title: Lack of genomic heterogeneity at high-resolution aCGH between primary breast cancers and their paired lymph node metastases.
abstract: Lymph-node metastasis (LNM) predict high recurrence rates in breast cancer patients. Systemic treatment aims to eliminate (micro)metastatic cells. However decisions regarding systemic treatment depend largely on clinical and molecular characteristics of primary tumours. It remains, however, unclear to what extent metastases resemble the cognate primary breast tumours, especially on a genomic level, and as such will be eradicated by the systemic therapy chosen. In this study we used high-resolution aCGH to investigate DNA copy number differences between primary breast cancers and their paired LNMs. To date, no recurrent LNM-specific genomic aberrations have been identified using array comparative genomic hybridization (aCGH) analysis. In our study we employ a high-resolution platform and we stratify on different breast cancer subtypes, both aspects that might have underpowered previously performed studies.To test the possibility that genomic instability in triple-negative breast cancers (TNBCs) might cause increased random and potentially also recurrent copy number aberrations (CNAs) in their LNMs, we studied 10 primary TNBC-LNM pairs and 10 ER-positive (ER+) pairs and verified our findings adding additionally 5 TNBC-LNM and 22 ER+-LNM pairs. We found that all LNMs clustered nearest to their matched tumour except for two cases, of which one was due to the presence of two distinct histological components in one tumour. We found no significantly altered CNAs between tumour and their LNMs in the entire group or in the subgroups. Within the TNBC subgroup, no absolute increase in CNAs was found in the LNMs compared to their primary tumours, suggesting that increased genomic instability does not lead to more CNAs in LNMs. Our findings suggest a high clonal relationship between primary breast tumours and its LNMs, at least prior to treatment, and support the use of primary tumour characteristics to guide adjuvant systemic chemotherapy in breast cancer patients.
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Division of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Marieke A
authors.initials: MA
authors.lastname: Vollebergh
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Christiaan
authors.initials: C
authors.lastname: Klijn
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Schouten
authors.affiliation: Department of Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.affiliation: Department of Pathology, Vrije Universiteit University Medical Center, Amsterdam, the Netherlands.
authors.forename: Danielle
authors.initials: D
authors.lastname: Israeli
authors.affiliation: Department of Pathology, Vrije Universiteit University Medical Center, Amsterdam, the Netherlands.
authors.forename: Bauke
authors.initials: B
authors.lastname: Ylstra
authors.affiliation: Department of Bioinformatics and Statistics, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, the Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.affiliation: Division of Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Division of Medical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D018740:Genetic Heterogeneity; D042822:Genomic Instability; D023281:Genomics; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms
references.citation: Cancer Genet Cytogenet. 2003 Oct 1;146(1):33-40
references.pmid: 14499694
references.citation: Breast Cancer Res. 2009;11(4):R47
references.pmid: 19589159
references.citation: Nucleic Acids Res. 2008 Feb;36(2):e13
references.pmid: 18187509
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Breast Cancer Res Treat. 2011 Jul;128(1):23-30
references.pmid: 20632083
references.citation: Oncogene. 2006 Sep 25;25(43):5846-53
references.pmid: 16998499
references.citation: BMC Cancer. 2010 Nov 30;10:654
references.pmid: 21118481
references.citation: Genome Res. 2010 Jan;20(1):68-80
references.pmid: 19903760
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16224-9
references.pmid: 18852474
references.citation: Oncogene. 2008 May 15;27(22):3165-75
references.pmid: 18071313
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Cancer Cell. 2011 Dec 13;20(6):797-809
references.pmid: 22172724
references.citation: Br J Cancer. 2006 Jan 30;94(2):333-7
references.pmid: 16333309
references.citation: BMC Res Notes. 2010 Nov 11;3:298
references.pmid: 21070656
references.citation: Cell Oncol. 2008;30(1):39-50
references.pmid: 18219109
references.citation: Nature. 2000 Aug 17;406(6797):747-52
references.pmid: 10963602
references.citation: Genes Chromosomes Cancer. 2008 Nov;47(11):994-1004
references.pmid: 18663753
references.citation: J Cancer Res Clin Oncol. 2011 May;137(5):795-809
references.pmid: 20680643
references.citation: N Engl J Med. 2003 Jul 3;349(1):7-16
references.pmid: 12840087
references.citation: Nat Rev Cancer. 2005 Aug;5(8):591-602
references.pmid: 16056258
references.citation: Ann Oncol. 2011 Jul;22(7):1561-1570
references.pmid: 21135055
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references.pmid: 11553815
references.citation: Breast Cancer Res Treat. 2013 Jun;139(2):317-27
references.pmid: 23670131
references.citation: Genes Chromosomes Cancer. 1997 Aug;19(4):267-72
references.pmid: 9258662
references.citation: Nature. 2011 Apr 7;472(7341):90-4
references.pmid: 21399628
references.citation: Genes Chromosomes Cancer. 2009 Dec;48(12):1091-101
references.pmid: 19760610
references.citation: Clin Cancer Res. 2011 Aug 1;17(15):4959-64
references.pmid: 21673065
references.citation: BMC Cancer. 2010 Aug 24;10:455
references.pmid: 20735817
references.citation: Breast Cancer Res Treat. 2007 Apr;102(2):143-55
references.pmid: 16906480
references.citation: N Engl J Med. 1988 Nov 10;319(19):1239-45
references.pmid: 2903446
references.citation: Ann Oncol. 2011 Apr;22(4):870-876
references.pmid: 20937646
references.citation: Cancer Res. 1997 Apr 15;57(8):1597-604
references.pmid: 9108466
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15901-5
references.pmid: 14665696
references.citation: World J Surg. 2010 Jul;34(7):1434-41
references.pmid: 20213203