Integrative Analysis of Methylation and Gene Expression in Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

The mechanisms of lung cancer are highly complex. Not only mRNA gene expression but also microRNAs, DNA methylation, and copy number variation (CNV) play roles in tumorigenesis. It is difficult to incorporate so much information into a single model that can comprehensively reflect all these lung cancer mechanisms. In this study, we analyzed the 129 TCGA (The Cancer Genome Atlas) squamous cell lung carcinoma samples with gene expression, microRNA expression, DNA methylation, and CNV data. First, we used variance inflation factor (VIF) regression to build the whole genome integrative network. Then, we isolated the lung cancer subnetwork by identifying the known lung cancer genes and their direct regulators. This subnetwork was refined by the Bayesian method, and the directed regulations among mRNA genes, microRNAs, methylations, and CNVs were obtained. The novel candidate key drivers in this refined subnetwork, such as the methylation of ARHGDIB and HOXD3, microRNA let-7a and miR-31, and the CNV of AGAP2, were identified and analyzed. On three large public available lung cancer datasets, the key drivers ARHGDIB and HOXD3 demonstrated significant associations with the overall survival of lung cancer patients. Our results provide new insights into lung cancer mechanisms.

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OA19.01 A Standardized and Validation of Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma by the SPECS Lung Consortium

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2016.11.337 ◽

2017 ◽

Vol 12 (1) ◽

pp. S317-S318

Author(s):

William Richards ◽

Raphael Bueno ◽

David Beer ◽

Karla Ballman ◽

Ramaswamy Govindan ◽

...

Keyword(s):

Gene Expression ◽

Squamous Cell ◽

Lung Carcinoma ◽

Squamous Cell Lung Carcinoma ◽

Cell Lung Carcinoma ◽

Prognostic Gene ◽

Gene Expression Signatures

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The landscape of ARID1A variants and correlation with tumor mutational burden in Chinese solid tumor patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14624 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14624-e14624

Author(s):

Jia Wei ◽

JieJie Zhang ◽

Qiang Wen ◽

Xiaoyi Zhu ◽

Dapeng Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Squamous Cell ◽

Lung Carcinoma ◽

Solid Tumor ◽

Immune Checkpoint ◽

Squamous Cell Lung Carcinoma ◽

Tumor Patients ◽

Cell Lung Carcinoma ◽

Mutational Burden ◽

Tumor Mutational Burden

e14624 Background: ARID1A (the AT-rich interaction domain 1A) is one of the most commonly mutated genes in cancer, mostly caused by frameshift variants. Here, we describe the mutational landscape of ARID1A in Chinese cancer patients and its correlation with tumor mutational burden (TMB). Methods: Formalin fixed paraffin embedded (FFPE) samples of 3,828 Chinese solid tumor patients were collected for next‐generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite stable (MSS) status and TMB were also acquired by NGS algorithms. Results: A total of 340 (8.9%) patients were found to have ARID1A variants. The frequency of ARID1A mutations was 4% in lung adenocarcinoma (N = 74/1833), 8% in squamous cell lung carcinoma (N = 23/278), 12% in colorectal adenocarcinoma (N = 61/530), 11% in hepatocellular carcinoma (N = 52/484), 14% in pancreatic adenocarcinoma (N = 25/177), 15% in gallbladder adenocarcinoma (N = 14/94), 22% in intrahepatic cholangiocarcinoma (N = 47/213), 20% in gastric adenocarcinoma (N = 39/200) and 26% in endometrial adenocarcinoma (N = 5/19). ARID1A variants included truncation (78%), missense/indel (non-frameshift substitution/indel) (16%), splicing site (4%) and rearrangement (2%). Truncation was the most common, recurring in a few hot spots (R1276*, D1850Gfs*4, A339Lfs*24, P224Rfs*8 and Q372Afs*28/Sfs*19). In general, ARID1A mutations correlated with higher TMB (median 17.6 vs 7.4 muts/Mb, P < 0.001) in MSS tumors; especially in lung adenocarcinoma (17 vs 7.5 muts/Mb, P < 0.01), squamous cell lung carcinoma (16.8 vs 11.2 muts/Mb, P < 0.01). TP53 (60%), APC (34%) and KRAS (32%) were the most common co-occurred mutated gene in ARID1A (+) tumors. In more than 20% of ARID1A mutations, PI3K/mTOR pathway genes were altered, such as PIK3CA, PTEN, RNF43 and PIK3R1 genes. Conclusions: Since ARID1A mutations correlate with higher TMB, it could be a potential predictor of response to PD-1/PD-L1 immune checkpoint pathway inhibitors. As reported, ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Patients harboring ARID1A and PI3K/mTOR pathway mutations may provide useful information for drug discovery and biomarker exploration.

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The prevalence of KRASG12C mutations utilizing circulating tumor DNA (ctDNA) in 80,911 patients with cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.3547 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 3547-3547 ◽

Cited By ~ 1

Author(s):

Kyaw Thein ◽

Kimberly Banks ◽

Jennifer Saam ◽

Victoria M. Raymond ◽

Jason Roszik ◽

...

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Lung Adenocarcinoma ◽

Solid Tumors ◽

Squamous Cell ◽

Lung Carcinoma ◽

Cancer Type ◽

Squamous Cell Lung Carcinoma ◽

Cell Lung Carcinoma ◽

Tumor Types

3547 Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most commonly mutated proto-oncogene identified in cancer and still remains an arduous therapeutic challenge. Recently, KRASG12C mutation has become special interest since it has now been considered potentially druggable after the introduction of covalent small-molecule KRASG12C inhibitors. Advances in next-generation sequencing (NGS) and embracing utilization of ctDNA have uncovered more genetic alterations in many cancers. We present a comprehensive analysis on the prevalence of KRASG12C mutations identified by ctDNA. Methods: We conducted a 5-year (July 2014 to June 2019) retrospective review of ctDNA NGS analysis in the Guardant360 CLIA database inclusive of treatment-naïve and previously treated patients with metastatic solid tumors. Data were retrieved from the 80,911 unique patients with ctDNA detected. Clonality and co-occurrence of cancer type were analyzed. Clonality was defined as variant allele fraction(AF) / maximum somatic AF in the sample. Results: 80,911 patients, which included more than 100 tumor histologies, were identified. 2,985 patients (3.7%) with > 40 tumor types had KRASG12C mutations identified in ctDNA. KRASG12C prevalence by cancer type were as follows: sarcomatoid lung carcinoma (13.5%), lung cancer NOS (9%), large cell lung carcinoma (9%), lung adenocarcinoma (7.4%), NSCLC (6.9%), carcinoma of unknown primary (CUP) (4.1%), lung carcinoid (4%), CRC (3.5%), squamous cell lung carcinoma (2%), small cell lung carcinoma (1.5%), pancreatic ductal adenocarcinoma (PDAC) (1.2%), cholangiocarcinoma (1.2%), bladder cancer (0.6%), ovarian cancer (0.6%) and breast cancer (0.3%). 53 additional patients with KRASG12C were identified across 24 other tumor types. The KRASG12C mutation was found to be clonal (clonality > 0.9%) in the majority of patients with lung adenocarcinoma, NSCLC, CUP, squamous cell lung carcinoma, and PDAC, compared to patients with CRC and breast cancer who had bimodal distribution of clonal and sub clonal mutations. Conclusions: To our knowledge, this is the largest analysis on the prevalence of KRASG12C mutations identified by ctDNA. Our study demonstrated the feasibility of utilizing ctDNA to identify KRASG12C mutations across solid tumors with the highest prevalence in lung cancer as previously reported in tissue. The clonality information available from ctDNA-based genotyping may provide insights into the clinical efficacy of targeting KRASG12C in different tumor types.

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A prognostic 4-gene expression signature for squamous cell lung carcinoma

Journal of Cellular Physiology ◽

10.1002/jcp.25846 ◽

2017 ◽

Vol 232 (12) ◽

pp. 3702-3713 ◽

Cited By ~ 14

Author(s):

Jun Li ◽

Jing Wang ◽

Yanbin Chen ◽

Lijie Yang ◽

Sheng Chen

Keyword(s):

Gene Expression ◽

Squamous Cell ◽

Lung Carcinoma ◽

Gene Expression Signature ◽

Squamous Cell Lung Carcinoma ◽

Cell Lung Carcinoma ◽

Expression Signature

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Anti-cancer gene expression profile of curcumin identifies new therapeutic targets in squamous cell lung carcinoma in vitro

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18203 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18203-18203

Author(s):

S. Sen ◽

A. Singh ◽

A. Pal ◽

C. Sharma ◽

R. Kar ◽

...

Keyword(s):

Gene Expression ◽

Real Time ◽

Squamous Cell ◽

Lung Carcinoma ◽

Mtt Assay ◽

Squamous Cell Lung Carcinoma ◽

Rt Pcr ◽

Curcumin Treatment ◽

Cell Lung Carcinoma

18203 Background: Lung cancer is notorious for early metastasis and very high mortality, worldwide. Curcumin, a chemopreventive has also shown chemotherapeutic potential but its mechanisms are still not well understood. In this study, the genes targeted by Curcumin were investigated to identify new targets for the therapy of squamous cell lung carcinoma (SCC) in vitro. Methods: Lung squamous cell carcinoma cells (H520) were cultured in DMEM with 10% FCS. They were treated with Curcumin (25μM) for 24 hours. Apoptosis was detected by morphological examination, MTT assay, flowcytometry and TUNEL assay. Microarray analysis of gene expression profiles on curcumin treatment was done. Real time quantitative RT-PCR confirmed the results. Results: Curcumin (25μM for 24 hours) caused 29.8 ± 2.1% cytotoxicity (MTT assay). Apoptosis was corroborated by flowcytometry (23.7 ± 1.4%) and TUNEL (21.6 ± 1.8%). Using microarray analysis, 34 genes were seen to be upregulated and 31 genes downregulated after curcumin treatment. Several apoptosis related genes were upregulated including GADD45a (3.36 fold), transcription factor Egr-1 (2.2 fold) and Peroxiredoxin-I (2 fold). In addition, Angiopoietin-2 (Ang-2), an angiogenic factor that promotes angiogenesis and tumor invasion was downregulated (1.7 fold). Real time quantitative RT-PCR confirmed the results. Conclusions: This study helps to identify novel putative intervention sites as targets for curcumin in the therapy of squamous cell lung carcinoma (SCC) in vitro and can contribute to better understanding of lung tumorigenesis and anticancer therapy. No significant financial relationships to disclose.

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