Amplification of chromosome 8q22 and metastasis of breast cancers
摘要
4297 Introduction. Metastasis is the major cause of the deaths of patients with breast cancer. However, the detailed mechanism and genetic basis for tumor recurrence and metastasis is still not completely understood. Gene amplification is a common mechanism for oncogenic activation causing tumor initiation and progression. The present study is to search for gene amplification associated with metastasis potential of primary breast cancers. Methods. A cohort of 121 unselected primary tumors with at least 24 months clinical follow-up (median 48 months) were examined for gene expression on Affymetrix U133 plus 2.0 arrays. A subset of 39 high-grade cases were further studied for DNA copy number changes on Affymetrix 10K SNP arrays. Supervised analyses compared cases with metastatic recurrence within 24 months, to cases with no recurrence for at least 24 months. Amplification was confirmed by fluorescence in situhybridization (FISH) on fixed tissue sections. Results. SNP array analysis of 39 high-grade tumors revealed frequent copy number gains on 8q, with a minimum 6MB amplified region on 8q22.1-q22.2. The 8q22 amplification was verified by FISH analysis using a BAC probe to this region. examination of gene expression array data highlighted several genes in this region with positive correlation between copy number gain and increased gene expression including, but not limited to, Cyclin E2, Metadherin, and LAPTM4B. By analysis of gene expression array dataset of 121 cases, we find the 8q22 amplification/gene over-expression is present in 10% of unselected breast cancers, and is particularly associated with high tumor grade (11/69 grade III, 16% vs. 1/52 grade I or II, 2%; p= 0.012) and estrogen receptor negativity (10/51 ER-, 20% vs.2/70 ER+, 3%; p= 0.0038). Cases with 8q22 amplification were significantly more likely to have distant metastatic recurrence within 24 mo. than cases without the 8q22 amplification (7/13, 54% vs.8/108, 7%; p= 0.0001). The association with meta