Abstract
To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes. Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs. We show that basal-like and HER-2 tumors are characterized by "sawtooth" and "firestorm" genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification. Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.
Highlights
To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes
Our analysis provided insights into the pattern of aberrations and type of genomic instability in each molecular subgroup of grade 3 IDC-NSTand identified subgroup-specific recurrent amplifications harboring putative therapeutic targets.The amplicon17q23.2 was found in 20% and 8% of HER-2 and luminal cancers, respectively
Using RNA interference, we show that expression of PPM1D, one of the genes pertaining to this amplicon, is required for the survival of cells harboring 17q23.2 amplification, suggesting that PPM1D may constitute a therapeutic target for subsets of HER-2 and luminal cancers
Summary
To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes. Our analysis provided insights into the pattern of aberrations and type of genomic instability in each molecular subgroup of grade 3 IDC-NSTand identified subgroup-specific recurrent amplifications harboring putative therapeutic targets.The amplicon17q23.2 was found in 20% and 8% of HER-2 and luminal cancers, respectively. Recent comparative genomic hybridization (CGH) profiling studies have concentrated on defining genomic signatures for different breast cancer subgroups, with the aim of identifying common subtype-specific alterations (6 – 8) The results of these studies have suggested that basal-like tumors display complex genomic profiles and less frequently harbor amplifications [7], whereas luminal cancers more often show focal, high-level amplifications [7]. Concurrent presence of grade 1 and 3 areas in the same specimen is seen in
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