The pancreatic adenocarcinoma genome harbors multiple amplifications and deletions, pointing to the existence of numerous oncogenes and tumor suppressor genes driving the genesis and progression of this lethal cancer. Here, array comparative genomic hybridization on a cDNA microarray platform and informatics tools have been used to define the copy number alterations in a panel of 24 pancreatic adenocarcinoma cell lines and 13 primary tumor specimens. This high-resolution genomic analysis has identified all known regional gains and losses as well as many previously uncharacterized highly recurrent copy number alterations. A systematic prioritization scheme has selected 64 focal minimal common regions (MCRs) of recurrent copy number change. These MCRs possess a median size of 2.7 megabases (Mb), with 21 (33%) MCRs spanning 1 Mb or less (median of 0.33 Mb) and possessing an average of 15 annotated genes. Furthermore, complementary expression profile analysis of a significant fraction of the genes residing within these 64 prioritized MCRs has enabled the identification of a subset of candidates with statistically significant association between gene dosage and mRNA expression. Thus, the integration of DNA and RNA profiles provides a highly productive entry point for the discovery of genes involved in the pathogenesis of pancreatic adenocarcinoma.array comparative genomic hybridization ͉ expression profile P ancreatic adenocarcinoma is among the most lethal of human cancers, typically presenting as advanced inoperable disease with a rapidly progressive clinical course characterized by intense resistance to all therapeutic modalities. Significant effort has been directed toward charting the molecular genetic events in this cancer with the goals of improving early detection and providing new therapeutic targets. The current compendium of validated genetic mutations has provided a multistep model for the initiation and progression of pancreatic adenocarcinoma that is typified by the near-universal and early occurrence of activating mutations in KRAS and frequent later-stage inactivation of p16 INK4A , p53, and͞or SMAD4 (1).These stereotypic genetic lesions take place against the backdrop of a high level of genomic instability that is evident in the earliest stages of the disease (2-4). Indeed, a hallmark genomic feature of this cancer is the presence of numerous complex chromosome structural aberrations, including nonreciprocal translocations, amplifications, and deletions. To date, karyotype analyses (5-10), chromosomal comparative genomic hybridization (CGH) (11-17), and loss of heterozygosity mapping (18-20) have identified recurrent regions of copy number change or allelic loss. In particular, frequent gains have been mapped to 3q, 5p, 7p, 8q, 11q, 12p, 17q, and 20q and losses to 3p, 4q, 6q, 8p, 9p, 10q, 12q, 13q, 17p, 18q, 21q, and 22q. In some instances, validated oncogenes and tumor suppressor genes residing within these loci have been identified, including MYC (8q24), p16 INK4A (9p21), p53 (17p13), SMAD4 (18q21...

Glioblastoma (GBM) is an astrocytic brain tumor characterized by an aggressive clinical course and intense resistance to all therapeutic modalities. Here, we report the identification and functional characterization of Bcl2L12 (Bcl2-like-12) that is robustly expressed in nearly all human primary GBMs examined. Enforced Bcl2L12 expression confers marked apoptosis resistance in primary cortical astrocytes, and, conversely, its RNA interference (RNAi)-mediated knockdown sensitizes human glioma cell lines toward apoptosis in vitro and impairs tumor growth with increased intratumoral apoptosis in vivo. Mechanistically, Bcl2L12 expression does not affect cytochrome c release or apoptosome-driven caspase-9 activation, but instead inhibits post-mitochondrial apoptosis signaling at the level of effector caspase activation. One of Bcl2L12's mechanisms of action stems from its ability to interact with and neutralize caspase-7. Notably, while enforced Bcl2L12 expression inhibits apoptosis, it also engenders a pronecrotic state, which mirrors the cellular phenotype elicited by genetic or pharmacologic inhibition of post-mitochondrial apoptosis molecules. Thus, Bcl2L12 contributes to the classical tumor biological features of GBM such as intense apoptosis resistance and florid necrosis, and may provide a target for enhanced therapeutic responsiveness of this lethal cancer. Supplemental material is available at http://www.genesdev.org.