Original Paper

Oncogene (2005) 24, 7281–7289. doi:10.1038/sj.onc.1208892; published online 18 July 2005

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

Leah M Prentice1,2, Ashleen Shadeo3, Valia S Lestou1,2,4, Melinda A Miller1,2, Ronald J deLeeuw3, Nikita Makretsov1,2, Dmitry Turbin1,2, Lindsay A Brown1,2, Nicol Macpherson5, Erika Yorida1,2, Maggie C U Cheang1,2, John Bentley1,2, Stephen Chia6, Torsten O Nielsen1,2, C Blake Gilks1,2, Wan Lam3 and David G Huntsman1,2

  1. 1Department of Pathology and Prostate Centre, Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada V6H 3Z6
  2. 2British Columbia Cancer Agency, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6H 3Z6
  3. 3Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3
  4. 4Department of Paediatric Laboratory Medicine, The Hospital for Sick Kids, Toronto, Canada M5G 1X8
  5. 5Department of Medical Oncology, British Columbia Cancer Agency, Victoria, Canada V8R 6V5
  6. 6Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6

Correspondence: DG Huntsman, British Columbia Cancer Agency, Department of Pathology and Laboratory Medicine, 600 West 10th Avenue, Vancouver, BC, Canada V5Z 4E6. E-mail: dhuntsman@bccancer.bc.ca

Received 18 April 2005; Revised 1 June 2005; Accepted 2 June 2005; Published online 18 July 2005.

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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.

Keywords:

NRG1, breast cancer, amplicon, SPFH2, 8p

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

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