High‐resolution genomic and expression analyses of copy number alterations in breast tumors

• DOI: 10.1002/gcc.20558
• Publication Date: 2008-03-11T18:37:24Z
• Authors: Peter M. Haverty; Jane Fridlyand; Li Li; Gad Getz; Rameen Beroukhim; Scott Lohr; Thomas D. Wu; Guy Cavet; Zemin Zhang; John Chant
• Keywords: 0301 basic medicine; Carcinoma, Ductal, Breast; DNA Mutational Analysis; Gene Amplification; Gene Dosage; Breast Neoplasms; DNA, Neoplasm; Oncogenes; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Humans; Female; Genes, Tumor Suppressor; Gene Deletion; Oligonucleotide Array Sequence Analysis

AbstractAnalysis of recurrent DNA amplification can lead to the identification of cancer driver genes, but this process is often hampered by the low resolution of existing copy number analysis platforms. Fifty‐one breast tumors were profiled for copy number alterations (CNAs) with the high‐resolution Affymetrix 500K SNP array. These tumors were also expression‐profiled and surveyed for mutations in selected genes commonly mutated in breast cancer (TP53,CDKN2A,ERBB2,KRAS,PIK3CA,PTEN). Combined analysis of common CNAs and mutations revealed putative associations between features. Analysis of both the prevalence and amplitude of CNAs defined regions of recurrent alteration. Compared with previous array comparative genomic hybridization studies, our analysis provided boundaries for frequently altered regions that were approximately one‐fourth the size, greatly reducing the number of potential alteration‐driving genes. Expression data from matched tumor samples were used to further interrogate the functional relevance of genes located in recurrent amplicons. Although our data support the importance of some known driver genes such asERBB2, refined amplicon boundaries at other locations, such as 8p11‐12 and 11q13.5‐q14.2, greatly reduce the number of potential driver genes and indicate alternatives to commonly suggested driver genes in some cases. For example, the previously reported recurrent amplification at 17q23.2 is reduced to a 249 kb minimal region containing the putative driverRPS6KB1as well as the putative oncogenic microRNAmir‐21. High‐resolution copy number analysis provides refined insight into many breast cancer amplicons and their relationships to gene expression, point mutations and breast cancer subtype classifications. This article contains Supplementary Material available athttp://www.interscience.wiley.com/jpages/1045‐2257/suppmat. © 2008 Wiley‐Liss, Inc.