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Peripheral T-cell lymphomas (PTCLs) are aggressive malignancies of mature T lym-phocytes with 5-year overall survival rates of only ∼ 35%. Improvement in outcomes has been stymied by poor understanding of the genetics and molecular pathogene-sis of PTCL, with a resulting paucity of molecular targets for therapy. We devel-oped bloinformatlc tools to Identify chro-mosomal rearrangements using genome-wide, next-generation sequencing analysis of mate-pair DNA libraries and applied these tools to 16 PTCL patient tissue samples and 6 PTCL cell lines. Thirteen recurrent abnormalities were identified, of which 5 involved p53-related genes (TP53, TP63, CDKN2A, WWOX, and ANKRD11). Among these abnormalities were novel TP63 rearrangements encod-ing fusion proteins homologous to ΔNp63, a dominant-negative p63 isoform that in-hibits the p53 pathway. TP63 rearrangements were seen in 11 (5.8%) of 190 PTCLs and were associated with infe-rior overall survival; they also were de-tected in 2 (1.2%) of 164 diffuse large B-cell lymphomas. As TP53mutations are rare in PTCL compared with other malig-nancies, our findings suggest that a con-stellation of alternate genetic abnormali-ties may contribute to disruption of p53-associated tumor suppressor function in PTCL. [ABSTRACT FROM AUTHOR]

Suppression of colon carcinogenesis by peroxisome proliferator-activated receptor (PPAR)-γ is likely due to some effect of PPAR-γ on normal colonic epithelial cells. However, our understanding of the effects of PPAR-γ in such cells is limited. We analyzed the abundance, distribution, and function of PPAR-γ in epithelial cells isolated from the murine proximal and distal colon. Marked differences in PPAR-γ abundance and distribution were observed, suggesting tissue-specific responses. Analysis of PPAR-γ effects on DNA synthesis, formation of preneoplastic lesions, and activation of MAPK signaling in proximal and distal colonic epithelial cells in vivo indicates that PPAR-γ regulates both tissue-specific and common responses within the proximal and distal colon. Three major functional cohorts of PPAR-γ target genes were identified by genomic profiling of isolated colonic epithelial cells: genes that are involved in metabolism, in signaling, and in cellular adhesion and motility. Two subsets of PPAR-γ target genes were differentially expressed in the proximal and distal epithelium. Proximal target genes were primarily involved in metabolic activities, whereas signal transduction, adhesion, and motility targets were more pronounced in the distal colon. Remarkably, those target genes that are differentially expressed in the proximal colon were all induced on activation of PPAR-γ, whereas all target genes that are preferentially expressed in the distal colon were repressed. Our data indicate that PPAR-γ exerts both common and tissue-specific effects in the colon and challenge the general conclusions that PPAR-γ is induced on differentiation of colonic epithelial cells and that this receptor stimulates differentiated function in epithelial cells throughout the colon. [ABSTRACT FROM AUTHOR]

Background: HER2 positive (HER2+) breast cancers involve chromosomal structural alterations that act as oncogenic driver events.Methods: We interrogated the genomic structure of 18 clinically-defined HER2+ breast tumors through integrated analysis of whole genome and transcriptome sequencing, coupled with clinical information.Results: ERBB2 overexpression in 15 of these tumors was associated with ERBB2 amplification due to chromoanasynthesis with six of them containing single events and the other nine exhibiting multiple events. Two of the more complex cases had adverse clinical outcomes. Chromosomes 8 was commonly involved in the same chromoanasynthesis with 17. In ten cases where chromosome 8 was involved we observed NRG1 fusions (two cases), NRG1 amplification (one case), FGFR1 amplification and ADAM32 or ADAM5 fusions. ERBB3 over-expression was associated with NRG1 fusions and EGFR and ERBB3 expressions were anti-correlated. Of the remaining three cases, one had a small duplication fully encompassing ERBB2 and was accompanied with a pathogenic mutation.Conclusion: Chromoanasynthesis involving chromosome 17 can lead to ERBB2 amplifications in HER2+ breast cancer. However, additional large genomic alterations contribute to a high level of genomic complexity, generating the hypothesis that worse outcome could be associated with multiple chromoanasynthetic events. [ABSTRACT FROM AUTHOR]