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NRG1 gene rearrangements in clinical breast cancer: identification of an adjacent novel amplicon associated with poor prognosis

Oncogene volume 24, pages 7281–7289 (2005)Cite this article

Abstract

Rearrangements of the neuregulin (NRG1) gene have been implicated in breast carcinoma oncogenesis. To determine the frequency and clinical significance of NRG1 aberrations in clinical breast tumors, a breast cancer tissue microarray was screened for NRG1 aberrations by fluorescent in situ hybridization (FISH) using a two-color split-apart probe combination flanking the NRG1 gene. Rearrangements of NRG1 were identified in 17/382 cases by FISH, and bacterial artificial chromosome array comparative genomic hybridization was applied to five of these cases to further map the chromosome 8p abnormalities. In all five cases, there was a novel amplicon centromeric to NRG1 with a minimum common region of amplification encompassing two genes, SPFH2 and FLJ14299. Subsequent FISH analysis for the novel amplicon revealed that it was present in 63/262 cases. Abnormalities of NRG1 did not correlate with patient outcome, but the novel amplicon was associated with poor prognosis in univariate analysis, and in multivariate analysis was of prognostic significance independent of nodal status, tumor grade, estrogen receptor status, and human epidermal growth factor receptor (HER)2 overexpression. Of the two genes in the novel amplicon, expression of SPFH2 correlated most significantly with amplification. This amplicon may emerge as a result of breakpoints and chromosomal rearrangements within the NRG1 locus.

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Abbreviations

TMA:

tissue microarray

FISH:

fluorescent in situ hybridization

HRG:

heregulin

HER:

human epidermal growth factor receptor

IHC:

immunohistochemistry

BAC:

bacterial artificial chromosome

CGH:

comparative genomic hybridization

MFISH:

multicolor karyotyping

MAR:

minimum common region of amplification

BFB:

break–fusion–bridge

References

  • Adelaide J, Chaffanet M, Mozziconacci MJ, Popovici C, Conte N, Fernandez F, Sobol H, Jacquemier J, Pebusque M, Ron D, Lafage-Pochitaloff M and Birnbaum D . (2000). Int. J. Oncol., 16, 683–688.

  • Adelaide J, Huang HE, Murati A, Alsop AE, Orsetti B, Mozziconacci MJ, Popovici C, Ginestier C, Letessier A, Basset C, Courtay-Cahen C, Jacquemier J, Theillet C, Birnbaum D, Edwards PA and Chaffanet M . (2003). Genes Chromosomes Cancer, 37, 333–345.

  • Atlas E, Cardillo M, Mehmi I, Zahedkargaran H, Tang C and Lupu R . (2003). Mol. Cancer Res., 1, 165–175.

  • Bautista S and Theillet C . (1998). Genes Chromosomes Cancer, 22, 268–277.

  • Bernardino J, Apiou F, Gerbault-Seureau M, Malfoy B and Dutrillaux B . (1998). Genes Chromosomes Cancer, 23, 100–108.

  • Birnbaum D, Adelaide J, Popovici C, Charafe-Jauffret E, Mozziconacci MJ and Chaffanet M . (2003). Lancet Oncol., 4, 639–642.

  • Camp RL, Dolled-Filhart M and Rimm DL . (2004). Clin. Cancer Res., 21, 7252–7259.

  • Coquelle A, Pipiras E, Toledo F, Buttin G and Debatisse M . (1997). Cell, 89, 215–225.

  • Chi B, DeLeeuw RJ, Coe BP, MacAulay C and Lam WL . (2004). BMC Bioinform., 5, 13.

  • Chomczynski P and Sacchi N . (1987). Anal. Biochem., 162, 156–159.

  • Courtay-Cahen C, Morris JS and Edwards PA . (2000). Genomics, 66, 15–25.

  • Cuny M, Kramar A, Courjal F, Johannsdottir V, Iacopetta B, Fontaine H, Grenier J, Culine S and Theillet C . (2000). Cancer Res., 60, 1077–1083.

  • de Leeuw RJ, Davies JJ, Rosenwald A, Bebb G, Gascoyne RD, Dyer MJ, Staudt LM, Martinez-Climent JA and Lam WL . (2004). Hum. Mol. Genet., 13, 1827–1837.

  • Falls DL . (2003). Exp. Cell Res., 284, 14–30.

  • Huang HE, Chin SF, Ginestier C, Bardou VJ, Adelaide J, Iyer NG, Garcia MJ, Pole JC, Callagy GM, Hewitt SM, Gullick WJ, Jacquemier J, Caldas C, Chaffanet M, Birnbaum D and Edwards PA . (2004). Cancer Res., 64, 6840–6844.

  • Ishkanian AS, Malloff CA, Watson SK, DeLeeuw RJ, Chi B, Coe BP, Snijders A, Albertson DG, Pinkel D, Marra MA, Ling V, MacAulay C and Lam WL . (2004). Nat. Genet., 36, 299–303.

  • Jacobson KK, Morrison LE, Henderson BT, Blondin BA, Wilber KA, Legator MS, O'Hare A, Van Stedum SC, Proffitt JH, Seelig SA and Coon JS . (2004). Genes Chromosomes Cancer, 40, 19–31.

  • Jong K, Marchori E, van der Vaart A, Ylstra B, Weiss M and Meijer G . (2003). Applications of Evolutionary Computing. EvoBIO: Evolutionary Computation and Bioinformatics Lecture Notes in Computer Science, Vol. 2611 Springer: Berlin, pp. 54–65.

    Google Scholar 

  • Khoury H, Lestou VS, Gascoyne RD, Bruyere H, Li CH, Nantel SH, Dalal BI, Naiman SC and Horsman DE . (2003). Mod. Pathol., 16, 716–724.

  • Koziczak M, Holbro T and Hynes NE . (2004). Oncogene, 23, 3501–3508.

  • Liu CL, Prapong W, Natkunam Y, Alizadeh A, Montgomery K, Gilks CB and van de Rijn M . (2002). Am. J. Pathol., 161, 1557–1565.

  • Liu X, Baker E, Eyre HJ, Sutherland GR and Zhou M . (1999). Oncogene, 18, 7110–7114.

  • Makretsov N, Gilks CB, Coldman AJ, Hayes M and Huntsman D . (2003). Hum. Pathol., 34, 1001–1008.

  • Makretsov N, He M, Hayes M, Chia S, Horsman DE, Sorensen PH and Huntsman DG . (2004a). Genes Chromosomes Cancer, 40, 152–157.

  • Makretsov NA, Huntsman DG, Nielsen TO, Yorida E, Peacock M, Cheang MC, Dunn SE, Hayes M, van de Rijn M, Bajdik C and Gilks CB . (2004b). Clin. Cancer Res., 10, 6143–6151.

  • Nagy P, Vereb G, Sebestyen Z, Horvath G, Lockett SJ, Damjanovich S, Park JW, Jovin TM and Szollosi J . (2002). J. Cell Sci., 115, 4251–4262.

  • Parker RL, Huntsman DG, Lesack DW, Cupples JB, Grant DR, Akbari M and Gilks CB . (2002). Am. J. Clin. Pathol., 117, 723–728.

  • Powers CJ, McLeskey SW and Wellstein A . (2000). Endocr. Relat. Cancer, 7, 165–197.

  • Ray ME, Yang ZQ, Albertson D, Kleer CG, Washburn JG, Macoska JA and Ethier SP . (2004). Cancer Res., 64, 40–47.

  • Rummukainen J, Kytola S, Karhu R, Farnebo F, Larsson C and Isola JJ . (2001). Cancer Genet. Cytogenet., 126, 1–7.

  • Schaefer G, Fitzpatrick VD and Sliwkowski MX . (1997). Oncogene, 15, 1385–1394.

  • Sprenger RR, Speijer D, Back JW, De Koster CG, Pannekoek H and Horrevoets AJ . (2004). Electrophoresis, 25, 156–172.

  • Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C and Sorensen PH . (2002). Cancer Cell, 2, 367–376.

  • Ugolini F, Adelaide J, Charafe-Jauffret E, Nguyen C, Jacquemier J, Jordan B, Birnbaum D and Pebusque MJ . (1999). Oncogene, 18, 1903–1910.

  • Wang XZ, Jolicoeur EM, Conte N, Chaffanet M, Zhang Y, Mozziconacci MJ, Feiner H, Birnbaum D, Pebusque MJ and Ron D . (1999). Oncogene, 18, 5718–5721.

  • Watson SK, deLeeuw RJ, Ishkanian AS, Malloff CA and Lam WL . (2004). BMC Genom., 5, 6.

  • Wiseman SM, Makretsov N, Neilsen TO, Gilks B, Yorida E, Cheang M, Turbin D, Gelmon K and Huntsman DG . (2005). Cancer, 103, 1770–1777.

  • Yarden Y and Sliwkowski MX . (2001). Nat. Rev. Mol. Cell. Biol., 2, 127–137.

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Acknowledgements

Funding for this project was provided by a Michael Smith Foundation for Health Research (MSFHR) Unit Grant and an Aventis Canada Educational Grant. Torsten O Nielsen and David G Huntsman are MSFHR scholars. Leah M Prentice is an MSFHR trainee.

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Authors and Affiliations

  1. Department of Pathology and Prostate Centre, Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, V6H 3Z6, BC, Canada

    Leah M Prentice, Valia S Lestou, Melinda A Miller, Nikita Makretsov, Dmitry Turbin, Lindsay A Brown, Erika Yorida, Maggie C U Cheang, John Bentley, Torsten O Nielsen, C Blake Gilks & David G Huntsman

  2. Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, University of British Columbia, Vancouver, V6H 3Z6, BC, Canada

    Leah M Prentice, Valia S Lestou, Melinda A Miller, Nikita Makretsov, Dmitry Turbin, Lindsay A Brown, Erika Yorida, Maggie C U Cheang, John Bentley, Torsten O Nielsen, C Blake Gilks & David G Huntsman

  3. Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, V5Z 1L3, BC, Canada

    Ashleen Shadeo, Ronald J deLeeuw & Wan Lam

  4. Department of Paediatric Laboratory Medicine, The Hospital for Sick Kids, Toronto, M5G 1X8, Canada

    Valia S Lestou

  5. Department of Medical Oncology, British Columbia Cancer Agency, Victoria, V8R 6V5, Canada

    Nicol Macpherson

  6. Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, V5Z 4E6, BC, Canada

    Stephen Chia

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  1. Leah M Prentice
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Correspondence to David G Huntsman.

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Prentice, L., Shadeo, A., Lestou, V. et al. NRG1 gene rearrangements in clinical breast cancer: identification of an adjacent novel amplicon associated with poor prognosis. Oncogene 24, 7281–7289 (2005). https://doi.org/10.1038/sj.onc.1208892

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