Copy number analysis to identify tumor suppressor genes associated with enzalutamide (Enza) resistance and poor prognosis in metastatic castration-resistant prostate cancer (mCRPC) patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5011-5011
Author(s):  
Xiangnan Guan ◽  
Duan-Chen Sun ◽  
Eric Lu ◽  
Joshua A. Urrutia ◽  
Robert Evan Reiter ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Copy Number ◽  
Poor Prognosis ◽  
Molecular Mechanisms ◽  
Prognostic Significance ◽  
Copy Number Loss ◽  
Castration Resistant Prostate Cancer ◽  
Suppressor Genes

5011 Background: Although enza prolongs life in mCRPC pts, the development of drug resistance and subsequent disease progression is nearly universal. Seeking to clarify molecular mechanisms that underlie enza resistance, we analyzed whole genome sequencing (WGS) and RNA sequencing (seq) of tumors obtained from patients with enza-naive or -resistant mCRPC. Methods: One hundred and one men with mCRPC who underwent image-guided biopsy and subsequent WGS were included (n = 64 with enza-naive and n = 37 with enza-resistant mCRPC). The differential copy number alteration (CNA) events enriched in enza-resistant vs. naïve samples were determined, and the prognostic significance of differential CNAs was assessed. RNA-seq data were evaluated to confirm that CNAs correlated with changes in gene expression of relevant loci and to identify potentially druggable targets selectively activated in tumors with specific CNAs. Results: Copy number loss was more common than gain in enza-resistant tumors. Specifically, we identified 123 protein-coding genes that were more commonly lost in enza-resistant samples—eight of which were previously described tumor suppressor genes. There was a strong concordance of copy number loss and reduced mRNA expression of these genes. We identified one gene from this list of eight genes whose copy number loss was associated with poor overall survival (median overall survival from date of CRPC was 19.1 months in tumors with gene loss vs. 42.0 months in intact tumors, hazard ratio 3.8 [1.46–9.8], log-rank p = 0.003). Finally, Master Regulator analysis determined that tumors with copy number loss of this poor prognosis gene had activation of several potentially targetable factors, including the kinases Akt and PLK1. Conclusions: Copy number loss of specific tumor suppressor genes is associated with enza resistance in mCRPC patients. Previously unappreciated molecular subsets of enza-resistant CRPC were identified, including one subset associated with poor clinical outcome.

Prognostic Significance of Promoter Methylation of Multiple Genes in Germinal Center Hyperplasia (GCH) and Lymphomas of Germinal Center Origin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3950-3950
Author(s):  
Jose M Paz-Carreira ◽  
Arantxa Garcia-Rivero ◽  
Raquel Losada ◽  
Jose C Mendez ◽  
Manuel Albors ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Suppressor ◽  
Promoter Methylation ◽  
Germinal Center ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Prognostic Significance ◽  
Promoter Hypermethylation ◽  
Aberrant Methylation ◽  
Suppressor Genes

Abstract Abstract 3950 Poster Board III-886 INTRODUCTION Germinal centers (GC) are unique sites in peripheral lymphoid tissue where clonal selection of B cells takes place. GC have been known to be a major source of B-cell lymphomas, including follicular (FL) and diffuse large cell (DLCL). DNA methylation of tumor-suppressor genes is a mechanism of gene silencing involved in the pathogenesis of FL and DLCBLs. Much less is known about the role of methylation in GCH. We determined the methylation status of 5 tumor-suppressor genes in 50 patients with lymphoma of GC origin and 50 GCH in order to find any differences between the pathological and the physiological state as well as its prognostic significance. MATERIAL AND METHODS. Genomic DNA extracted from paraffin-embedded samples of 30 DLCL, 20 FL and 50 GCH were analyzed by methylation-specific polymerase chain-reaction to determine promoter hypermethylation of DAP-k, SHP1, Rarβ, p14 and MGMT. Methylation status of each gene was correlated with clinicopathological status. Overall survival (OS) rates were calculated by the Kaplan-Meier method and differences were compared with the log-rank test. RESULTS. Median age was 65 in patients with lymphoma and 19 for GCH. Sex distribution was similar in all entities (60% females). Both lymphoma groups were balanced with respect to the presence of B symptoms, bulky disease, bone marrow infiltration, advanced stage and high IPI/FLIPI. DAP-k promoter methylation was present in more patients with lymphoma (89 and 87%) than with BFH (37%) p<0.0001. RaRB was methylated with higher frequency in FL (60%) than in DLCL (23%) and FH (12%) p<0.0001. SHP1 was more frequently methylated in FL (67%) and GCH (58%) than in DLCL (20%) p=0.01. Promoter hypermethylation of SHP1 was significantly associated with longer OS (p=0.021). Methylation of RaRB, p14 and MGMT were associated with shortened OS but the differences were not statistically significant. Those patients with DAPK methylated live longer but not significantly. In multivariate analysis hypermethylation of none of the genes studied remained an independent prognostic factor. CONCLUSIONS. Inactivation of DAP-K, and Rarβ is present in GC lymphomas with significantly higher frequency than in BFH. Thus, it may have pathogenic significance. SHP1 is methylated more frequently if FL and BFH than in DLCL, therefore that gene may be associated with aggressive disease. Methylation of DAP-k, SHP1, Rarβ, p14 and MGMT has no significant impact on overall survival. Markers for aberrant methylation may represent a promising way to monitor the onset and progression of malignancies but more extensive and prospective trials are needed to precisely define its role. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Carcinoma ex-pleomorphic adenoma of upper lip showing copy number loss of tumor suppressor genes

2013 ◽  
Vol 116 (1) ◽  
pp. 69-74 ◽  
Author(s):  
Fernanda Viviane Mariano ◽  
Daniel Rincon ◽  
Rogério Oliveira Gondak ◽  
Rogério Jorge ◽  
Márcio Ajudarte Lopes ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Pleomorphic Adenoma ◽  
Tumor Suppressor Genes ◽  
Copy Number ◽  
Carcinoma Ex Pleomorphic Adenoma ◽  
Copy Number Loss ◽  
Upper Lip ◽  
Suppressor Genes

CDKN2A copy number loss in HPV- and HPV+ head and neck cancer to indicate poor prognosis: An integrated genomic and clinical TCGA analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6060-6060 ◽  
Author(s):  
William S. Chen ◽  
Ranjit Bindra ◽  
Allen Mo ◽  
Thomas Hayman ◽  
Zain Husain ◽  
...  
Keyword(s):  
Overall Survival ◽  
Head And Neck Cancer ◽  
Protein Expression ◽  
Head And Neck ◽  
Copy Number ◽  
Poor Prognosis ◽  
Copy Number Loss ◽  
P16 Protein ◽  
Hpv Status ◽  
Disease Free

6060 Background: HPV infection is associated with high p16 expression and relatively good prognosis in head and neck cancers. Analysis of CDKN2A, the gene that encodes the p16 tumor suppressor protein, may further elucidate the association between HPV status and prognosis in head and neck squamous cell carcinomas (HNSCCs). We aimed to identify whether CDKN2A copy number loss was associated with poor survival in HNSCCs stratified by HPV status. Methods: We analyzed The Cancer Genome Atlas (TCGA) head and neck cancer data, integrating genomic measurements with clinical metadata. Patients 85 years old or younger with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Defining CDKN2A copy number loss as a relative log2 copy number ratio < −0.6, CDKN2A mRNA and p16 protein expression levels were compared to confirm significant differences in gene transcription and translation between the copy number loss and non-copy number loss patient groups. Overall survival (OS) and disease-free survival (DFS) were evaluated to characterize prognostic differences between genomic groups. Results: 397 patients negative for HPV (HPV−) and 91 patients positive for HPV (HPV+) HNSCC were identified. 139 HPV− patients and 9 HPV+ patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group in both HPV+ and HPV− disease. Median OS for HPV− patients with and without CDKN2A copy number loss was 21.8 months and 46.0 months (P = 0.02). Median DFS was 12.0 and 19.4 months respectively (P < 0.05). Median OS for HPV+ patients with and without CDKN2A copy number loss was 12.7 months and 57.4 months (P = 0.004) and median DFS was 7.0 and 36.6 months respectively (P = 0.02). Conclusions: CDKN2A copy number loss was associated with low CDKN2A mRNA and p16 protein expression, with poor prognosis in terms of disease-free and overall survival.

Molecular Pathogenesis of MDS

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 156-160 ◽  
Author(s):  
A. Thomas Look
Keyword(s):  
Tumor Suppressor ◽  
Progenitor Cells ◽  
Tumor Suppressors ◽  
Tumor Suppressor Genes ◽  
Molecular Mechanisms ◽  
Point Mutations ◽  
Suppressor Genes ◽  
Hematopoietic Stem ◽  
Chromosomal Deletions ◽  
Genes Encoding

Abstract Clonal disorders of hematopoiesis, such as myelodysplastic syndromes (MDS) and myeloproliferative diseases (MPD), affect both hematopoietic stem cells and progenitor cells within the erythroid, platelet and granulocytic lineages and can have devastating consequences in children and adults. The genetic features of these diseases often include clonal, nonrandom chromosomal deletions (e.g., 7q–, 5q–, 20q–, 6q–, 11q– and 13q–) that appear to inactivate tumor suppressor genes required for the normal development of myeloid cells (reviewed in Bench1 and Fenaux2). These putative tumor suppressors have proved to be much more difficult to identify than oncogenes activated by chromosomal translocations, the other major class of chromosomal lesions in MDS and MPD.3 Although MDS and MPD are almost certainly caused by mutations in stem/progenitor cells,4 the role of inactivated tumor suppressor genes in this process remains poorly understood. In a small portion of myeloid diseases, mutations have been identified in genes encoding factors known to be required for normal hematopoiesis, such as PU.1, RUNX1, CTNNA1 (α-catenin) and c/EBPα, and implicating these genes as tumor suppressors.5–7 Nonetheless, the identities of most deletion-associated tumor suppressors in these diseases remains elusive, despite complete sequencing of the human genome. The deleted regions detected by cytogenetic methods are generally very large, containing many hundreds of genes, thus making it hard to locate the critical affected gene or genes. It is also unclear whether dysfunctional myelopoiesis results from haploinsufficiency, associated with the deletion of one allele, or from homozygous inactivation due to additional point mutations or microdeletions of the retained wild-type allele. In general MDS have proved surprisingly resistant to conventional treatments. Targeted therapeutic advances in MDS will likely depend on a full comprehension of underlying molecular mechanisms, in particular the tumor suppressor genes lost through clonal, nonrandom chromosomal deletions, such as the 7q– and (del)5q.

ALV-J and REV synergistically activate a new oncogene of KIAA1199 via NF-κB and EGFR signaling regulated by miR-147

2018 ◽  
Author(s):  
Defang Zhou ◽  
Jingwen Xue ◽  
Pingping Zhuang ◽  
Xiyao Cui ◽  
Shuhai He ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Molecular Mechanism ◽  
Tumor Suppressor Genes ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Tumor Formation ◽  
Signalling Pathway ◽  
Suppressor Genes ◽  
Pathway Crosstalk ◽  
Pathogenic Effects

AbstractThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection of avian leucosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV), as two oncogenic retroviruses, showed synergistic pathogenic effects characterized by enhanced tumor initiation and progression. The molecular mechanism underlying synergistic effects of ALV-J and REV on the neoplasia remains unclear. Here, we found co-infection of ALV-J and REV enhanced the ability of virus infection, increased viral life cycle, maintained cell survival and enhanced tumor formation. We combined the high-throughput proteomic readout with a large-scale miRNA screening to identify which molecules are involved in the synergism. Our results revealed co-infection of ALV-J and REV activated a latent oncogene of KIAA1199 and inhibited the expression of tumor suppressor miR-147. Further, enhanced KIAA1199, down-regulated miR-147, activated NF-κB and EGFR were demonstrated in co-infected tissues and tumor. Mechanistically, we showed ALV-J and REV synergistically enhanced KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. Our results contributed to the understanding of the molecular mechanisms of viral synergistic tumorgenesis, which provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes.Author summaryThe tumorigenesis is the result of the accumulation of multiple oncogenes and tumor suppressor genes changes. Co-infection with ALV-J and REV showed synergistic pathogenic effects characterized by enhanced tumor progression, however, the molecular mechanism on the neoplasia remains unclear. Our results revealed co-infection of ALV-J and REV promotes tumorigenesis by both induction of a latent oncogene of KIAA1199 and suppression of the expression of tumor suppressor miR-147. Mechanistic studies revealed that ALV-J and REV synergistically enhance KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by targeting the 3’UTR region sequences of NF-κB p50 and KIAA1199. These results provided the evidence that suggested the synergistic actions of two retroviruses could result in activation of latent pro-oncogenes, indicating the potential preventive target and predictive factor for ALV-J and REV induced tumorigenesis.

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