A 19-Gene Classifier Distinguishes Invasive Ductal and Classic Lobular Breast Carcinomas: Amplification of Chromosome 8q Characterizes Ductal While Estrogen-Related EGR-1 Characterizes Lobular Cancers
AC Culhane, A Nasir, DT Chen, C Venkataramu, J White, T Andersson, M Gruidl, G Bloom, R Rubio, BA Centeno, J Quackenbush, TJ Yeatman. Dana-Farber Cancer Institute, Boston, MA; Moffitt Cancer Center, Tampa, FL
Background: Invasive ductal and lobular breast carcinomas (IDCs and ILCs) have distinct clinico-pathologic profile, spread and response to chemotherapy. Cases of 'mixed ductal and lobular histology' (IDLCs) are not uncommon. Aim of this study was to decipher the molecular differences between histologically pure IDCs and ILCs and to develop a classifier that could further define the molecular basis of IDLCs.
Design: Fresh frozen IDC-ILC tissues (n=76) from 64 adult female patients with primary breast cancer were subjected to gene expression profiling on Affymetrix u133 plus 2.0 GeneChip arrays. Archival sections were reviewed to select pure ductal (N=49) and pure lobular, classic-subtype (N=27) (excluding basal-like IDCs) for analysis. Data were normalized using robust multichip averaging and post-processed with ComBat. A 115-fold nested cross validation was used to obtain an optimal support vector machine gene classifier that distinguished IDCs and ILCs. The performance of these classifiers had a median accuracy of 89%, with a 93% sensitivity and 78% specificity. The genes that appeared most frequently (>60%) across classifiers were selected to provide a robust gene signature.
Results: Based on supervised analysis of gene expression profiles of 'histologically pure' IDCs and ILCs a 23 probeset, 19-gene classifier was developed. Our classifier could accurately cluster pure IDCs and ILCs into 2 distinct molecular subgroups, except 2 of 27 ILCs clustered with the IDCs (ductal like ILCs). Prominent genes in this classifier included CDH1 and EGR1 which were down regulated and up-regulated in ILC respectively. In addition, 7/19 genes were expressed and predictive of IDC co-localized to chromosome 8q21-24 indicative of amplification of this locus. We successfully cross-validated our 19-gene classifier on publically available IDCs-ILC gene expression data sets.
Conclusions: Our 19-gene classifier supports that pure IDCs and ILCs are distinct molecular subtypes, and suggest they have distinct chromosomal abnormalities. Based on this classifier, the mixed ductal-lobular histology cases may be assigned to pure ductal cancers or may be truly mixed to merit further investigation.
Monday, March 9, 2009 1:00 PM
Poster Session II # 62, Monday Afternoon