Abstract
BackgroundOncogene amplification and overexpression occur in tumor cells. Amplification status may provide diagnostic and prognostic information and may lead to new treatment strategies. Chromosomal regions 8p12, 8q24, 11q13, 17q12 and 20q13 are recurrently amplified in breast cancers.MethodsTo assess the frequencies and clinical impact of amplifications, we analyzed 547 invasive breast tumors organized in a tissue microarray (TMA) by fluorescence in situ hybridization (FISH) and calculated correlations with histoclinical features and prognosis. BAC probes were designed for: (i) two 8p12 subregions centered on RAB11FIP1 and FGFR1 loci, respectively; (ii) 11q13 region centered on CCND1; (iii) 12p13 region spanning NOL1; and (iv) three 20q13 subregions centered on MYBL2, ZNF217 and AURKA, respectively. Regions 8q24 and 17q12 were analyzed with MYC and ERBB2 commercial probes, respectively.ResultsWe observed amplification of 8p12 (amplified at RAB11FIP1 and/or FGFR1) in 22.8%, 8q24 in 6.1%, 11q13 in 19.6%, 12p13 in 4.1%, 17q12 in 9.9%, 20q13Z (amplified at ZNF217 only) in 9.9%, and 20q13Co (co-amplification of two or three 20q13 loci) in 8.5% of cases. The 8q24, 12p13, and 17q12 amplifications were correlated with high grade. The most frequent single amplifications were 8p12 (9.8%), 8q24 (3.3%) and 12p13 (3.3%), 20q13Z and 20q13Co (1.6%) regions. The 17q12 and 11q13 regions were never found amplified alone. The most frequent co-amplification was 8p12/11q13. Amplifications of 8p12 and 17q12 were associated with poor outcome. Amplification of 12p13 was associated with basal molecular subtype.ConclusionOur results establish the frequencies, prognostic impacts and subtype associations of various amplifications and co-amplifications in breast cancers.
Highlights
Oncogene amplification and overexpression occur in tumor cells
Amplification status may be determined in clinics as an indicator of prognosis or before applying a specific treatment: ERBB2 amplification, found in 15 to 25% of breast cancers, is a marker of adverse prognosis and encodes a tyrosine kinase receptor that is the target of trastuzumab (Herceptin) [8,9,10]
Bacterial artificial chromosome (BAC) probes were designed for: (i) two 8p12 subregions [5] centered on RAB11FIP1 and FGFR1 loci, respectively; (ii) 11q13 region centered on CCND1; (iii) 12p13 region spanning NOL1; and (iv) three 20q13 subregions [29] centered on MYBL2, ZNF217 and AURKA, respectively
Summary
Oncogene amplification and overexpression occur in tumor cells. Amplification status may provide diagnostic and prognostic information and may lead to new treatment strategies. Amplification is a frequent and important mechanism for oncogene overexpression in breast tumor cells. Amplification status may be determined in clinics as an indicator of prognosis or before applying a specific treatment: ERBB2 amplification, found in 15 to 25% of breast cancers, is a marker of adverse prognosis and encodes a tyrosine kinase receptor that is the target of trastuzumab (Herceptin) [8,9,10]. The identity of the driver genes has not been definitely established, the importance of the FGFR1 tyrosine kinase receptor gene has been suggested [5,14] Amplification of this region has an adverse impact on prognosis in breast cancer [5]. Several potential oncogenes have been suggested, including MYBL2 [23,30], AURKA [31], and ZNF217 [32,33,34]
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