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01-11-2007 | Breast Oncology

Genomic Instability and the Development of Metastatic Lymph Node Tumors

Authors: Karen A. Callaghan, MD, Tyson E. Becker, MD, Darrell L. Ellsworth, PhD, Jeffrey A. Hooke, MD, Rachel E. Ellsworth, PhD, Craig D. Shriver, MD

Published in: Annals of Surgical Oncology | Issue 11/2007

Abstract

Background

Although recent data suggest that cells with metastatic potential disseminate from the primary breast tumor early in tumor development, the mechanism by which disseminated breast cancer cells proliferate within foreign tissues is not well understood. Here, we examined levels and patterns of allelic imbalance (AI) in metastatic lymph node (LN) tumors to identify molecular signals that promote the survival and growth of disseminated breast tumor cells.

Methods

DNA from 106 metastatic LN tumors from 25 patients was isolated after laser microdissection of pure tumor cell populations. AI was assessed at 26 chromosomal regions frequently altered in breast cancer. Tumor burden was calculated by dividing the area of the metastatic tumor in the node by the area of the entire LN.

Results

Metastatic tumor burden ranged from focal to complete replacement of the LN with tumor. Grouping the nodes as <25% tumor, 25–50% tumor, 50–75% tumor, and ≥75% tumor replacement revealed the average frequency of AI ranged from 0.13 (±0.11) in the <25% group to 0.17 (±0.13) in LNs with ≥75% tumor burden. The range of AI in both the <25% and >75% replacement group was 0.00–0.48. Allelic losses at chromosomal regions 1p36.1–36.2, 5q21.1–21.3, 6q15, 10q23.31–23.33, and 17p13.1 were significantly higher in metastatic LNs with >75% compared with <25% tumor burden.

Conclusions

In metastatic LNs, levels of AI were not associated with tumor burden, suggesting that accumulation of genetic changes is not coincidental with tumor growth; rather the accumulation of specific genetic changes is a prerequisite to the transformation of disseminated breast cells into metastatic LN tumors.

Ellsworth RE, Ellsworth DL, Neatrour DM, Deyarmin B, Lubert SM, Sarachine MJ, Brown P, Hooke JA, Shriver CD. Allelic imbalance in primary breast carcinomas and metastatic tumors of the axillary lymph nodes. Mol Cancer Res 2005; 3:71–7PubMedCrossRef

Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N, Pennanen S, Kallioniemi A, Kallioniemi OP, Isola J. Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 1997; 57:1597–604PubMed

Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJF, Kaufmann M, Diebold J, Arnholdt H, Muller P, Bischoff J, Harch D, Schlimok G, Riethmuller G, Eils R, Klein CA. From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci 2003; 100:7737–42PubMedCrossRef

Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2:563–72PubMedCrossRef

Hampl M, Hampl JA, Schwarz P, Frank S, Hahn M, Schackert G, Saeger HD, Schackert HK. Accumulation of genetic alterations in brain metastases of sporadic breast carcinomas is associated with reduced survival after metastasis. Invasion Metastasis 1999; 18:81–95CrossRef

Hampl M, Hampl JA, Reiss G, Schackert G, Saeger HD, Schackert HK. Loss of heterozygosity accumulation in primary breast carcinomas and additionally in corresponding distant metastases is associated with poor outcome. Clin Cancer Res 1999; 5:1417–25PubMed

American Joint Committee on Cancer. AJCC Cancer Staging Manual. New York: Springer; 2002

Ellsworth RE, Ellsworth DL, Lubert SM, Hooke JA, Somiari RI, Shriver CD. High-throughput loss of heterozygosity mapping in 26 commonly deleted regions in breast cancer. Cancer Epidemiol Biomark Prev 2003; 12:915–9

Medintz IL, Lee CCR, Wong WW, Pirkola K, Sidransky D, Mathies RA. Loss of heterozygosity assay for molecular detection of cancer using energy-transfer primers and capillary array electrophoresis. Genome Res 2000; 10:1211–8PubMedCrossRef

10.

Ellsworth DL, Ellsworth RE, Love B, Deyarmin B, Lubert SM, Mittal V, Shriver CD. Genomic patterns of allelic imbalance in disease free tissue adjacent to primary breast carcinomas. Breast Cancer Res Treat 2004; 88:131–9PubMedCrossRef

11.

Klein CA, Holzel D. Systemic cancer progression and tumor dormancy. Cell Cycle 2006; 5:1788–98PubMed

12.

Dahiya R, Deng G. Molecular prognostic markers in breast cancer. Breast Cancer Res Treat 1998; 52:185–200PubMedCrossRef

13.

Eccles SA. The role of c-erbB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neoplasia 2001; 6:393–406PubMedCrossRef

14.

Yang H, Crawford N, Lukes L, Finney R, Lancaster M, Hunter KW. Metastasis predictive signature profiles pre-exist in normal tissues. Clin Exp Metastasis 2005; 22:593–603PubMedCrossRef

15.

Miyakis S, Spandidos DA. Allelic loss in breast cancer. Cancer Detect Prev 2002; 26:426–34PubMedCrossRef

16.

Adeyinka A, Mertens F, Idvall I, Bondeson L, Ingvar C, Mitelman F, Pandis N. Different patterns of chromosomal imbalances in metastasising and non-metastasising primary breast carcinomas. Int J Cancer 1999; 84:370–5PubMedCrossRef

17.

Cleton-Jansen AM, Callen DF, Seshadri R, Goldup S, McCallum B, Crawford J, Powell JA, Settasatian C, van Beerendonk H, Moerland EW, Smit V, Harris WH, Millis R, Morgan NV, Barnes D, Mathew CG, Cornelisse CJ. Loss of heterozygosity mapping at chromosome arm 16q in 712 breast tumors reveals factors that influence delineation of candidate regions. Cancer Res 2001; 61:1171–7PubMed

18.

Vos CBJ, ter Haar NT, Rosenberg C, Peterse JL, Cleton-Jansen AM, Cornelisse CJ, van de Vijver MJ. Genetic alterations on chromosome 16 and 17 are important features of ductal carcinoma in situ of the breast and are associated with histologic type. Brit J Cancer 1999; 81:1410–8PubMedCrossRef

19.

Driouch K, Dorion-Bonnet F, Brifford M, Champeme M, Longy M, Lidereau R. Loss of heterozygosity on chromosome arm 16q in breast cancer metastases. Genes, Chromosomes Cancer 1997; 19:185–91PubMedCrossRef

20.

Bae SC, Choi JK. Tumor suppressor activity of RUNX3. Oncogene 2004; 23:4336–40PubMedCrossRef

21.

Fukamachi H, Ito K. Growth regulation of gastric epithelial cells by Runx3. Oncogene 2004; 23:4330–5PubMedCrossRef

22.

Lau QC, Raja E, Salto-Tellez M, Liu Q, Ito K, Inoue M, Putti TC, Loh M, Ko TK, Huang C, Bhalla KN, Zhu T, Ito Y, Sukumar S. RUNX3 is frequently inactivated by dual mechanisms of protein mislocalization and promoter hypermethylation in breast cancer. Cancer Res 2006; 66:6512–20PubMedCrossRef

23.

Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. Cell 2000; 103:311–20PubMedCrossRef

24.

van Es JH, Barker N, Clevers H. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Gen Dev 2003; 13:28–33CrossRef

25.

Gentile M, Bergman Jungestrom M, Olsen KE, Soderkvist P, Wingren S. p53 and survival in early onset breast cancer: Analysis of gene mutations, loss of heterozygosity and protein accumulation. Eur J Cancer 1999; 35:1202–7PubMedCrossRef

26.

Hanby AM, Kelsell DP, Potts HW, Gillett CE, Bishop DT, Spurr NK, Barnes DM. Association between loss of heterozygosity of BRCA1 and BRCA2 and morphological attributes of sporadic breast cancer. Int J Cancer 2000; 88:204–8PubMedCrossRef

27.

Katsama A, Sourvinos G, Zachos G, Spandidos DA. Allelic Loss at the BRCA1, BRCA2 and TP53 loci in human sporadic breast carcinoma. Cancer Lett 2000; 150:165–70PubMedCrossRef

28.

Johnson SM, Shaw JA, Walker RA. Sporadic breast cancer in young women: prevalence of loss of heterozygosity at p53, BRCA1 and BRCA2. Int J Cancer 2002; 98:205–9PubMedCrossRef

29.

Noviello C, Courjal F, Theillet C. Loss of heterozygosity on the long arm of chromosome 6 in breast cancer: possibly four regions of deletion. Clin Cancer Res 1996; 2:1601–6PubMed

30.

Trent J, Stanbridge EJ, McBride HL, Meese EU, Casey G, Araujo DE, Witkowski CM, Nagle RB. Tumorigenicity in human melanoma cell lines controlled by introduction of human chromosome 6. Science 1990; 247:568–71PubMedCrossRef

31.

Sandhu AK, Hubbard K, Kaur GP, Jha KK, Ozer HL, Athwal RS. Senescence of immortal human fibroblasts by the introduction of normal human chromosome 6. Proc Natl Acad Sci 1994; 91:5498–502PubMedCrossRef

32.

Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol 2001; 14:672–6PubMedCrossRef

33.

Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 1998; 17:123–7PubMedCrossRef

34.

Garcia JM, Silva JM, Dominguez G, Gonzalez R, Navarro A, Carretero L, Provencio M, Bonilla F. Allelic loss of the PTEN region (10q23) in breast carcinoma of poor pathophenotype. Breast Cancer Res Treat 1999; 57:237–43PubMedCrossRef

35.

Chung MJ, Jung SH, Lee BJ, Kang MJ, Lee DG. Inactivation of the PTEN gene protein product is associated with the invasiveness and metastasis, but not angiogenesis, of breast cancer. Pathol Int 2004; 54:10–5PubMedCrossRef

36.

Chu LW, Pettaway CA, Liang JC. Genetic abnormalities specifically associated with varying metastatic potential of prostate cancer cell lines as detected by comparative genomic hybridization. Cancer Genet Cytogenet 2001; 127:161–7PubMedCrossRef

Title: Genomic Instability and the Development of Metastatic Lymph Node Tumors
Authors: Karen A. Callaghan, MD
Tyson E. Becker, MD
Darrell L. Ellsworth, PhD
Jeffrey A. Hooke, MD
Rachel E. Ellsworth, PhD
Craig D. Shriver, MD
Publication date: 01-11-2007
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 11/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-007-9504-7

At a glance: The STEP trials

Springer Medicine

Genomic Instability and the Development of Metastatic Lymph Node Tumors

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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