A reason why the ERBB2 gene is amplified and not mutated in breast cancer

Alterations of receptor-type tyrosine kinases (RTK) are frequent in human cancers. They can result from translocation, mutation or amplification. The ERBB2 RTK is encoded by a gene that is amplified in about 20% breast cancers. The question is: why is this RTK specifically subjected to this type of alteration? We propose that ERBB2 gene amplification is used to overcome repression of its expression by sequence-specific transcription factors

Regional perturbation of gene transcription is associated with intrachromosomal rearrangements and gene fusion transcripts in high grade ovarian cancer.

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data

Loss, mutation and deregulation of L3MBTL4 in breast cancers

Many alterations are involved in mammary oncogenesis, including amplifications of oncogenes and losses of tumor suppressor genes (TSG). Losses may affect almost all chromosome arms and many TSGs remain to be identified.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Genome profiling of ERBB2-amplified breast cancers

<p>Abstract</p> <p>Background</p> <p>Around 20% of breast cancers (BC) show <it>ERBB2 </it>gene amplification and overexpression of the ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs, genomically and biologically heterogeneous, may help understand their behavior and design new therapeutic strategies.</p> <p>Methods</p> <p>We defined the high resolution genome and gene expression profiles of 54 <it>ERBB2</it>-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. Expression of ERBB2, phosphorylated ERBB2, EGFR, IGF1R and FOXA1 proteins was assessed by immunohistochemistry to evaluate the functional ERBB2 status and identify co-expressions.</p> <p>Results</p> <p>First, we identified the <it>ERBB2</it>-<it>C17orf37</it>-<it>GRB7 </it>genomic segment as the minimal common 17q12-q21 amplicon, and <it>CRKRS </it>and <it>IKZF3 </it>as the most frequent centromeric and telomeric amplicon borders, respectively. Second, GISTIC analysis identified 17 other genome regions affected by copy number aberration (CNA) (amplifications, gains, losses). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in <it>ERBB2</it>-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) <it>ERBB2</it>-amplified BCs were different. The WNT/β-catenin signaling pathway was involved in ER- <it>ERBB2</it>-amplified BCs, and <it>PVT1 </it>and <it>TRPS1 </it>were candidate oncogenes associated with ER+ <it>ERBB2</it>-amplified BCs. The size of the <it>ERBB2 </it>amplicon was different in inflammatory (IBC) and non-inflammatory BCs. <it>ERBB2</it>-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. IHC results showed (i) a linear relationship between <it>ERBB2 </it>gene amplification and its gene and protein expressions with a good correlation between ERBB2 expression and phosphorylation status; (ii) a potential signaling cross-talk between EGFR or IGF1R and ERBB2, which could influence response of <it>ERBB2</it>-positive BCs to inhibitors. FOXA1 was frequently coexpressed with ERBB2 but its expression did not impact on the outcome of patients with <it>ERBB2</it>-amplified tumors.</p> <p>Conclusion</p> <p>We have shown that ER+ and ER- <it>ERBB2</it>-amplified BCs are different, distinguished <it>ERBB2 </it>amplicons in IBC and non-IBC, and identified genomic features that may be useful in the design of alternative therapeutical strategies.</p

Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers

BACKGROUND: Oncogene amplification and overexpression occur in tumor cells. Amplification status may provide diagnostic and prognostic information and may lead to new treatment strategies. Chromosomal regions 8p12, 8q24, 11q13, 17q12 and 20q13 are recurrently amplified in breast cancers. METHODS: To assess the frequencies and clinical impact of amplifications, we analyzed 547 invasive breast tumors organized in a tissue microarray (TMA) by fluorescence in situ hybridization (FISH) and calculated correlations with histoclinical features and prognosis. BAC probes were designed for: (i) two 8p12 subregions centered on RAB11FIP1 and FGFR1 loci, respectively; (ii) 11q13 region centered on CCND1; (iii) 12p13 region spanning NOL1; and (iv) three 20q13 subregions centered on MYBL2, ZNF217 and AURKA, respectively. Regions 8q24 and 17q12 were analyzed with MYC and ERBB2 commercial probes, respectively. RESULTS: We observed amplification of 8p12 (amplified at RAB11FIP1 and/or FGFR1) in 22.8%, 8q24 in 6.1%, 11q13 in 19.6%, 12p13 in 4.1%, 17q12 in 9.9%, 20q13(Z )(amplified at ZNF217 only) in 9.9%, and 20q13(Co )(co-amplification of two or three 20q13 loci) in 8.5% of cases. The 8q24, 12p13, and 17q12 amplifications were correlated with high grade. The most frequent single amplifications were 8p12 (9.8%), 8q24 (3.3%) and 12p13 (3.3%), 20q13(Z )and 20q13(Co )(1.6%) regions. The 17q12 and 11q13 regions were never found amplified alone. The most frequent co-amplification was 8p12/11q13. Amplifications of 8p12 and 17q12 were associated with poor outcome. Amplification of 12p13 was associated with basal molecular subtype. CONCLUSION: Our results establish the frequencies, prognostic impacts and subtype associations of various amplifications and co-amplifications in breast cancers

Génomique fonctionnelle des cancers du sein

Les technologies à haut débit dressent un portrait détaillé et permettent de cerner les différents aspects du cancer. L analyse du transcriptome a permis d établir une taxonomie des cancers du sein en 5 sous-types. Le travail réalisé durant cette thèse a analysé deux sous-types moléculaires associés au mauvais pronostic : ERBB2 et Luminal B. Nous avons observé une hétérogénéité génomique des tumeurs ERBB2 réflétant les variations d expression des récepteurs hormonaux. L analyse intégrée génome-transcriptome a identifié les gènes cibles PVT1 et TRSP1 dans les tumeurs exprimant le récepteur aux oestrogènes (RE). Au contraire, les tumeurs n exprimant pas RE expriment des gènes associés à la voie Wnt/ß-Caténine, une autre piste thérapeutique intéressante. L analyse génomique des tumeurs de sous-type luminal B a indentifié l amplification de la région 8p12 comme un événement caractérisant ce soustype. Cette amplification cible plusieurs oncogènes potentiels (RCP, ZNF703, PPAPDC1B ). La surexpression de ZNF703 induit une augmentation des cellules souches cancéreuses dans la lignée MCF7. ZNF703 est localisé au noyau avec les protéines SMRT et PHB-2. Enfin, la surexpression de ZNF703 provoque une diminution de l activité transcriptionnelle de RE. Ceci rejoint d autres études ayant montré que ZNF703 est un répresseur transcriptionnel dépendant des HDAC. Ainsi, Les inhibiteurs des HDAC pourraient être une thérapie pour le traitement des tumeurs luminales B. Ces résultats montrent l intérêt d associer plusieurs angles de vue (transcriptomique et génomique), permettant ainsi de développer des stratégies thérapeutiques adaptées aux sous-types moléculaires.High Troughput technologies dissect several aspects of cancer. Transcriptomic analyses have defined five breast cancer molecular subtypes. During my phD I analysed two molecular subtypes associated with agressive phénotype and bad prognosis : ERBB2 and Luminal B subtypes. Firstly, I caracterized genomic heterogenity of ERBB2 amplified tumors which is related to estrogen receptor (ER) expression. Integrated genomictranscriptomic analyses identified PVT1 and TRSP1 as candidate oncogenes in ER positive ERBB2 amplified tumors. On the contrary, RE négative tumors express Wnt/ß-catenin related genes, an other interesting therapeutic strategy. Secondly, genomic analyses of Luminal B tumors point 8p12 amplification as the major genomic évents. This amplification target several known putative oncogenes (RCP, ZNF703, PPAPDC1B ). ZNF703 overexpression induced cancer stem cells increase in MCF7 cell line. ZNF703 co-localise with SMRT and PHB-2 in the nucleus. Finally, ZNF703 overexpression reduce RE transcriptionnal activity. These results are concordant with others showing that ZNF703 as un HDAC dependant transcriptionnal répression activity. Thus, HDAC inhibitors could be a interesting therapeutic strategy for luminal B tumors. Together, these studies show importance of combination of several aspect to define potential therapeutic strategy associated with breast cancer molecular subtypes.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

ZNF703: a novel oncogene involved in breast cancer

International audienceno abstrac

CaPSID: A bioinformatics platform for computational pathogen sequence identification in human genomes and transcriptomes

Abstract Background It is now well established that nearly 20% of human cancers are caused by infectious agents, and the list of human oncogenic pathogens will grow in the future for a variety of cancer types. Whole tumor transcriptome and genome sequencing by next-generation sequencing technologies presents an unparalleled opportunity for pathogen detection and discovery in human tissues but requires development of new genome-wide bioinformatics tools. Results Here we present CaPSID (Computational Pathogen Sequence IDentification), a comprehensive bioinformatics platform for identifying, querying and visualizing both exogenous and endogenous pathogen nucleotide sequences in tumor genomes and transcriptomes. CaPSID includes a scalable, high performance database for data storage and a web application that integrates the genome browser JBrowse. CaPSID also provides useful metrics for sequence analysis of pre-aligned BAM files, such as gene and genome coverage, and is optimized to run efficiently on multiprocessor computers with low memory usage. Conclusions To demonstrate the usefulness and efficiency of CaPSID, we carried out a comprehensive analysis of both a simulated dataset and transcriptome samples from ovarian cancer. CaPSID correctly identified all of the human and pathogen sequences in the simulated dataset, while in the ovarian dataset CaPSID’s predictions were successfully validated in vitro

Regional perturbation of gene transcription is associated with intrachromosomal rearrangements and gene fusion transcripts in high grade ovarian cancer.

Genomic rearrangements are a hallmark of cancer biology and progression, allowing cells to rapidly transform through alterations in regulatory structures, changes in expression patterns, reprogramming of signaling pathways, and creation of novel transcripts via gene fusion events. Though functional gene fusions encoding oncogenic proteins are the most dramatic outcomes of genomic rearrangements, we investigated the relationship between rearrangements evidenced by fusion transcripts and local expression changes in&nbsp;cancer using transcriptome data alone. 9,953 gene fusion predictions from 418 primary serious ovarian cancer tumors were analyzed, identifying depletions of gene fusion breakpoints within coding regions of fused genes as well as an N-terminal enrichment of breakpoints within fused genes. We identified 48 genes with significant fusion-associated upregulation and furthermore demonstrate that significant regional overexpression of intact genes in patient transcriptomes occurs within 1 megabase of 78 novel gene fusions that function as central markers of these regions. We reveal that cancer transcriptomes select for gene fusions that preserve protein and protein domain coding potential. The association of gene fusion transcripts with neighboring gene overexpression supports rearrangements as mechanism through which cancer cells remodel their transcriptomes and identifies a new way to utilize gene fusions as indicators of regional expression changes in diseased cells with only transcriptomic data