Global search for chromosomal abnormalities in infiltrating ductal carcinoma of the breast using array-comparative genomic hybridization

Abstract

Array-comparative genomic hybridization (a-CGH) is a molecular cytogenetic technique for detection of multiple chromosomal abnormalities in genomic DNA samples. Using an a-CGH with 287 probes, we examined 14 cases of breast infiltrating ductal carcinoma (IDCA) that had previously been classified by fluorescent in situ hybridization (FISH) as either human epidermal growth factor receptor-2 positive (HER2+) or HER2- and analyzed the data by hierarchical, K-means, and principal component analyses. The aim of the study was to identify the genetic abnormalities that are present in breast IDCAs and determine if the global status of 287 cytogenetic locations could be used as a more objective method for breast IDCA classification. Concordance between FISH and a-CGH at the HER2 locus was 78.6% (11/14). In general, a-CGH detected more abnormalities in HER2+ cases. In HER 2+ cases, chromosomes 1, 2, 3, 7, 9, 17, and 20 had more regions that showed statistically significant (P < or = 0.01) changes in DNA copy number. Among all the aberrant cytogenetic locations detected, 20q13, 7p12.3 approximately p12.1, and 17q23.2 approximately q25.3, which contain among others, genes for TNFRSF6B, EGFR, and TK1 showed statistically significant gains (P < or = 0.01) in 83, 66.7, and 50% of the HER2+ IDCA cases, respectively. Chromosome location 8q24.12 approximately q24.13 was the only region that showed consistent amplification in approximately 50% of the HER2- cases. Unsupervised hierarchical and K-means cluster analyses and principal component analysis using the DNA copy number status of 287 cytogenetic locations or the 177 cytogenetic locations that showed statistically significant differences revealed a cluster consisting of mainly HER2- IDCA cases. Even though this study demonstrates the usefulness of a-CGH in the rapid identification of aberrant DNA regions in tumor samples, we conclude that an array-CGH with more than 287 probes will be needed for a more precise mapping of DNA aberrations at the global level.