SMARCA4-mutated lung adenocarcinoma, a distinctive non-small cell lung cancer with worse prognosis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20548-e20548
Author(s):  
Longfeng Zhang ◽  
Weijin Xiao ◽  
Fangjun Wu ◽  
Ran Peng ◽  
Jialong Shi ◽  
...  
Keyword(s):  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Enrichment Analysis ◽  
Outcome Data ◽  
Copy Number Loss ◽  
Missense Mutations ◽  
Cellular Processes ◽  
Pathological Characteristics ◽  
Worse Prognosis

e20548 Background: SMARCA4 gene is one of the catalytic subunits of the SWI/SNF chromosomal remodeling complex, which can regulate important cellular processes and functions and is closely associated to tumors. The clinical features, therapeutic efficacy, prognosis and pathological features of lung adenocarcinoma with this genetic variation are still unknown and controversial. Methods: The study recruited 274 patients (pts) with lung adenocarcinoma whose samples were sent to perform parallel hybridization-based next-generation sequencing. Two categories of SMARCA4 mutations were divided into Type1 mutations (frameshift mutations, nonsense mutations, splice-3 mutations, copy number amplification) and Type2 mutations (missense mutations and copy number loss) based on whether the mutation may result in defective protein. Furthermore, comparative analysis by using the clinical outcome data, the genomic and pathological characteristics were be performed in SMARCA4 Type 1 alterations corhort and Type 2 alterations corhort. Results: Among 274 pts were recruited, the mutation rate of SMARCA4 gene in lung adenocarcinoma was 9.1%. Furthermore, the presence of SMARCA4 alteration was associated with smoking (P＜0.05). Missense, nonsense, frameshift and splice were the most common types of mutations (92%). The pts with SMARCA4 Type1 alterations which probably lead to defective protein expression, had a worse prognosis compared with pts with SMARCA4 Type1 alterations (The role leading to defective protein expression is uncertain) and SMARCA4 Wild groups (P＜0.05). In addition, EGFR alterations were strongly associated with SMARCA4 Wild corhort compared to SMARCA4 Type1 alterations corhort (67% vs. 31% ), and SMARCA4 Type1 alterations was more associated with the absence of TP53, RB1, and Robo3 alterations. GO enrichment analysis suggested that the differentiated mutated genes between SMARCA4 Type1 alterations corhort and SMARCA4 Wild corhort were mainly enriched in cell cycle regulation. Pathologically, The SMARCA4 Type1 alterations was mostly poorly or moderately differentiated and strongly accompanied by the loss of expression of TTF-1(83.3%) and BRG1(80%) in immunohistochemistry. Conclusions: SMARCA4 Type1 alterations which probably lead to abnormality of protein was associated with poor prognosis and having different the genomic and pathological characteristics.

Inhibition of Phosphatidylinositol 3-Kinase Is Effective to Suppress the Growth of CD20-Negative Refractory Diffuse Large B-Cell Lymphoma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2421-2421
Author(s):  
Tsuyoshi Nakamaki ◽  
Kunihiko Fukuchi ◽  
Hidetoshi Nakashima ◽  
Hirotsugu Ariizumi ◽  
Takashi Maeda ◽  
...  
Keyword(s):  
Dna Binding ◽  
Protein Expression ◽  
B Cell ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Copy Number ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Copy Number Loss ◽  
Cd20 Expression

Abstract Abstract 2421 CD20 is not only a therapeutic target but also its expression has prognostic importance in B cell lymphoma. Decreased CD20 expression is often associated with refractory phenotypes, especially in lymphoma treated with therapy including rituximab, an anti-CD20 antibody. To address the molecular mechanism(s) of down-regulation of its expression and to find an alternative therapeutic target(s) in resistant lymphoma, we analyzed a CD20-negative B-cell lymphoma cell line (SD07). SD07 was established from lymphoma cells without expressing CD20, which appeared in pleural effusion in a patient with diffuse large B-cell lymphoma (DLBCL), after 2-years of repeated anti-lymphoma therapy including rituximab, While initial diagnosis was CD20 positive activated B cell-like DLBCL (ABCDLBCL). SD07 selectively lacks CD20 protein expression, but not other B cell antigens, such as CD19, CD21 and CD22 by flowcytometry(FCM). In SCID mice, subcutaneously transplanted SD07 developed tumors which are positive for B cell antigen such as CD79a, but not CD20 (L26) and EBER. Array CGH revealed 0.7 Mb region with copy number loss less than −1.0 of log2 ratios on chromosome 11q12 in SD07. Within this region, 30 kb segment, which showed further loss (less than −2.0),contained two genes, MS4A1(CD20) and MS4A5. Southern blot analysis using CD20 exon 1 as a probe showed homozygous deletion of CD20 gene in SD07. As expected, incubation with rituximab in culture failed to suppress the cell growth of SD07 up to 20 μg/ml(cell No. rituximab/control=0.98±0.04, P=NS). This suggests deletion of CD20 gene with genomic copy number loss in 11q12 produced the loss of CD20 expression and resulted in resistant to rituximab. It is currently studied whether the loss of CD20 expression is directly involved in the tumorigenicity of SD07. Array CGH also showed several genomic regions with copy number loss which are possibly involved in refractory phenotype of SD07. Those includes 10q23 (PTEN), 12q23 (APAF1) and 16q21 (NFATC3). Immunoblot analysis showed the absence of PTEN protein expression and constitutive AKT Ser473 phosphorylation in SD07. SDO7 also showed constitutive phosphorylation of both SykTyr525/526 and Btk Tyr223,however, those did not differ much in those in three germinal center B-like(GCB) cell lines, two Burkitt lymphoma cell lines, Daudi and N8, and a DLBCL cell line, TK, derived from follicular lymphoma. In SD07, somatic mutations of ITAM of either CD79A or CD79B was not detected. This suggests inactivation of PTEN, rather than chronic active BCR signaling, is likely to promote constitutive PI3K-AKT signaling in SD07. Nuclear NF-kB DNA binding by EMSA, SD07 showed constitutively higher binding signals of NF-kB, compared with either Daudi, N8 or TK (SD07=3.6±0.1,GCB cell lines(Daudi,N8,TK)=1.2±0.2, p<0.01, arbitrary density units). Supershift analysis showed increased NF-kB DNA binding in SD07 mainly consist of p50 and c-Rel. By immunoblot, SD07 showed steady-state increased accumulation of p50 protein, but not p65, in nuclear fraction, compared with either in Duadi,N8 or TK. Protein expression of BClxL, a NF-kB target gene, increased in SD07 (SD07=1.9±0.1, GCB cell lines=0.7±0.2, p<0.01, signal intensity, SI). Those suggest that oncogenic PI3K-AKT activation and/or constitutive activation of NF-kB pathway contribute pro-survival signaling in SD07 and those are possible therapeutic target in SD07. Incubation with LY294002(LY), selective PI3K inhibitor, at more than 0.1μM for 4 days, dose-dependently inhibited the cell growth of SD07(10μMLY/DMSO=0.35±0.01, P<0.01), without significant effects on cell viability. FCM analysis with PI showed that incubation with LY produced G1 accumulation and decrease of cells in the S (LY/DMSO,G1=1.5±0.1,S=0.2±0.1,G2M=0.4±0.1, P<0.05). 10 μM LY inhibited both AKT Ser473 phosphorylation (LY/DMSO=0.18±0.01,SI,P<0.01) and protein expression of BClxL (LY/DMSO=0.43±0.02,P<0.05) in SD07. LY increased p27 protein expression (LY/DMSO=1.83±0.04, P<0.05), without affecting NF-kB DNA binding in SD07. It may suggest PI3K are required for expression of some NF-kB target gene without suppressing nuclear NF-kB DNA binding. In summary, although a limited in a cell line, we clarify a novel molecular mechanism of acquired loss of expression of CD20 in DLBCL. In addition, we show that de-regulated PI3K-AKT pathway is a possible therapeutic target for CD20-negative refractory ABCDLBCL. Disclosures: No relevant conflicts of interest to declare.

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 profiling of lung adenocarcinoma using pleural effusion specimens.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21709-e21709
Author(s):  
Wei Zhang ◽  
Bei Zhang ◽  
Yifan Zhou ◽  
Xiaochen Zhao ◽  
Yuezong Bai
Keyword(s):  
Targeted Therapy ◽  
Next Generation Sequencing ◽  
Pleural Effusion ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Copy Number Gain ◽  
Molecular Profiling ◽  
Copy Number Loss ◽  
Next Generation ◽  
Generation Sequencing

e21709 Background: Molecular profiling of lung adenocarcinoma is essential for therapeutic decision-making and prognosis predicting. Pleural effusion may provide an opportunity for molecular profiling and thereby possibly provide information enabling targeted therapy. In this study, we performed next generation sequencing (NGS) in pleural effusion samples in order to study molecular profiling of lung adenocarcinoma using pleural effusion specimens. Methods: 45 Chinese lung adenocarcinoma patients with pleural effusion specimens were included. The pleural effusion samples were centrifugated, then cell pellets were collected and prepared into cell blocks. Genetic mutations were assessed using a validated targeted next generation sequencing assay. Immunohistochemistry (IHC) of PD-L1 was performed with 22C3 kit. Results: In 45 pleural effusion samples collected, 43 (95.5%) patients had at least one mutation classed as pathogenic or likely pathogenic. There were 245 somatic mutation and 160 germline mutations were detected, with an average of 8.0 mutations per patient. Of the 45 specimens with somatic mutations, seventeen (37.8%) of harbored EGFR mutations. The most frequent mutations were the deletion mutation in exon19 (15/17, 40.9%), the point mutation (L858R) in exon 21 (13/17, 76.5%), and resistance mutation (T790M) in exon 20(4/17,23.5%). Aside from the EGFR mutation, 1 case exhibited KRAS mutation (G12C), 1 case harbored ERBB2 mutation(Y772_A775dup),1 case harbored TP53 mutation, and 2 cases exhibited fusion (EML4-ALK, KIF5B-RET). 2 cases exhibited CD274 copy number gain, 2 cases exhibited CDK4 copy number gains, and one case carried CDK6 copy number gain, one case carried CKD6 copy number loss. The top frequent germline mutation genes were APC (5/45), ALK (4/45), ARID1A (4/45) and BARD1 (4/45). Regarding biomarkers for immunotherapy, three sample showed TMB-H (6.7%), and one sample showed MSI-H (2.2%). Of 29 samples underwent PDL1 IHC test, 21 samples (72.4%) show positive PDL1 expression, in concordance with previous reported rates. Conclusions: These results suggest that pleural effusions are important specimens for oncogene mutation analysis and enable targeted therapy for patients with lung adenocarcinoma.

scholarly journals Chromosomal rearrangements and copy number abnormalities of TP63 correlate with p63 protein expression in lung adenocarcinoma

2014 ◽  
Vol 28 (3) ◽  
pp. 359-366 ◽  
Author(s):  
Marie-Christine Aubry ◽  
Anja Roden ◽  
Stephen J Murphy ◽  
George Vasmatzis ◽  
Sarah H Johnson ◽  
...  
Keyword(s):  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Chromosomal Rearrangements

Usefulness of tissue microarrays for assessment of protein expression, gene copy number and mutational status of EGFR in lung adenocarcinoma

2010 ◽  
Vol 457 (4) ◽  
pp. 483-495 ◽  
Author(s):  
Marius I. Ilie ◽  
Véronique Hofman ◽  
Christelle Bonnetaud ◽  
Katia Havet ◽  
Virginie Lespinet-Fabre ◽  
...  
Keyword(s):  
Protein Expression ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Gene Copy Number ◽  
Tissue Microarrays ◽  
Gene Copy ◽  
Mutational Status

scholarly journals Integrated Multiomics Analyses Revealing Different Molecular Profiles Between Early- and Late-Stage Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Dongsheng Yue ◽  
Weiran Liu ◽  
Liuwei Gao ◽  
Lianmin Zhang ◽  
Tao Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
Late Stage ◽  
Copy Number ◽  
Copy Number Variations ◽  
Regulatory Mechanisms ◽  
Gene Copy ◽  
Molecular Characteristics ◽  
Open Chromatin ◽  
Copy Number Loss

The molecular differences in genetic and epigenetic profiling between early-stage (ES) and late-stage (LS) lung adenocarcinoma (LUAD), which might help to understand cancer progression and biomarker guided precision treatment, need further be investigated. In this study, we performed comprehensive analysis using multi-omics next-generation sequencing (NGS) on tissue samples from 7 ES (stage I) and 10 LS (stage III/IV) LUAD patients to study molecular characteristics between the two groups. Characterization of the genomic and transcriptomic profiles showed stage-specific somatic mutations, copy number variations (CNVs) and differentially expressed genes (DEGs). LS samples tend to have more TP53, ERBB2 and CHD4 mutations. Gene copy number loss occurs in immune-related gene pathways in the late stage of LUAD. ATAC-seq analysis showed that LS samples harbored more open chromatin peaks around promoter regions and transcription start sites (TSS) than ES samples. We then identified the known transcription factor (TF) binding motifs for the differentially abundant ATAC-seq peaks between the ES and LS samples and found distinct regulatory mechanisms related to each stage. Furthermore, integrative analysis of ATAC-seq with WGS and RNA-seq data showed that the degree of chromatin accessibility is related to copy number changes, and the open chromatin regions could directly regulate the expression of some DEGs. In conclusion, we performed a comprehensive multi-omics analysis of the early and late stages of LUAD and highlighted some important molecular differences in regulatory mechanisms during cancer progression. Those findings help to further understand mechanism and biomarker related targeted therapy.

scholarly journals Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Zhiyong Deng ◽  
Liang Cui ◽  
Pansong Li ◽  
Nianjun Ren ◽  
Zhe Zhong ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cerebrospinal Fluid ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Genetic Factors ◽  
Lung Tumor ◽  
Copy Number Variant ◽  
Tumor Evolution ◽  
Copy Number Loss ◽  
Genomic Comparison

AbstractLung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.

scholarly journals BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas

2017 ◽  
Vol 12 (4) ◽  
pp. 724-733 ◽  
Author(s):  
Noémie Leblay ◽  
Frédéric Leprêtre ◽  
Nolwenn Le Stang ◽  
Amandine Gautier-Stein ◽  
Laurent Villeneuve ◽  
...  
Keyword(s):  
Protein Expression ◽  
Copy Number ◽  
Copy Number Loss

scholarly journals On the Need to Tell Apart Fraternal Twins eEF1A1 and eEF1A2, and Their Respective Outfits

2021 ◽  
Vol 22 (13) ◽  
pp. 6973
Author(s):  
Alberto Mills ◽  
Federico Gago
Keyword(s):  
De Novo ◽  
Elongation Factor ◽  
Missense Mutations ◽  
Developmentally Regulated ◽  
High Sequence Identity ◽  
80S Ribosome ◽  
Cellular Effects ◽  
Cellular Processes ◽  
Eukaryotic Elongation Factor ◽  
A Site

eEF1A1 and eEF1A2 are paralogous proteins whose presence in most normal eukaryotic cells is mutually exclusive and developmentally regulated. Often described in the scientific literature under the collective name eEF1A, which stands for eukaryotic elongation factor 1A, their best known activity (in a monomeric, GTP-bound conformation) is to bind aminoacyl-tRNAs and deliver them to the A-site of the 80S ribosome. However, both eEF1A1 and eEF1A2 are endowed with multitasking abilities (sometimes performed by homo- and heterodimers) and can be located in different subcellular compartments, from the plasma membrane to the nucleus. Given the high sequence identity of these two sister proteins and the large number of post-translational modifications they can undergo, we are often confronted with the dilemma of discerning which is the particular proteoform that is actually responsible for the ascribed biochemical or cellular effects. We argue in this review that acquiring this knowledge is essential to help clarify, in molecular and structural terms, the mechanistic involvement of these two ancestral and abundant G proteins in a variety of fundamental cellular processes other than translation elongation. Of particular importance for this special issue is the fact that several de novo heterozygous missense mutations in the human EEF1A2 gene are associated with a subset of rare but severe neurological syndromes and cardiomyopathies.

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