Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 6/2005

Open Access 01-12-2005 | Research article

High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization

Authors: Tara L Naylor, Joel Greshock, Yan Wang, Theresa Colligon, QC Yu, Virginia Clemmer, Tal Z Zaks, Barbara L Weber

Published in: Breast Cancer Research | Issue 6/2005

Login to get access

Abstract

Introduction

Genomic aberrations in the form of subchromosomal DNA copy number changes are a hallmark of epithelial cancers, including breast cancer. The goal of the present study was to analyze such aberrations in breast cancer at high resolution.

Methods

We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines.

Results

Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses.

Conclusion

High resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.
Appendix
Available only for authorised users
Literature
1.
2.
Winston JS, Ramanaryanan J, Levine E: HER-2/neu evaluation in breast cancer are we there yet?. Am J Clin Pathol. 2004, 121 (Suppl): S33-49.PubMed
3.
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, et al: EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004, 304: 1497-1500. 10.1126/science.1099314.CrossRefPubMed
4.
Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004, 350: 2129-2139. 10.1056/NEJMoa040938.CrossRefPubMed
5.
Kallioniemi A, Kallioniemi OP, Piper J, Tanner M, Stokke T, Chen L, Smith HS, Pinkel D, Gray JW, Waldman FM: Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc Natl Acad Sci USA. 1994, 91: 2156-2160.CrossRefPubMedPubMedCentral
6.
Tirkkonen M, Tanner M, Karhu R, Kallioniemi A, Isola J, Kallioniemi OP: Molecular cytogenetics of primary breast cancer by CGH. Genes Chromosomes Cancer. 1998, 21: 177-184. 10.1002/(SICI)1098-2264(199803)21:3<177::AID-GCC1>3.0.CO;2-X.CrossRefPubMed
7.
Seute A, Sinn HP, Schlenk RF, Emig R, Wallwiener D, Grischke EM, Hohaus S, Dohner H, Haas R, Bentz M: Clinical relevance of genomic aberrations in homogeneously treated high-risk stage II/III breast cancer patients. Int J Cancer. 2001, 93: 80-84. 10.1002/ijc.1296.CrossRefPubMed
8.
Rennstam K, Ahlstedt-Soini M, Baldetorp B, Bendahl PO, Borg A, Karhu R, Tanner M, Tirkkonen M, Isola J: Patterns of chromosomal imbalances defines subgroups of breast cancer with distinct clinical features and prognosis. A study of 305 tumors by comparative genomic hybridization. Cancer Res. 2003, 63: 8861-8868.PubMed
9.
Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO: Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet. 1999, 23: 41-46. 10.1038/14385.CrossRefPubMed
10.
Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE, Tibshirani R, Botstein D, Borresen-Dale AL, Brown PO: Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA. 2002, 99: 12963-12968. 10.1073/pnas.162471999.CrossRefPubMedPubMedCentral
11.
Albertson DG: Profiling breast cancer by array CGH. Breast Cancer Res Treat. 2003, 78: 289-298. 10.1023/A:1023025506386.CrossRefPubMed
12.
Albertson DG, Ylstra B, Segraves R, Collins C, Dairkee SH, Kowbel D, Kuo WL, Gray JW, Pinkel D: Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet. 2000, 25: 144-146. 10.1038/75985.CrossRefPubMed
13.
Jain AN, Chin K, Borresen-Dale AL, Erikstein BK, Eynstein Lonning P, Kaaresen R, Gray JW: Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival. Proc Natl Acad Sci USA. 2001, 98: 7952-7957. 10.1073/pnas.151241198.CrossRefPubMedPubMedCentral
14.
Zafarana G, Grygalewicz B, Gillis AJ, Vissers LE, Van De Vliet W, Van Gurp RJ, Stoop H, Debiec-Rychter M, Oosterhuis JW, Van Kessel AG, et al: 12p-Amplicon structure analysis in testicular germ cell tumors of adolescents and adults by array CGH. Oncogene. 2003, 22: 7695-7701. 10.1038/sj.onc.1207011.CrossRefPubMed
15.
Greshock J, Naylor TL, Margolin A, Diskin S, Cleaver SH, Futreal PA, deJong PJ, Zhao S, Liebman M, Weber BL: 1-Mb resolution array-based comparative genomic hybridization using a BAC clone set optimized for cancer gene analysis. Genome Res. 2004, 14: 179-187. 10.1101/gr.1847304.CrossRefPubMedPubMedCentral
16.
Hodgson G, Hager JH, Volik S, Hariono S, Wernick M, Moore D, Nowak N, Albertson DG, Pinkel D, Collins C, et al: Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas. Nat Genet. 2001, 29: 459-464. 10.1038/ng771.CrossRefPubMed
17.
18.
Futreal PA, Kasprzyk A, Birney E, Mullikin JC, Wooster R, Stratton MR: Cancer and genomics. Nature. 2001, 409: 850-852. 10.1038/35057046.CrossRefPubMed
19.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S: The protein kinase complement of the human genome. Science. 2002, 298: 1912-1934. 10.1126/science.1075762.CrossRefPubMed
20.
Futreal PA, Coin L, Marshall M, Down T, Hubbard T, Wooster R, Rahman N, Stratton MR: A census of human cancer genes. Nat Rev Cancer. 2004, 4: 177-183. 10.1038/nrc1299.CrossRefPubMedPubMedCentral
21.
Dahlquist KD, Salomonis N, Vranizan K, Lawlor SC, Conklin BR: GenMAPP, a new tool for viewing and analyzing microarray data on biological pathways. Nat Genet. 2002, 31: 19-20. 10.1038/ng0502-19.CrossRefPubMed
22.
23.
Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, et al: Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res. 2003, 63: 2872-2880.PubMed
24.
van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al: Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002, 415: 530-536. 10.1038/415530a.CrossRef
25.
Hedenfalk I, Ringner M, Ben-Dor A, Yakhini Z, Chen Y, Chebil G, Ach R, Loman N, Olsson H, Meltzer P, et al: Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci USA. 2003, 100: 2532-2537. 10.1073/pnas.0533805100.CrossRefPubMedPubMedCentral
26.
Garnis C, Coe BP, Ishkanian A, Zhang L, Rosin MP, Lam WL: Novel regions of amplification on 8q distinct from the MYC locus and frequently altered in oral dysplasia and cancer. Genes Chromosomes Cancer. 2004, 39: 93-98. 10.1002/gcc.10294.CrossRefPubMed
27.
Schlaepfer DD, Mitra SK: Multiple connections link FAK to cell motility and invasion. Curr Opin Genet Dev. 2004, 14: 92-101. 10.1016/j.gde.2003.12.002.CrossRefPubMed
28.
Ignatoski KM, Ethier SP: Constitutive activation of pp125fak in newly isolated human breast cancer cell lines. Breast Cancer Res Treat. 1999, 54: 173-182. 10.1023/A:1006135331912.CrossRefPubMed
29.
Agochiya M, Brunton VG, Owens DW, Parkinson EK, Paraskeva C, Keith WN, Frame MC: Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells. Oncogene. 1999, 18: 5646-5653. 10.1038/sj.onc.1202957.CrossRefPubMed
30.
Thompson HG, Harris JW, Wold BJ, Quake SR, Brody JP: Identification and confirmation of a module of coexpressed genes. Genome Res. 2002, 12: 1517-1522. 10.1101/gr.418402.CrossRefPubMedPubMedCentral
31.
Heidenblad M, Schoenmakers EF, Jonson T, Gorunova L, Veltman JA, van Kessel AG, Hoglund M: Genome-wide array-based comparative genomic hybridization reveals multiple amplification targets and novel homozygous deletions in pancreatic carcinoma cell lines. Cancer Res. 2004, 64: 3052-3059. 10.1158/0008-5472.CAN-03-3159.CrossRefPubMed
32.
Aarbiou J, Verhoosel RM, Van Wetering S, De Boer WI, Van Krieken JH, Litvinov SV, Rabe KF, Hiemstra PS: Neutrophil defensins enhance lung epithelial wound closure and mucin gene expression in vitro. Am J Respir Cell Mol Biol. 2004, 30: 193-201. 10.1165/rcmb.2002-0267OC.CrossRefPubMed
33.
Zhao J, Zheng C, Guan J: Pyk2 and FAK differentially regulate progression of the cell cycle. J Cell Sci. 2000, 113: 3063-3072.PubMed
34.
Guo X, Lui WO, Qian CN, Chen JD, Gray SG, Rhodes D, Haab B, Stanbridge E, Wang H, Hong MH, et al: Identifying cancer-related genes in nasopharyngeal carcinoma cell lines using DNA and mRNA expression profiling analyses. Int J Oncol. 2002, 21: 1197-1204.PubMed
35.
Metadata
Title
High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization
Authors
Tara L Naylor
Joel Greshock
Yan Wang
Theresa Colligon
QC Yu
Virginia Clemmer
Tal Z Zaks
Barbara L Weber
Publication date
01-12-2005
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2005
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1356

Other articles of this Issue 6/2005

Breast Cancer Research 6/2005 Go to the issue

Research article

Targeted therapy against Bcl-2-related proteins in breast cancer cells

Letter

CYP2D6 variants and the prediction of tamoxifen response in randomized patients: author response

Research article

Quantification of the response of circulating epithelial cells to neodadjuvant treatment for breast cancer: a new tool for therapy monitoring

Commentary

Aromatase inhibitors as adjuvant therapy for postmenopausal women: a therapeutic advance but many unresolved questions

Research article

Antisense oligonucleotides targeting the progesterone receptor inhibit hormone-independent breast cancer growth in mice

Research article

XRCC1 and XPDgenetic polymorphisms, smoking and breast cancer risk in a Finnish case-control study
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits