ccnd1 amplification
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2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21552-e21552
Author(s):  
Yu Chen ◽  
Liu Jun ◽  
Jing Lin ◽  
Xuefeng Wang ◽  
Xiao-bin Zheng ◽  
...  

e21552 Background: Melanoma is generally regarded as an immunogenic type of tumor that will respond to immune checkpoint therapy. However, melanoma tumors with CCND1 amplification respond poorly to checkpoint therapy. Further understanding of how CCND1 amplification modifies the effect of checkpoint therapy is necessary to design future clinical trials. Methods: We used the data from the Geneplus Institute (n = 302), The Cancer Genome Atlas (TCGA) (n = 367),and the Memorial Sloan Kettering Cancer Center (MSKCC) (n = 350) to identify the incidence of CCND1 amplification and the relationship between CCND1 amplification and survival in melanoma patients and explored molecular mechanisms. Results: The frequency of CCND1 amplification co-occurring with BRAF V600, NRAS, NF1, and KIT mutations was low in these three cohorts. Data from TCGA did not show a statistically significant correlation between CCND1 amplification levels and prognosis of melanoma patients irrespective of immune checkpoint inhibitors (ICIs). In contrast, we found opposite results using the MSKCC cohort where CCND1 amplification was an unfavorable prognostic factor for melanoma patients. This was especially true for patients received ICIs who were harboring a high tumor mutation burden (TMB). The TCGA data showed that CCND1 amplification were related to a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immunity boosting cells (follicular helper T-cells, naive B-cells, CD8+ T-cells). Furthermore, GSEA analysis from the TCGA database suggests that the signaling pathways such as oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and myc targets were differentially enriched in melanoma tumors with CCND1 amplification. Finally, we found that angiogenesis related molecules (HIF1A, VEGFA, VEGFR1, FGF2, FGFR1, FGFR4, HGF, PDGFA, PDGFRA, ANGPT1, and ANGPT2) were remarkable decreased in a CCND1 High Amplification group from the TCGA database. Conclusions: Melanoma with CCND1 amplificationis an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Taken together, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, targeting oxidative and lipid metabolism pathway may be effective and promising therapeutic strategies for melanoma patients harboring CCND1 amplification.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18010-e18010
Author(s):  
Shengjin Dou ◽  
Lin Zhang ◽  
Rongrong Li ◽  
Debin Sun ◽  
Lijia Wu ◽  
...  

e18010 Background: PDL-1 and tumor mutation burden are only useful to select a small portion of patients with head and neck squamous cell carcinoma for immunotherapy, more biomarkers are in an urgent need for the majority. Methods: Ninety-nine recurrent/metastatic patients were analyzed. PD-1 cohort including 78 patients; Non-PD-1(NPD-1) cohort including 28 patients received anti-EGFR antibody and harbored at least one of EGFR amplification/mutation, CCND1 amplification, FGF3/4/19 amplification, or CDKN2A/B mutations (including 7 patients received with both treatment). Patients were evaluated as no clinical benefit (NCB) if experiencing progressive disease or stable disease lasting < 6 months and were discontinued from immunotherapy within 3 months; otherwise, patients were evaluated as clinical benefit (CB). Tumor genomic DNA was isolated from formalin-fixed paraffin-embedded tissue for the targeted sequencing by a 769-gene panel. R package was used for fisher test to evaluate the variants. p < 0.05 was set as significant. Results: With median age of 57 years old, this study included 75 (75.8%) oral squamous cell carcinoma patients,17 (17.2%) oropharyngeal carcinoma patients and 7 others. Sixty-nine (69.7%) patients have PD-L1 CPS≥1, 27 (27.3%) patients have CPS<1 and 3 (3.0%) have an unknown CPS. The estimated 10-month progression-free survival of the NPD-1 cohort and PD-1cohort were 60.0%and 47.6% (p = 0.06) respectively. In NPD-1 cohort, 23 patients were evaluated as CB (78.3%), and in PD-1 cohort, 41 were evaluated as CB (52.6%) (p = 0.00682), indicating EGFR amplification/mutation, CCND1 amplification, FGF3/4/19 amplification, or CDKN2A/B mutations may be negatively correlated with immunotherapies. There were 14 patients who harbored either EGFR amplification or SNV mutation. Of the 8 patients who received NPD-1 treatment, 7 were CB (87.5%); Of the 8 patients who received PD-1 treatment, 2 were CB (25%) Statistically, the difference between NPD-1 treatment group and PD-1 treatment group was significant with a p value of 0.04056. There were 16 patients who harbored CCND1 amplification, or FGF3/4/19 amplification. Of the 12 patients who received NPD-1 treatment, 10 were evaluated as CB (83.3%); Of the 7 patients who received PD-1 treatment, 1 was evaluated as CB (14.3%). The difference was significant with a p value of 0.00627. There were 44 patients who obtained CDKN2A/B mutations. Of the 12 patients who received NPD-1 treatment, 11 acquired CB (81.7%); Of the 33 patients who received PD-1 treatment, 18 acquired CB (54.5%). The difference was significant with a p value of 0.03325. Conclusions: We for the first time showed that genetic-altered EGFR, FGF3/4/19, CCND1 and CDKN2A/B were negatively correlated with anti-PD-1 therapy in clinical cohorts retrospectively and these genetic aberrations may serve as novel immune-negative biomarkers for immunotherapies.


Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1314
Author(s):  
Lucía González-Ruiz ◽  
Miguel Ángel González-Moles ◽  
Isabel González-Ruiz ◽  
Isabel Ruiz-Ávila ◽  
Pablo Ramos-García

Our objective was to evaluate the prognostic and clinicopathological significance of cyclin D1 (CD1) overexpression/CCND1 amplification in melanomas. We searched studies published before September 2019 (PubMed, Embase, Web of Science, Scopus). We evaluated the quality of the studies included (QUIPS tool). The impact of CD1 overexpression/CCND1 amplification on overall survival and relevant clinicopathological characteristic were meta-analyzed. We performed heterogeneity, sensitivity, small-study effects, and subgroup analyses. Forty-one studies and 3451 patients met inclusion criteria. Qualitative evaluation demonstrated that not all studies were performed with the same rigor, finding the greatest risk of bias in the study confounding domain. Quantitative evaluation showed that immunohistochemical CD1 overexpression had a statistical association with Breslow thickness (p = 0.007; OR = 2.09,95% CI = 1.23–3.57), significantly higher frequency of CCND1/cyclin D1 abnormalities has been observed in the primary tumor compared to distant metastases (p = 0.004), revealed also by immunohistochemical overexpression of the protein (p < 0.001; OR = 0.53,95% CI = 0.40–0.71), while the CCND1 gene amplification does not show association (p = 0.43); while gene amplification, on the contrary, appeared more frequently in distant metastases (p = 0.04; OR = 1.70,95% CI = 1.01–2.85) and not in the primary tumor. In conclusion, CCND1/cyclin D1 upregulation is a common molecular oncogenic alteration in melanomas that probably favors the growth and expansion of the primary tumor. This upregulation is mainly consequence to the overexpression of the cyclin D1 protein, and not to gene amplification.


2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 2-2
Author(s):  
Philippe E. Spiess ◽  
Douglas A Mata ◽  
Gennady Bratslavsky ◽  
Joseph M Jacob ◽  
Andrea Necchi ◽  
...  

2 Background: Although SCC of the penile skin (pSCC) and the male urethral surface epithelium (uSCC) arise in nearby locations and can feature similar histology, their clinical manifestations, disease course, and surgical and medical treatment options are distinct. We performed CGP on pSCC and uSCC to examine genomic profiles differences. Methods: Tissues obtained from men with clinically advanced pSCC (n = 230) and uSCC (n = 17) underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: The median ages were similar in both groups. pSCC exhibited a slightly higher frequency of HPV-16/18 infection (29% vs. 12%, P = .16), although the TP53 mutation frequencies were nearly identical (55% vs. 59%, NS). CDKN2A inactivation (P = .08), CCND1 amplification trending higher and TERT promoter mutations (P = .01) were more frequent in pSCC, potentially indicating prior HPV infection. GAs in NOTCH1 were exclusively identified in pSCC. Potentially actionable GAs identified in both groups included PIK3CA activating mutations (TKIs) as well as pathogenic alterations in FBXW7 and PTEN (MTOR inhibitors). Rare BRCA1 and BRCA2 inactivation (PARP inhibitors) was seen in pSCC only. High-positive PD-L1 staining was elevated in pSCC (34 vs. 14%, P = .06). Although average TMB was similar in both groups, pSCC exhibited an elevated frequency of cases with CD274 ( PD-L1) amplification as well as TMB >10 mut/Mb which are on label for immune checkpoint inhibitor (ICPI) treatment. Conclusions: CGP of pSCC and uSCC identifies opportunities for both targeted and ICPI therapies. Compared to uSCC, pSCC had genomic features more similar to head and neck SCC including slightly increased cell-cycle perturbation, HPV infection, and NOTCH pathway signaling alterations. Further use of CGP in the treatment planning for pSCC and uSCC may be warranted. [Table: see text]


2020 ◽  
pp. 647-661
Author(s):  
Erik A. Williams ◽  
Adrienne J. Werth ◽  
Radwa Sharaf ◽  
Meagan Montesion ◽  
Ethan S. Sokol ◽  
...  

PURPOSE Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures. MATERIALS AND METHODS Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed. RESULTS One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P = .001). Compared with HPV-negative (HPV–) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P = .004), PTEN (14% v 2%; P < .0001), EP300 (14% v 1%; P < .0001), STK11 (14% v 1%; P < .0001), AR (5% v 0%; P = .006), and FBXW7 (10% v 3%; P = .03). In contrast, HPV– vSCCs showed more alterations in TP53 (83% v 6%; P < .0001), TERTp (71% v 9%; P < .0001), CDKN2A (55% v 2%; P < .0001), CCND1 amplification (22% v 2%; P < .0001), FAT1 (25% v 4%; P < .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P < .0001), as well as a higher rate of 9p24.1 ( PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04). CONCLUSION Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV– vSCCs showed alterations in TP53, TERTp, CDKN2A, CCND1, and EGFR, and biomarkers associated with responsiveness to immunotherapy.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15249-e15249 ◽  
Author(s):  
Yingying Huang ◽  
Chuan-ben Chen ◽  
Yu Chen ◽  
Xuan Gao ◽  
Yi Li ◽  
...  

e15249 Background: CCND1 amplification relevant to malignant biological behavior exist in solid tumors. The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to immune checkpoint inhibitors (ICIs) therapy is unknown. Methods: This study included three cohorts: Geneplus Institute ( n= 6536), The Cancer Genome Atlas ( n= 10562) and Memorial Sloan Kettering Cancer Center ( n= 106109). Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and their correlation with the prognosis and the response to ICIs. Results: CCND1 amplification occurs in many cancer types, correlates with shorter overall survival and inferior outcomes with ICIs therapy. Transcriptomic analysis showed various degrees of immune cells exclusion, including cytotoxic cells, T cells, CD8+ T cells, DC cells, B cells in the tumor microenvironment (TME) in a CCND1 amplification population. The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial mesenchymal transition, TGF-β signaling, KRAS signaling, PI3K/AKT/mTOR signaling, p53 pathway and hypoxia signaling in solid tumors. Conclusions: Our study indicated that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs in solid tumors.


2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 179-179
Author(s):  
Denis Leonardo Fontes Jardim ◽  
Sherri Z. Millis ◽  
Michele Sue-Ann Woo ◽  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
...  

179 Background: The cyclin pathway is comprised of possible targetable alterations as well as resistant alterations that affect treatment, including hormonal agents. We describe the landscape of cyclin genomic alterations in prostate cancer. Methods: Consecutive samples were analyzed in a CLIA-certified laboratory using comprehensive genomic profiling (CGP) performed by next-generation sequencing (315 genes, >500X coverage). We describe alterations in activating genes (Table) and co-alterations in resistant genes ( RB1 and CCNE1) (related to cyclin inhibition) and androgen receptor ( AR). Results: Alterations in any cyclin pathway genes were found in 9.7% of the 5,356 tumors analyzed. Frequent alterations included CCND1 amplification (4.2%) and CDKN2A and B loss (2.4% each). Frequencies were substantially different according to prostate cancer histology (Table). The majority of alterations were copy number changes. Alterations in possible resistance genes, RB1 and CCNE1 were detected in 9.7% (up to 54.6% in neuroendocrine) and 1.2% of cases, respectively, while AR alterations were seen in 20.9% (up to 27.3% in anaplastic). Co-occurrence analysis demonstrated a lower likelihood of concomitant vs. isolated alterations in cyclin activating and resistance pathway (odds ratio (OR), 0.44, p<0.001). Conversely, we detected a higher likelihood of co-occurrence between AR and cyclin alterations (OR 1.79, p<0.001). Conclusions: Cyclin pathway genomic abnormalities were observed in about 10% of prostate cancer tumors, and are more frequently associated with concomitant AR alterations and absence of co-alterations associated with resistance to cyclin inhibition.[Table: see text]


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