Abstract 810: Amplification of 8q21 in breast cancer is independent of MYC and associated with poor patient outcome

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Abstract Introduction Copy number gains involving the long arm of chromosome 8 including high-level amplifications at 8q21 and 8q24 have been reported in up to 60% of breast cancers. While the role of the MYC gene is well established, the significance of the 8q21 amplicon is less clear. The aim of our study was to analyze 8q21 amplification in a large set of breast cancers with clinical follow up data. Experimental procedures The breast cancer tissue microarray used for this study contains a total of 2.197 tumors and has been described in detail. A fluorescence in situ hybridization (FISH) probe was generated from genomic clone RZPDB737E022003D (imaGenes GmbH, Germany) that maps to the centre of the 8q21 amplicon as previously described in the SK-BR-3 breast cancer cell line. The probe contains the entire TMEM70 gene (transmembrane protein 70) and locates 4 kb downstream from TCEB1 (transcription elongation factor B, polypeptide 1), amplification of which was recently described in prostate cancer. A commercially available pericentromeric probe for chromosome 8 was used as reference (CEP 8Z2 SpectrumOrange, Vysis Inc.). A tumor was considered amplified if the ratio of 8q21/centromere 8 was ≥2.0. Ratios >1.0 and <2.0 had been considered as gains and a ratio ≤1.0 as normal. Results A total of 1458 (66.4%) of arrayed cancer samples were assessable by FISH. Copy number alterations of the 8q21 locus were found in 157 (10.7%) interpretable breast cancers, including amplification in 50 (3.4%) tumors and gains in 107 (7.3%). Amplification at 8q21 was associated to high tumor grade (p=0.042). There was no association between aberrations of the 8q21 locus and tumor stage, presence of lymph node metastases or estrogen receptor status (p>0.05 each). Data on MYC amplification were available from a previous study. A combined analysis of MYC and 8q21 identified 90 tumors with amplifications of MYC and/or 8q21. Of these, 28 tumors were amplified for 8q21 only and 54 for MYC only. Co-amplification of both genes was found in the remaining eight tumors. 8q21 amplification was strongly linked to adverse prognosis (hazard ratio 2.18, confidence interval 1.36 to 3.46, p=0.001). There was no impact of 8q21 gains on patient survival (p=0.48). However, a multivariate Cox analysis did not reveal an independent prognostic value of 8q21 amplification (p=0.23). Conclusions In summary, amplification of 8q21 occurs in a subgroup of breast carcinomas with poor prognosis. Copy number changes of 8q21 are independent from MYC and represent a separate amplicon in this chromosomal region. TMEM70 and the close TCEB1 gene in the centre of the 8q21 amplicon are the most likely possible candidate driver genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 810.