scholarly journals EPEN-27. CDKN2A DELETION IN SUPRATENTORIAL EPENDYMOMA WITH RELA ALTERATION INDICATES A DISMAL PROGNOSIS – A RETROSPECTIVE ANALYSIS OF THE HIT EPENDYMOMA TRIAL COHORT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii313-iii313
Author(s):  
Stephanie T Jünger ◽  
Felipe Andreiuolo ◽  
Martin Mynarek ◽  
Evelyn Dörner ◽  
Anja zur Mühlen ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mitotic Activity ◽  
Cell Morphology ◽  
Copy Number ◽  
Pediatric Patients ◽  
Clear Cell ◽  
Homozygous Deletion ◽  
P16 Protein ◽  
High Mitotic Activity ◽  
Cdkn2a Deletion

Abstract INTRODUCTION Since supratentorial RELA-fusion positive ependymomas are considered a biologically distinct disease, we aimed to identify histological and genetic predictors of outcome in a defined cohort of pediatric patients. MATERIALS AND METHODS We analyzed 54 RELA ependymomas in pediatric patients treated according to HIT2000-E protocols. All cases underwent central neuropathological review. Genome-wide copy number alterations were assessed by molecular inversion probe or SNP array. RELA alterations were detected by RT-PCR, sequencing and assessment of nuclear p65-RelA protein. Copy number alteration of the CDKN2A (cyclin dependent kinase inhibitor 2A) locus and concordant p16 protein expression were analyzed. RESULTS Fifty-two tumors were classified as WHO-grade III (96.3%) with high mitotic activity in 39 cases (72.2%), vascular proliferation in 47 (87.0%), necrosis in 43 (79.6%) and clear cell morphology in 19 (35.2%). All tumors harbored RELA alterations. Homo- or heterozygous CDKN2A deletions were detected in 9 (16.7%) and 14 (25.9%) cases, respectively. p16 protein expression was lost in all cases with homozygous deletion. Median follow-up was 5.4 years with 5-years EFS and OS of 74.1% and 92.6%. In Kaplan-Meier analysis high mitotic activity was related to shorter EFS (p=0.016) and clear cell morphology to longer OS (p=0.039); CDKN2A deletion was associated with shorter OS (homozygous deletion, p=0.009; homo-or heterozygous deletion, p=0.034). No correlation between CDKN2A deletion and high mitotic activity was found but with higher age at diagnosis (p=0.001). CONCLUSION Deletion of CDKN2A occurred in 42.6% of supratentorial ependymomas with RELA alteration and represented a genetic predictor of worse overall outcome in pediatric patients.

Evaluation of p16 protein expression and CDKN2A deletion in conventional and fibrosarcomatous dermatofibrosarcoma protuberans

Pathology ◽  
2018 ◽  
Vol 50 (4) ◽  
pp. 474-475 ◽  
Author(s):  
Andrew Siref ◽  
Vatsal Patel ◽  
John D. Reith ◽  
Bonnie L. Balzer ◽  
Wonwoo Shon
Keyword(s):  
Protein Expression ◽  
Dermatofibrosarcoma Protuberans ◽  
P16 Protein ◽  
Cdkn2a Deletion

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.

scholarly journals Correlations between p16 Protein Expression and Genomic Profile in Mantle Cell Lymphoma and Impact on Survival, a Lyma-Genomic Project Conducted on Behalf of the Lysa Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2846-2846
Author(s):  
Yannick LE Bris ◽  
Danielle Canioni ◽  
Barbara Burroni ◽  
Anne Moreau ◽  
Benoit Tessoulin ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mantle Cell Lymphoma ◽  
Copy Number ◽  
Research Funding ◽  
Cell Lymphoma ◽  
P53 Protein ◽  
P53 Overexpression ◽  
P16ink4a Expression ◽  
Mantle Cell ◽  
Cdkn2a Deletion

Abstract Introduction Mantle cell lymphoma (MCL) is a heterogeneous disease with a complex genetic landscape. Among genetic anomalies, alterations of several tumor suppressor genes are prognostic markers. The p16INK4A protein, encoded by CDKN2A, is known to bind and inactivate the cyclin-dependent kinase CDK4/6, blocking the phosphorylation of the retinoblastoma protein Rb and inducing cell cycle arrest. The p16INK4A and p53 overexpression are associated with poor prognosis (D. Canioni et al. ASH 2017). Here we compared the expression levels of p16INK4A and p53 in immunohistochemistry (IHC) with the profile (copy number alterations, CNAs) of the genes encoding these proteins, on diagnosis MCL lymph nodes. Results were correlated with patients' outcome in order to identify prognostic biomarkers in MCL. Methods All samples (n=86) used in the present work were collected from untreated MCL patients enrolled in the LyMa trial (S. Le Gouill et al. NEJM 2017). IHC was performed for p16INK4A and p53 protein expression assessment on formalin fixed paraffin embedded diagnostic Tissue Micro Arrays. Cut-offs for over expression of p16INK4A and p53 proteins were 10% and 30% respectively (D. Canioni et al. ASH 2016). A pan-genomic copy number analysis was performed with the Oncoscan® SNP-array on DNA extracted from the same samples. Data were compared using chi² tests. Progression free survival (PFS) and overall survival (OS) were studied by log rank test and Kaplan Meier representation. Results Patients characteristics (n=86) were similar to the whole LyMa trial population (n= 299) regarding age, gender, Ann Arbor stage and blastoid morphology. Overexpression of p16INK4A was observed in 11% of the patients and was not associated with any deletion of CDKN2A. There was a significant association between p16INK4A protein overexpression and TP53 mono-allelic deletion (38% vs 7%; p<0.05). CNAs of the CDK4 and RB genes were not associated with p16INK4A protein expression level. Mono and bi-allelic losses of CDKN2A were observed in 19% and 8% of the cases respectively. As expected, bi-allelic loss of CDKN2A (n=7) was associated with a weak p16INK4A expression <5% (p<10-6). However, a similar p16INK4A expression was observed between patients with mono-allelic losses (n=16) and those retaining both copies of CDKN2A (n=65) (p=NS). The 3q26 (BCL6) gains (n=32) were also associated with a higher p16 expression (70% vs 33%; p=0.04). Overexpression of the p53 protein (55% of the patients) was negatively associated with the 15q11 deletion (4% versus 29%; p=0.005) and positively associated with the 1q23 deletion (22% vs 4%; p=0.04) but not with the 17p13 (TP53) deletion. Regarding patients' outcome, early relapse or progression (<1y) were associated with TP53 deletion (HR=5.8; 95%CI 1.0-33.4), CDKN2A deletion (HR=4.0; 95%CI 0.8-22.5), p53 overexpression (HR=7.6; 95%CI 0.9-354) and p16INK4A overexpression (HR=9.0; 95%CI 1.4-56.9) (p<0.05). Overexpression of p16INK4A (p= 0.009) and TP53 deletion (p=0.05) were both found to be associated with a shorter OS in univariate analysis. Only p16INK4A overexpression had an independent impact on OS after multivariate analysis including TP53 and CDKN2A deletion, p16 and p53 expression, (p=0.03; HR=4.3; CI95%: 1.2-15.0). Patients with p16INK4A overexpression or double CDKN2A deletion displayed a worse PFS (p=0.05; HR= 2.7; 95%CI 0.8-8.6) and OS (p=0.02; HR=2.7; 95%CI 0.8-8.6) (Figure). Conclusion This work shows that p16INK4A protein expression is correlated with TP53 deletion and BCL6 gain. The p16INK4A overexpression or CDKN2A double deletion could be used as prognostic biomarkers at diagnosis to predict poor response in first line treatment. Figure. Figure. Disclosures Hermine: Hybrigenics: Research Funding; Erythec: Research Funding; Novartis: Research Funding; Celgene Corporation: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding.

1651: Molecular Prognostic Modeling Using Protein Expression Profile in Clear Cell Renal Carcinoma

2004 ◽  
Vol 171 (4S) ◽  
pp. 436-436 ◽  
Author(s):  
Hyung L. Kim ◽  
David B. Seligson ◽  
Nicolette Janzen ◽  
Matthew H. Bui ◽  
Robert A. Figlin ◽  
...  
Keyword(s):  
Protein Expression ◽  
Expression Profile ◽  
Renal Carcinoma ◽  
Clear Cell ◽  
Clear Cell Renal Carcinoma ◽  
Protein Expression Profile ◽  
Cell Renal Carcinoma ◽  
Prognostic Modeling

scholarly journals Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wuping Yang ◽  
Kenan Zhang ◽  
Lei Li ◽  
Yawei Xu ◽  
Kaifang Ma ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Renal Cell Carcinoma ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Clinical Significance ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Level ◽  
Cell Renal Cell Carcinoma ◽  
Qrt Pcr

Abstract Background Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear. Methods Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level. Results ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression. Conclusions This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.

scholarly journals Insulin-like Growth Factor Receptor 1 (IGF1R) Gene Copy Number Is Associated With Survival in Operable Non–Small-Cell Lung Cancer: A Comparison Between IGF1R Fluorescent In Situ Hybridization, Protein Expression, and mRNA Expression

2010 ◽  
Vol 28 (13) ◽  
pp. 2174-2180 ◽  
Author(s):  
Rafal Dziadziuszko ◽  
Daniel T. Merrick ◽  
Samir E. Witta ◽  
Adelita D. Mendoza ◽  
Barbara Szostakiewicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Protein Expression ◽  
Squamous Cell ◽  
Copy Number ◽  
Gene Copy Number ◽  
Growth Factor Receptor ◽  
Gene Copy ◽  
Cell Versus

PurposeThe purpose of this study was to characterize insulin-like growth factor-1 receptor (IGF1R) protein expression, mRNA expression, and gene copy number in surgically resected non–small-cell lung cancers (NSCLC) in relation to epidermal growth factor receptor (EGFR) protein expression, patient characteristics, and prognosis.Patients and MethodsOne hundred eighty-nine patients with NSCLC who underwent curative pulmonary resection were studied (median follow-up, 5.3 years). IGF1R protein expression was evaluated by immunohistochemistry (IHC) with two anti-IGF1R antibodies (n = 179). EGFR protein expression was assessed with PharmDx kit. IGF1R gene expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) from 114 corresponding fresh-frozen samples. IGF1R gene copy number was assessed by fluorescent in situ hybridization using customized probes (n = 181).ResultsIGF1R IHC score was higher in squamous cell carcinomas versus other histologies (P < .001) and associated with stage (P = .03) but not survival (P = .46). IGF1R and EGFR protein expression showed significant correlation (r = 0.30; P < .001). IGF1R gene expression by qRT-PCR was higher in squamous cell versus other histologies (P = .006) and did not associate with other clinical features nor survival (P = .73). Employing criteria previously established for EGFR copy number, patients with IGF1R amplification/high polysomy (n = 48; 27%) had 3-year survival of 58%, patients with low polysomy (n = 87; 48%) had 3-year survival of 47% and patients with trisomy/disomy (n = 46; 25%) had 3-year survival of 35%, respectively (P = .024). Prognostic value of high IGF1R gene copy number was confirmed in multivariate analysis.ConclusionIGF1R protein expression is higher in squamous cell versus other histologies and correlates with EGFR expression. IGF1R protein and gene expression does not associate with survival, whereas high IGF1R gene copy number harbors positive prognostic value.

Solitary Fibrous Tumor of the Prostate

2001 ◽  
Vol 125 (2) ◽  
pp. 274-277
Author(s):  
Michael R. Pins ◽  
Steven C. Campbell ◽  
William B. Laskin ◽  
Karen Steinbronn ◽  
Daniel P. Dalton
Keyword(s):  
Mitotic Activity ◽  
Solitary Fibrous Tumor ◽  
Growth Pattern ◽  
Spindle Cell ◽  
Cytologic Atypia ◽  
Diffuse Growth ◽  
High Mitotic Activity ◽  
Spindle Cell Tumors ◽  
Fibrous Tumor

Abstract We report 2 cases of solitary fibrous tumor of the prostate. Histologically, both tumors demonstrated a multipatterned architecture with varying degrees of collagenization and hemangiopericytoma-like foci, and both were composed of CD34-immunopositive spindled cells that insinuated themselves between strips of collagen. The tumor in case 1 was well circumscribed and showed minimal mitotic activity or pleomorphism, whereas the tumor in case 2 was more cellular, less collagenous, had a more diffuse growth pattern, and exhibited cytologic atypia and high mitotic activity. Prostatic solitary fibrous tumor must be distinguished from other spindle cell tumors reported to occur in the prostate. To our knowledge, these cases represent only the fifth and sixth reported cases of prostatic solitary fibrous tumor.

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