scholarly journals Genomic landscape and its correlations with tumor mutational burden, PD-L1 expression, and immune cells infiltration in Chinese lung squamous cell carcinoma

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Tao Jiang ◽  
Jinpeng Shi ◽  
Zhengwei Dong ◽  
Likun Hou ◽  
Chao Zhao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Cells ◽  
Lung Squamous Cell Carcinoma ◽  
Mutational Burden ◽  
Genomic Landscape ◽  
Tumor Mutational Burden

Association of tumor mutational burden in cutaneous squamous cell carcinoma with genomic alterations in Notch family receptors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13031-e13031
Author(s):  
Eric Allan Severson ◽  
Shakti Ramkissoon ◽  
Sugganth Daniel ◽  
Jo-Anne Vergilio ◽  
Laurie M. Gay ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Family Member ◽  
Squamous Cell ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Genomic Alterations ◽  
Functional Impact ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Frameshift Indels

e13031 Background: In Cutaneous Squamous Cell Carcinoma (cSqCC), Notch1, Notch2, and Notch3 have been identified as tumor suppressors with a high rate of inactivating mutations early in cSqCC pathogenesis. Despite the high frequency of alterations, the biologic and therapeutic implications of Notch genomic alterations (GAs) in cSqCC are incompletely understood. Methods: 232 FFPE samples of cSqCC were evaluated by comprehensive genomic profiling (CGP) of 315 genes and analyzed for all classes of GAs, with diagnoses confirmed by central pathology review. Notch GAs with unknown functional impact were excluded. Tumor mutational burden (TMB) was calculated from 1.11 Mb of sequenced DNA and reported as mutations/Mb. Results: The cohort of 232 samples was 78% male and 22% female, aged from 17 to 88, with confirmed metastatic disease in 32% of cases. 115 (50%) samples had a Notch family member GA with a known or predicted functional impact. 96 cases had Notch1 GAs, 43 cases had Notch2 GAs, and 14 cases had Notch3 GAs with 40 cases having GAs in multiple Notch family members. These mutations were 41% missense, 34% nonsense, 15% splice site, 9% frameshift indels, and 1% non-frameshift indels alterations. Patients with Notch GAs were significantly older (median 70 years old vs median 64, p < 0.01). TMB was increased among samples with Notch GAs (median TMB of 63 mutations/mb versus 20 mutations/mb, p < 1x10-6), with similar differences for primary and metastatic samples. Cases with Notch GAs had more total GAs per case (mean 10.4 vs 7.4, p < 1.5x10-10); however, the top co-mutated genes were the same (TP53, CDKN2A, FAT1, MLL2). Both groups had a high proportion of C- > T/G- > A transitions, consistent with UV damage; however, the proportion was higher in cases with Notch GAs (median 83% vs 80%) - a difference seen in primary and metastatic samples. Conclusions: 50% of cSqCC cases had a Notch family member loss of function GA, which was associated with increased TMB in the primary and metastatic setting. With pre-clinical models and case studies showing responses to PD-1 inhibitors in cSqCC, further investigations are warranted into the associations of Notch GAs with mutational burden and response to immunotherapy.

Clinical response and biomarker analysis of a phase II basket trial of toripalimab, a PD-1 mAb in combination with standard chemotherapy as a first-line treatment for patients with solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15083-e15083
Author(s):  
Chao Ren ◽  
Xiao-Li Wei ◽  
Nong Xu ◽  
Lin Shen ◽  
Guanghai Dai ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Response ◽  
Solid Tumors ◽  
Squamous Cell ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Mutational Burden ◽  
Tumor Mutational Burden

e15083 Background: Platinum based chemotherapy is the standard care for 1st line treatment of metastatic gastric adenocarcinoma (GC), esophageal squamous cell carcinoma (ESSC), nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC). Combinations of PD-1 blockade with chemotherapy have shown promising but mixed results in solid tumors. Predictive biomarkers for chemo-immunotherapy combination as 1st line treatment remain undefined. Methods: Patients (n = 60) included in this analysis were four complete cohorts from a multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in combination with standard chemotherapy for the 1st line treatment of GC, EC, NPC and HNSCC (excluding NPC). Whole exome sequencing (WES), RNA sequencing and immunohistochemistry were performed on tumor biopsy samples. PD-L1 expression and tumor mutational burden (TMB) were evaluated for correlation with clinical efficacy. Results: From Oct 2016 to Feb 2019, 33 GC, 12 ESSC, 12 NPC and 3 HNSCC patients were enrolled and treated with 240mg or 360 mg toripalimab Q3W via IV infusion in combination with Oxaliplatin/Capecitabine (XELOX), Paclitaxel/Cisplatin (PP), Gemcitabine/Cisplatin (GP) and Docetaxel/Cisplatin/5-FU(TPF) respectively. By the data cutoff date of Nov 15, 2019, all patients experienced treatment related adverse event (TRAE). There was one TRAE (heart failure) leading to death. Grade 3-4 TRAEs occurred in 67% patients, mostly attributed to chemotherapy, including 27% neutropenia, 23% thrombocytopenia, 18% leukopenia and 12% anemia. As assessed by investigators according to RECIST v1.1, the ORR/DCR were 54.5%/84.8%, 66.7%/91.7%, 75.0%/83.3% and 33.3%/100% respectively for GC, EC, NPC and HSNCC cohorts. The median duration of response was 8.3, 6.8, 7.7 and 7.1 months respectively. WES showed distinctive patterns of genomic alterations among different cohorts. The clinical response was not correlated with either PD-L1 expression or tumor mutational burden. Conclusions: Toripalimab in combination with chemotherapy as first-line treatments showed promising results for metastatic GC, EC, NPC and HNSCC patients. Two randomized Phase III trials of toripalimab in combination with Paclitaxel/Cisplatin or Gemcitabine/Cisplatin versus chemotherapy alone are ongoing to further evaluate the combination as first-line treatments in metastatic EC and NPC patients. Clinical trial information: NCT02915432 .

Mine TCGA Database for Tumor Microenvironment-Related Genes of Prognostic value in lung squamous cell carcinoma

2020 ◽  
Author(s):  
Xiao Chen ◽  
Rui Li ◽  
Yun-Hong Yin ◽  
Xiao Liu ◽  
Xi-Jia Zhou ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Cells ◽  
Lung Squamous Cell Carcinoma ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Hub Genes

Abstract Background: Tumor microenvironment (TME) plays a significant role in the development of cancer. However, the roles of TME in lung squamous cell carcinoma (LUSC) are not well studied. In our study, we aimed to identify differentially expressed tumor microenvironment-related genes as biomarker for predicting the prognosis of LUSC.Methods: We combined The Cancer Genome Atlas (TCGA) and Estimation of Stromal and Immune cells in Malignant Tumor tissue using Expression data (ESTIMATE) datasets to identified differentially expressed genes in lung squamous cell carcinoma microenvironment. Then, functional enrichment analysis and protein-protein interaction (PPI) network were conducted. The top six genes in the PPI network were regarded as tumor microenvironment-related hub genes. Finally, the relationship between hub genes and tumor-infiltrating immune cells was deciphered using TIMER.Results: Our study revealed that immune and stromal scores are associated with specific clinicopathologic variables in LUSC. These variables include gender, age, distant metastasis and prognosis. In addition, a total of 874 upregulated and 72 downregulated genes were identified. Functional enrichment analysis demonstrated a correlation between DEGs and the tumor microenvironment, tumor immune cells differentiation and activation. C3AR1, CSF1R, CCL2, CCR1, TYROBP, CD14were selected as the hub genes. A positive correlation was obtained between the expression of hub genes and the abundance of six immune cells.Conclusions: The results of the present study showed that ESTIMATE algorithm-based stromal and immune scores may be a reference indicator of cancer prognosis. We identified five TME-related genes, which could be used to predict the prognosis of LUSC patients.

TGM2 Has Potential to Be A Prognostic Factor for Lung Squamous Cell Carcinoma and an Indicator of Immune Infiltrates

2020 ◽  
Author(s):  
Binglin Chen ◽  
Wenqi Liu ◽  
Chunxiao Liang ◽  
Feifeng Lan
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Cells ◽  
T Regulatory Cells ◽  
Lung Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Interactive Analysis ◽  
Cox Analysis

Abstract Background: TGM2 is a functionally diverse molecule that has multiple roles in mediating signal transduction and inflammation. However, the prognostic value of TGM2 and its correlation with tumor-infiltrating immune cells in lung squamous cell carcinoma (LUSC) remains elusive. Methods: Datasets of LUSC were downloaded from The Cancer Genome Atlas (TCGA) to analyze the expression of TGM2 in LUSC. Then, Univariable survival and Multivariate Cox analysis was used to analyze the survival effect of several clinical characteristics. The influence of TGM2 on survival of LUSC patients was evaluated by Gene Expression Profiling Interactive Analysis (GEPIA). The relationship between TGM2 and tumor-infiltrated immune cells was analyzed using the Tumor Immune Estimation Resource (TIMER).Results: TGM2 expression was remarkably lower in LUSC tissues than in the corresponding normal tissues. Low TGM2 expression was correlated with better OS in LUSC. Multivariate survival analysis demonstrated that high TGM2 expression was an independent risk factor for OS.TGM2 expression was significantly positively associated with infiltrating levels of macrophages, meanwhile was strongly correlated with various markers of immune cells, especially tumor-associated macrophages (TAMs) and T-regulatory cells (Tregs).Conclusions: TGM2 is a prognostic biomarker and correlated with immune infiltrates in LUSC.

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