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NRG1 Gene Rearrangements in Clinical Breast Cancer: Identification of an Adjacent Novel Amplicon Associated with Poor Prognosis

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NRG1 Gene Rearrangements in Clinical Breast Cancer: Identification of an Adjacent Novel Amplicon Associated with Poor Prognosis Oncogene (2005) 24, 7281–7289 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc 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 CU Cheang1,2, John Bentley1,2, Stephen Chia6, Torsten O Nielsen1,2, C Blake Gilks1,2, Wan Lam3 and David G Huntsman*,1,2 1Department of Pathology and Prostate Centre, Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, BC, Canada V6H 3Z6; 2British Columbia Cancer Agency, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada V6H 3Z6; 3Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3; 4Department of Paediatric Laboratory Medicine, The Hospital for Sick Kids, Toronto, Canada M5G 1X8; 5Department of Medical Oncology, British Columbia Cancer Agency, Victoria, Canada V8R 6V5; 6Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 4E6 Rearrangements of the neuregulin (NRG1) gene have been Introduction implicated in breast carcinoma oncogenesis. To determine the frequency and clinical significance of NRG1 aberra- Chromosomal translocations are a common feature of tions in clinical breast tumors,a breast cancer tissue sarcoma, leukemia and lymphoma, but little is known microarray was screened for NRG1 aberrations by about their role in common epithelial malignancies. A fluorescent in situ hybridization (FISH) using a two-color translocation t(12;15) leading to ETV6-NTRK3 gene split-apart probe combination flanking the NRG1 gene. fusion is a specific event in secretory carcinoma, a rare Rearrangements of NRG1 were identified in 17/382 cases formof breast cancer (Tognon et al., 2002; Makretsov by FISH,and bacterial artificial chromosome array et al., 2004a). This was the first report of a recurrent and comparative genomic hybridization was applied to five of subtype-specific translocation in breast cancer and raises these cases to further map the chromosome 8p abnorm- the possibility that translocations could define other alities. In all five cases,there was a novel amplicon clinically relevant subtypes of breast cancer. The short centromeric to NRG1 with a minimum common region of arm of chromosome 8 is a site of frequent chromosomal amplification encompassing two genes, SPFH2 and abnormalities in breast cancers and breast cancer cell FLJ14299. Subsequent FISH analysis for the novel lines, including gene amplification events and transloca- amplicon revealed that it was present in 63/262 cases. tions. In breast cancers, the NRG1 and FGFR1 genes Abnormalities of NRG1 did not correlate with patient have frequently been involved in cytogenetic abnormal- outcome,but the novel amplicon was associated with poor ities of 8p11–12 (Bernardino et al., 1998; Liu et al., 1999; prognosis in univariate analysis,and in multivariate Ugolini et al., 1999; Adelaide et al., 2000, 2003; analysis was of prognostic significance independent of Birnbaum et al., 2003; Ray et al., 2004). nodal status,tumor grade,estrogen receptor status,and NRG1 codes for at least 15 different isoforms through human epidermal growth factor receptor (HER)2 over- alternative splicing, including four heregulin (HRG) expression. Of the two genes in the novel amplicon, isoforms, which are ligands for members of the ERBB/ expression of SPFH2 correlated most significantly with human epidermal growth factor receptor (HER) family amplification. This amplicon may emerge as a result of (Adelaide et al., 2003; Falls, 2003). These HRG isoforms breakpoints and chromosomal rearrangements within the start transcription at exon 2, completely bypassing exon NRG1 locus. 1, which is located 955 kb away at the telomeric end of Oncogene (2005) 24, 7281–7289. doi:10.1038/sj.onc.1208892; the gene. Binding of HRG ligands to HER3 facilitates published online 18 July 2005 heterodimerization of HER3 with HER2 and stimulates a signaling cascade that effects proliferation, survival, Keywords: NRG1; breast cancer; amplicon; SPFH2;8p and differentiation (as reviewed by Yarden and Sliw- kowski, 2001). HER2 is overexpressed in 15–25% of ductal breast cancers and this overexpression correlates with poor prognosis (Yarden and Sliwkowski, 2001). HER1 and HER3 overexpression are also associated with poor prognosis in breast cancer (Wiseman et al., *Correspondence: DG Huntsman, British Columbia Cancer Agency, 2005). Furthermore, HRG has been shown to promote Department of Pathology and Laboratory Medicine, 600 West 10th tumor growth in vivo and induce metastasis (Atlas et al., Avenue, Vancouver, BC, Canada V5Z 4E6; E-mail: [email protected] 2003). The known oncogenic role of HRG has provided Received 18 April 2005; revised 1 June 2005; accepted 2 June 2005; the rationale for considering NRG1 as a potential target published online 18 July 2005 of 8p12 rearrangements in breast carcinoma. 8p abnormalities in clinical breast cancer LM Prentice et al 7282 In breast cancer cell lines, there have been seven were not assessable due to poor FISH hybridization, breakpoints described within or around NRG1,anda insufficient numbers of tumor cells, tissue loss, or tissue translocation with DOC4 located on chromosome 11 over/underdigestion. In all, 17 (4.7%) of the cases has been described in the MDA-MB-175 cell line (Liu showed abnormal NRG1 signals, excluding aneuploidy. et al., 1999; Wang et al., 1999; Adelaide et al., 2003). Three distinct types of abnormalities were seen: (A) low This translocation gives rise to a secreted fusion protein copy number of the 30 (centromeric)-end of the gene (Liu et al., 1999; Wang et al., 1999; Adelaide et al., 2003) with respect to the 50 (telomeric)-end of the gene (two that has been demonstrated to have an autocrine growth cases), (B) low copy number of the 50-end of the gene effect (Schaefer et al., 1997). with respect to the 30-end of the gene (12 cases), and (C) Huang et al. (2004) identified NRG1 breaks in 6% of amplification of both ends of the gene (three cases) breast cancers. The cases with NRG1 breaks tended to (Figure 1a). The two cases with type A NRG1 be HER2 negative and estrogen receptor (ER) positive. aberrations showed either loss of the 30-end of NRG1 They also reported a significant correlation with FGFR1 (case number 152) or gain of the 50-end of NRG1 overexpression. They hypothesized that these break- (case number 77) (Figure 1b). Type B aberrations were points result in translocation events that lead to breast the most frequently observed, with loss of the 50 signal cancer development through abnormal expression of the being present in 11 cases, two of which also had 30 30-end of NRG1. They have shown translocation events amplification events (cases 87 and 179). The remaining in four breast cancer cell lines (ZR-75-1, HCC1937, nine cases with type B abnormalities had increased copy UACC-812, and MDA-MB-175) and demonstrated gain number of the 30-end of NRG1 due to loss of the 50-end of the 8p11–12 region in three cell lines (SUM-52, ZR- of the gene without 30 amplification. A single case (case 75-1, and MDA-MB-134) (Adelaide et al., 2003). It is, 286) with type B abnormality showed amplification of however, possible that chromosomal rearrangements the 30-end of NRG1 only (Figure 1c). Three cases: 285, within intron 1 of the NRG1 gene do not represent gene- 303, and 382 showed type C abnormalities (Figure 1d), specific translocations and that these events may be part and this is most likely indicative of whole gene of some other cytogenetic process. Factors that make amplification. the gene-specific hypothesis less likely include: (1) the A second set of FISH probes was applied to the 17 lack of common fusion partners or a clearly oncogenic cases demonstrating NRG1 aberrations, one covering fusion transcript, (2) the lack of a consistent association exon 1 and the other covering exons 2–17 of the gene. between NRG1 breaks and NRG1 mRNA or protein Exon 2 is located 955 kb away fromexon 1 and levels, (3) the lack of any correlation between NRG1 specifically represents the start of the HRG coding region abnormalities and expression of the epidermal growth (Adelaide et al., 2003). This specific (internal) probe set factor receptors (HER1, HER2, HER3, and HER4), showed fewer abnormalities than were seen with the and (4) the lack of strong and specific clinical associa- flanking (external) probes. For example, both cases tions with NRG1 rearrangements, as has been seen for showing type A abnormalities (loss of the 30-end) no the t(12;15) translocation and secretory carcinomas. longer showed a difference in copy number between the To determine the frequency and further delineate the 50-andthe30-end of NRG1. The different locations of clinical significance of chromosomal rearrangements both specific and flanking probe sets are demonstrated in within and surrounding the NRG1 gene, we analysed Figure 2a and complete results are listed in Figure 1a. 438 clinically annotated breast cancers using fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC). In five cases with NRG1 rearrangements, HRG correlates significantly with tumor grade, p53, bacterial artificial chromosome (BAC) array compara- and HER1 tive genomic hybridization (CGH) was performed. A second series of cases with matched frozen tissue There was no statistically significant correlation between samples was used to determine the association bet- NGR1 aberrations, either individually or taken as a ween gene copy number and expression levels of specific group, and the biomarkers, ER, p53, Ki67, HER1, genes identified as being amplified through BAC HER2, or HER3, nor with tumor grade, nodal status, or array CGH. histological subtype.
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