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Genetics and Genomics of Lung Cancer May Contribute to the...
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Genetics and Genomics of Lung Cancer May Contribute to the Development of Precision Medicine

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 December 2021) | Viewed by 9633

Special Issue Editor

Dr. Vienna Ludovini

E-Mail Website
Guest Editor
Department of Medical Oncology, Molecular biology laboratory, S. Maria Della Misericordia Hospital, 06132 Perugia, Italy
Interests: lung cancer; prognostic and/or predictive biomarkers; gene expression profiles; tumoral microenvironment–immunotherapy; liquid biopsy in lung cancer; cancer genes; oncogenes; somatic mutations; Breast cancer; sistems biology

Special Issue Information

Dear Colleagues, 

Lung cancer results from multiple changes in the genome of susceptible pulmonary cells caused by exposure to carcinogens found in tobacco smoke, the environment, or the workplace. Recent studies suggest that histologically apparent lung cancer is due to the sequential accumulation of specific genetic and morphologic changes to the normal epithelial cells of the lung. Positive signallers, such as those mediated by the oncogene RAS, and negative signallers, such as those mediated by the tumor suppressor retinoblastoma protein (RB), contribute to unchecked cell growth and proliferation. Other key molecular derangements can also be considered hallmarks of cancer, including evasion of apoptosis and senescence, angiogenesis, tissue invasion, and metastases. Epigenetic inactivation of genes via DNA methylation provides another novel way of evading normal cellular control mechanisms. The new knowledge of the human genome coupled with global methods of detecting genetic abnormalities and profiling gene expression in tumor cells may enable us to understand the signaling pathways of lung cancer cells. These are molecular targets for new cancer therapeutics, such as receptor tyrosine kinase inhibitors. This information could advance risk assessment, early detection, prognosis, and therapy for lung cancer. 

This Special Issue will provide a comprehensive update on the latest findings on lung cancer-associated genes, with a focus on the clinical application of some mutation genes as biomarkers for cancer diagnosis and prognosis, and treatment prediction, as well as mutation-based therapeutic strategies, may contribute to the development of precision medicine. Original papers and review articles that describe advances in detection methodology, bioinformatics approaches, and statistical analysis with an impact on the clinical application of mutation genes as cancer biomarkers are welcome.

Dr. Vienna Ludovini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Lung cancer
  • Cancer genes
  • Oncogenes
  • Somatic mutations
  • Gene expression profiles
  • Novel therapeutic approaches

Published Papers (3 papers)

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Research

14 pages, 1259 KiB  
Article
Higher TLR7 Gene Expression Predicts Poor Clinical Outcome in Advanced NSCLC Patients Treated with Immunotherapy
by Sara Baglivo, Fortunato Bianconi, Giulio Metro, Alessio Gili, Francesca Romana Tofanetti, Guido Bellezza, Biagio Ricciuti, Martina Mandarano, Valeria Teti, Annamaria Siggillino, Maria Sole Reda, Rita Chiari, Lorenza Pistola, Angelo Sidoni, Vincenzo Minotti, Fausto Roila and Vienna Ludovini
Genes 2021, 12(7), 992; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12070992 - 29 Jun 2021
Cited by 4 | Viewed by 2326
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, their clinical benefit is limited to a minority of patients. To unravel immune-related factors that are predictive of sensitivity or resistance to immunotherapy, we performed a gene expression analysis by RNA-Seq using the Oncomine Immuno Response Assay (OIRRA) on a total of 33 advanced NSCLC patients treated with ICI evaluating the expression levels of 365 immune-related genes. We found four genes (CD1C, HLA-DPA1, MMP2, and TLR7) downregulated (p < 0.05) and two genes (IFNB1 and MKI67) upregulated (p < 0.05) in ICI-Responders compared to ICI-Non-Responders. The Bayesian enrichment computational analysis showed a more complex interaction network that involved 10 other genes (IFNA1, TLR4, CD40, TLR2, IL12A, IL12B, TLR9, CD1E, IFNG, and HLA-DPB1) correlated with different functional groups. Five main pathways were identified (FDR < 0.0001). High TLR7 expression levels were significantly associated with a lack of response to immunotherapy (p < 0.0001) and worse outcome in terms of both PFS (p < 0.001) and OS (p = 0.03). The multivariate analysis confirmed TLR7 RNA expression as an independent predictor for both poor PFS (HR = 2.97, 95% CI, 1.16–7.6, p = 0.023) and OS (HR = 2.2, 95% CI, 1–5.08, p = 0.049). In conclusion, a high TLR7 gene expression level was identified as an independent predictor for poor clinical benefits from ICI. These data could have important implications for the development of novel single/combinatorial strategies TLR-mediated for an efficient selection of “individualized” treatments for NSCLC in the era of immunotherapy. Full article
(This article belongs to the Special Issue Genetics and Genomics of Lung Cancer May Contribute to the Development of Precision Medicine)
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11 pages, 1093 KiB  
Article
Sensitivity to Immune Checkpoint Blockade in Advanced Non-Small Cell Lung Cancer Patients with EGFR Exon 20 Insertion Mutations
by Giulio Metro, Sara Baglivo, Guido Bellezza, Martina Mandarano, Alessio Gili, Giovanni Marchetti, Marco Toraldo, Carmen Molica, Maria Sole Reda, Francesca Romana Tofanetti, Annamaria Siggillino, Enrico Prosperi, Antonella Giglietti, Bruna Di Girolamo, Miriam Garaffa, Francesca Marasciulo, Vincenzo Minotti, Marco Gunnellini, Annalisa Guida, Monica Sassi, Angelo Sidoni, Fausto Roila and Vienna Ludoviniadd Show full author list remove Hide full author list
Genes 2021, 12(5), 679; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050679 - 30 Apr 2021
Cited by 29 | Viewed by 3577
Abstract
Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with [...] Read more.
Besides platinum-based chemotherapy, no established treatment option exists for advanced non-small-cell lung cancer (NSCLC) patients with EGFR exon 20 (Ex20ins) insertion mutations. We sought to determine the clinical outcome of patients with this EGFR mutation subtype in the immunotherapy era. Thirty NSCLCs with EGFR Ex20ins mutations were identified, of whom 15 had received immune checkpoint blockade (ICB) treatment as monotherapy (N = 12), in combination with chemotherapy (N = 2) or with another immunotherapeutic agent (N = 1). The response rate was observed in 1 out of 15 patients (6.7%), median progression-free survival (PFS) was 2.0 months and median overall survival (OS) was 5.3 months. A trend towards an inferior outcome in terms of PFS and OS was observed for patients receiving ICB treatment in the first versus second line setting (PFS: 1.6 months versus 2.7 months, respectively, p = 0.16—OS: 2.0 months versus 8.1 months, respectively, p = 0.09). Median OS from the time of diagnosis of advanced disease was shorter for patients treated with ICB versus those who did not receive immunotherapy (12.9 months versus 25.2 months, respectively, p = 0.08), which difference remained associated with a worse survival outcome at multivariate analysis (p = 0.04). Treatment with ICB is poorly effective in NSCLCs with EGFR Ex20ins mutations, especially when given in the first-line setting. This information is crucial in order to select the optimal treatment strategy for patients with this subtype of EGFR mutation. Full article
(This article belongs to the Special Issue Genetics and Genomics of Lung Cancer May Contribute to the Development of Precision Medicine)
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15 pages, 1310 KiB  
Article
High PD-L1/IDO-2 and PD-L2/IDO-1 Co-Expression Levels Are Associated with Worse Overall Survival in Resected Non-Small Cell Lung Cancer Patients
by Vienna Ludovini, Fortunato Bianconi, Annamaria Siggillino, Jacopo Vannucci, Sara Baglivo, Valeria Berti, Francesca Romana Tofanetti, Maria Sole Reda, Guido Bellezza, Martina Mandarano, Maria Laura Belladonna, Giulio Metro, Rita Chiari, Angelo Sidoni, Francesco Puma, Vincenzo Minotti and Fausto Roila
Genes 2021, 12(2), 273; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020273 - 15 Feb 2021
Cited by 13 | Viewed by 2935
Abstract
Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression [...] Read more.
Programmed death ligand 1 (PD-L1) expression is a predictive biomarker of the success of PD-1/PD-L1 inhibitor therapy for patients with advanced non-small cell lung cancer (NSCLC) but its role as a prognostic marker for early-stage resectable NSCLC remains unclear. We studied gene expression levels of immune-related genes PD-1, PD-L1, PD-L2, IDO-1, IDO-2 and INFγ in tumor tissue of surgically resected NSCLC and correlated the finding with clinicopathological features and patient outcomes. A total of 191 consecutive early-stage NSCLC patients who underwent curative pulmonary resection were studied. The mRNA expression levels of immune-related genes were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Arrays (Qiagen). PD-1, PD-L2 and IDO-2 gene expression levels were significantly higher in patients with squamous histology (p = 0.001, p = 0.021 and p < 0.001; respectively). PD-1, PD-L1 and IDO-2 gene expression levels were significantly higher in patients with higher stage (p = 0.005, p = 0.048 and p = 0.002, respectively). The univariate analysis for recurrence-free survival (RFS) and overall survival (OS) showed that patients with higher levels of three-genes (PD-L1/PD-L2/INFγ) (hazard ratio (HR)) 1.90 (95% confidence interval (CI), 1.13–3.21), p = 0.015) were associated with a worse RFS, while patients with higher levels of both genes (PD-L1/IDO-2) or (PD-L2/IDO-1) were associated with a worse OS (HR 1.63 95% CI, 1.06–2.51, p = 0.024; HR 1.54 95% CI, 1.02–2.33, p = 0.04; respectively). The multivariate interaction model adjusted for histology and stage confirmed that higher levels of three genes (PD-L1/PD-L2/INFγ) were significantly associated with worse RFS (HR 1.98, p = 0.031) and higher levels of both genes (PD-L1/IDO-2) and (PD-L2/IDO-1) with worse OS (HR 1.98, p = 0.042, HR 1.92, p = 0.022). PD-L1/IDO-2 and PD-L2/IDO-1 co-expression high levels are independent negative prognostic factors for survival in early NSCLC. These features may have important implications for future immune-checkpoint therapeutic approaches. Full article
(This article belongs to the Special Issue Genetics and Genomics of Lung Cancer May Contribute to the Development of Precision Medicine)
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