High-Resolution Genomic Profiling Reveals Association of Chromosomal Aberrations on 1q and 16p with Histologic and Genetic Subgroups of Invasive Breast Cancer

Abstract

Purpose: Invasive ductal carcinoma and invasive lobular carcinoma (ILC) represent the major histologic subtypes of invasive breast cancer. They differ with regard to presentation, metastatic spread, and epidemiologic features. To elucidate the genetic basis of these differences, we analyzed copy number imbalances that differentiate the histologic subtypes. Experimental Design: High-resolution genomic profiling of 40 invasive breast cancers using matrix-comparative genomic hybridization with an average resolution of 0.5 Mb was conducted on bacterial artificial chromosome microarrays. The data were subjected to classification and unsupervised hierarchical cluster analyses. Expression of candidate genes was analyzed in tumor samples. Results:The highest discriminating power was achieved when combining the aberration patterns of chromosome arms 1q and16p, which were significantly more often gained in ILC.These regions were further narrowed down to subregions 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. Located within the candidate gains on 1q are two genes, FMO2 and PTGS2, known to be overexpressed in ILC relative to invasive ductal carcinoma. Assessment of four candidate genes on 16p11.2 by real-time quantitative PCR revealed significant overexpression of FUS and ITGAX in ILC with 16p copy number gain. Unsupervised hierarchical cluster analysis identified three molecular subgroups that are characterized by different aberration patterns, in particular concerning gain of MYC (8q24) and the identified candidate regions on 1q24.2-25.1, 1q25.3-q31.3, and 16p11.2. These genetic subgroups differed with regard to histology, tumor grading, frequency of alterations, and estrogen receptor expression. Conclusions: Molecular profiling using bacterial artificial chromosome arrays identified DNA copy number imbalances on 1q and 16p as significant classifiers of histologic and molecular subgroups.Invasive ductal carcinoma (IDC) represents the predominant histologic subtype of breast cancer, constituting 40% to 75% of mammary carcinomas, whereas invasive lobular carcinoma (ILC) ranges second in frequency and accounts for 5% to 15% of cases. Besides differences in the histopathologic morphology, ILC and IDC differ with regard to clinical and epidemiologic features. There has been a steady and disproportionate increase in the incidence of ILC compared with IDC in women over 50 years during the last 20 years, which has been attributed to the increased use of hormone replacement therapy (1, 2). The molecular basis for this development as well as for differences in phenotype and clinical behavior between ILC and IDC is not yet understood.The molecular portrait of breast cancer was previously explored by a number of groups (3, 4), with two recent studies specifically comparing the gene expression profiles of IDC and ILC (5,6). Using unsupervised cluster analysis, Zhoa et al. (5) were able to subdivide ILC into a ''typical'' and a ''ductal-like'' subgroup. The typical ILC showed expression patterns similar to those of tumors that p...

Microarray-based comparative genomic hybridisation of breast cancer patients receiving neoadjuvant chemotherapy

“…This is expected, given that only breast carcinomas of histological grades 2 and 3 were present in the population and gains of 8q are rather frequent in grade 2 and 3 breast cancers (Buerger et al, 1999a, b;Roylance et al, 1999). The comparison between the genomic profiles obtained for ductal and lobular carcinomas were also in agreement with previous studies (Buerger et al, 1999b;Shelley Hwang et al, 2004;Reis-Filho et al, 2005a;Simpson et al, 2005;Stange et al, 2006): gain of 1q and deletions of 16q were the most prevalent changes in lobular carcinomas, whereas gain of 8q was significantly more frequent in grade 2 and 3 ductal carcinomas. However, we could define the smallest region of overlap of the deletions of 16q, which mapped to 16q21 -q22.1 and encompassed the region of the cadherin gene cluster, and the gain of 8q, which encompassed two regions 8q13.2 -q21.13 and 8q21.3 -qtel (Supplementary Table 3).…”

GAS5, a non-protein-coding RNA, controls apoptosis and is downregulated in breast cancer

“…Human GAS5 is encoded at 1q25, a locus that has been associated with abnormalities in several types of cancer, including melanoma (Smedley et al, 2000), prostate (Nupponen and Carpten, 2001) and breast (Stange et al, 2006;Morrison et al, 2007). Chromosomal rearrangements involving GAS5 have been reported recently in a human B-cell lymphoma (Nakamura et al, 2008) as well as in radiation-induced murine thymic lymphoma TL10 (Tsuji et al, 2003).…”

Protein phosphatase PP4 is overexpressed in human breast and lung tumors

“…Gain of DNA copy number within this locus has been reported in invasive breast tumors [11]. Therefore, we sought to determine the expression levels of PP4C and its associated proteins in human breast cancer cell lines by immunoblotting ( Figure 1A).…”