 16(2). PMID: 33534788    Free PMC article.
Blood-based genomics of triple-negative breast cancer progression in patients treated with neoadjuvant chemotherapy.
E Ortolan, V Appierto, +14 authors, S Di Cosimo.
ESMO Open, 2021 Mar 21; 6(2). PMID: 33743331    Free PMC article.