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Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 16227

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Dr. Fabian Dominik Mairinger

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Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Interests: molecular pathology; translational cancer research; bioinformatics; thoracic oncology; biomarkers; cellular signaling; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Thomas Mairinger

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Department of Tissue Diagnostics, Helios Klinikum Emil von Behring, 14165 Berlin, Germany
Interests: thoracic pathology; biomarkers; molecular diagnostics; digital pathology; telemedicine; artificial intelligence in pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the last 15 years, lung cancer diagnosis and therapy underwent two game-changing revolutions. We witnessed the introduction of so-called “individualized” therapy driven by, in addition to more conventional tumor characteristics, a well-defined molecular phenotype from each tumor that serve as prognostic and much more predictive factors for the therapeutic faith of patients.

In only a short time, the therapeutic use of immune checkpoint inhibitors followed tailored therapeutic approaches, opening a new field of effective treatment for a remarkable proportion of lung cancer patients. The suitability criteria that must be treated following this approach, however, are not that well-defined and based on semiquantitative (merely classical) immunohistochemistry scoring.

Paying tribute to these 15 years of development, this Special Issue targets aims to share the state-of-the-art advances in biomarker-based lung cancer diagnosis and therapy, and its promising concepts for future developments. This clear focus is on the interface between molecular diagnosis and lung cancer therapy, thus all types of papers with a clear focus on the molecular alterations that influence the pathology aspects of lung cancer patients are welcomed.

Dr. Fabian Dominik Mairinger
Prof. Dr. Thomas Mairinger
Guest Editors

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

lung cancer
molecular pathology
molecular diagnosis
biomarker-driven therapy
immunotherapy
immune checkpoint inhibitors
personalized tumor therapy
cancer diagnosis

Published Papers (8 papers)

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Research

13 pages, 4996 KiB

Open AccessArticle

Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model

by Sabrina Borchert, Alexander Mathilakathu, Alina Nath, Michael Wessolly, Elena Mairinger, Daniel Kreidt, Julia Steinborn, Robert F. H. Walter, Daniel C. Christoph, Jens Kollmeier, Jeremias Wohlschlaeger, Thomas Mairinger, Luka Brcic and Fabian D. Mairinger

Int. J. Mol. Sci. 2023, 24(15), 12426; https://doi.org/10.3390/ijms241512426 - 04 Aug 2023

Cited by 1 | Viewed by 1183

Abstract

The exact mechanism of desmoplastic stromal reaction (DSR) formation is still unclear. The interaction between cancer cells and cancer-associated fibroblasts (CAFs) has an important role in tumor progression, while stromal changes are a poor prognostic factor in pleural mesothelioma (PM). We aimed to assess the impact of CAFs paracrine signaling within the tumor microenvironment and the DSR presence on survival, in a cohort of 77 PM patients. DSR formation was evaluated morphologically and by immunohistochemistry for Fibroblast activation protein alpha (FAP). Digital gene expression was analyzed using a custom-designed CodeSet (NanoString). Decision-tree-based analysis using the “conditional inference tree” (CIT) machine learning algorithm was performed on the obtained results. A significant association between FAP gene expression levels and the appearance of DSR was found (p = 0.025). DSR-high samples demonstrated a statistically significant prolonged median survival time. The elevated expression of MYT1, KDR, PIK3R1, PIK3R4, and SOS1 was associated with shortened OS, whereas the upregulation of VEGFC, FAP, and CDK4 was associated with prolonged OS. CIT revealed a three-tier system based on FAP, NF1, and RPTOR expressions. We could outline the prognostic value of CAFs-induced PI3K signaling pathway activation together with FAP-dependent CDK4 mediated cell cycle progression in PM, where prognostic and predictive biomarkers are urgently needed to introduce new therapeutic strategies. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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10 pages, 1100 KiB

Open AccessCommunication

Rapid and Cost-Efficient Detection of RET Rearrangements in a Large Consecutive Series of Lung Carcinomas

by Vladislav I. Tiurin, Elena V. Preobrazhenskaya, Natalia V. Mitiushkina, Aleksandr A. Romanko, Aleksandra A. Anuskina, Rimma S. Mulkidjan, Evgeniya S. Saitova, Elena A. Krivosheyeva, Elena D. Kharitonova, Mikhail P. Shevyakov, Ilya A. Tryakin, Svetlana N. Aleksakhina, Aigul R. Venina, Tatiana N. Sokolova, Aleksandr S. Martianov, Anna D. Shestakova, Alexandr O. Ivantsov, Aglaya G. Iyevleva and Evgeny N. Imyanitov

Int. J. Mol. Sci. 2023, 24(13), 10530; https://doi.org/10.3390/ijms241310530 - 23 Jun 2023

Cited by 4 | Viewed by 1250

Abstract

RET-kinase-activating gene rearrangements occur in approximately 1–2% of non-small-cell lung carcinomas (NSCLCs). Their reliable detection requires next-generation sequencing (NGS), while conventional methods, such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) or variant-specific PCR, have significant limitations. We developed an assay that compares the level of RNA transcripts corresponding to 5′- and 3′-end portions of the RET gene; this test relies on the fact that RET translocations result in the upregulation of the kinase domain of the gene and, therefore, the 5′/3′-end expression imbalance. The present study included 16,106 consecutive NSCLC patients, 14,449 (89.7%) of whom passed cDNA quality control. The 5′/3′-end unbalanced RET expression was observed in 184 (1.3%) tumors, 169 of which had a sufficient amount of material for the identification of translocation variants. Variant-specific PCR revealed RET rearrangements in 155/169 (91.7%) tumors. RNA quality was sufficient for RNA-based NGS in 10 cases, 8 of which carried exceptionally rare or novel (HOOK1::RET and ZC3H7A::RET) RET translocations. We also applied variant-specific PCR for eight common RET rearrangements in 4680 tumors, which emerged negative upon the 5′/3′-end unbalanced expression test; 33 (0.7%) of these NSCLCs showed RET fusion. While the combination of the analysis of 5′/3′-end RET expression imbalance and variant-specific PCR allowed identification of RET translocations in approximately 2% of consecutive NSCLCs, this estimate approached 120/2361 (5.1%) in EGFR/KRAS/ALK/ROS1/BRAF/MET-negative carcinomas. RET-rearranged tumors obtained from females, but not males, had a decreased level of expression of thymidylate synthase (p < 0.00001), which is a known predictive marker of the efficacy of pemetrexed. The results of our study provide a viable alternative for RET testing in facilities that do not have access to NGS due to cost or technical limitations. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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19 pages, 8846 KiB

Open AccessArticle

Prognostic Value and Genome Signature of m6A/m5C Regulated Genes in Early-Stage Lung Adenocarcinoma

by Long Tian, Yan Wang, Jie Tian, Wenpeng Song, Lu Li and Guowei Che

Int. J. Mol. Sci. 2023, 24(7), 6520; https://doi.org/10.3390/ijms24076520 - 30 Mar 2023

Cited by 3 | Viewed by 2058

Abstract

RNA modifications implicate pathological and prognosis significance in cancer development and progression, of which, m6A and m5C are representative regulators. These RNA modifications could produce effects on the function of other RNA by regulating gene expression. Thus, in this study, we aimed to explore the correlation between m6A/m5C regulators and early-stage lung adenocarcinoma (LUAD). Only the early-stage LUAD samples were included in this investigation, and the RNA-seq dataset of The Cancer Genome Atlas (TCGA) cohort was utilized to evaluate the expression of 37 m6A/m5C regulated genes. Based on the expression level of these 37 genes, early-stage LUAD patients were divided into 2 clusters, which were performed by consensus clustering, and the m6A/m5C subtypes had significantly different prognostic outcomes (p < 0.001). Cluster1, which has a better prognosis, was characterized by the C3 (inflammatory) immune subtype, low immune infiltration, chemokine expression, major histocompatibility complex (MHC) expression, and immune checkpoint molecule expression. Furthermore, compared with cluster1, cluster2 showed a T cell exhaustion state, characterized by a high expression of immune checkpoint genes, and immune cells, such as T cells, CD8+ T cells, cytotoxic lymphocytes, NK cells, and so on. In addition, patients in cluster2 were with high tumor mutational burden (TMB) and numerous significant mutated oncogene and tumor suppressor genes, such as WNT10B, ERBB4, SMARCA4, TP53, and CDKN2A (p < 0.001). A total of 19 genes were mostly related to the prognosis of LUAD and were upregulated in cluster2 (p < 0.05), showing a positive correlation with the mRNA expression of 37 m6A/m5C regulated genes. The predictive risk model was constructed using Cox and LASSO (least absolute shrinkage and selection operator) regression analysis. Finally, a seven-gene m6A/m5C risk model, comprising of METTL3, NPLOC4, RBM15, YTHDF1, IGF2BP1, NSUN3, and NSUN7, was constructed to stratify the prognosis of early-stage LUAD (p = 0.0049, AUC = 0.791). The high-risk score was associated with a poorer prognosis. This model was also validated using two additional GEO datasets: GSE72094 (p = 0.011, AUC = 0.736) and GSE50081 (p = 0.012, AUC = 0.628). In summary, it was established that the m6A/m5C-regulated genes performed a crosstalk function in the mRNA expression of early-stage LUAD. By interacting with other mRNA genes, m6A/m5C modification disturbs DNA replication and the tumor immune microenvironment (TIME). The seven-gene risk model may be a critical tool for the prognostic assessment of early-stage LUAD. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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13 pages, 928 KiB

Open AccessArticle

Comparison between Three Different Techniques for the Detection of EGFR Mutations in Liquid Biopsies of Patients with Advanced Stage Lung Adenocarcinoma

by Milena Casula, Marina Pisano, Panagiotis Paliogiannis, Maria Colombino, Maria Cristina Sini, Angelo Zinellu, Davide Santeufemia, Antonella Manca, Stefania Casula, Silvia Tore, Renato Lobrano, Sardinian Lung Cancer Study Group, Antonio Cossu and Giuseppe Palmieri

Int. J. Mol. Sci. 2023, 24(7), 6410; https://doi.org/10.3390/ijms24076410 - 29 Mar 2023

Cited by 4 | Viewed by 1588

Abstract

Oncogenic mutations in the EGFR gene are targets of tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LC) patients, and their search is mandatory to make decisions on treatment strategies. Liquid biopsy of circulating tumour DNA (ctDNA) is increasingly used to detect EGFR mutations, including main activating alterations (exon 19 deletions and exon 21 L858R mutation) and T790M mutation, which is the most common mechanism of acquired resistance to first- and second-generation TKIs. In this study, we prospectively compared three different techniques for EGFR mutation detection in liquid biopsies of such patients. Fifty-four ctDNA samples from 48 consecutive advanced LC patients treated with TKIs were tested for relevant EGFR mutations with Therascreen^® EGFR Plasma RGQ-PCR Kit (Qiagen). Samples were subsequently tested with two different technologies, with the aim to compare the EGFR detection rates: real-time PCR based Idylla™ ctEGFR mutation assay (Biocartis) and next-generation sequencing (NGS) system with Ion AmpliSeq Cancer Hotspot panel (ThermoFisher). A high concordance rate for main druggable EGFR alterations was observed with the two real-time PCR-based assays, ranging from 100% for T790M mutation to 94% for L858R variant and 85% for exon 19 deletions. Conversely, lower concordance rates were found between real-time PCR approaches and the NGS method (L858R: 88%; exon19-dels: 74%; T790M: 37.5%). Our results evidenced an equivalent detection ability between PCR-based techniques for circulating EGFR mutations. The NGS assay allowed detection of a wider range of EGFR mutations but showed a poor ability to detect T790M. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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19 pages, 6199 KiB

Open AccessArticle

Fascaplysin Induces Apoptosis and Ferroptosis, and Enhances Anti-PD-1 Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) by Promoting PD-L1 Expression

by Lianxiang Luo and Guangxiang Xu

Int. J. Mol. Sci. 2022, 23(22), 13774; https://doi.org/10.3390/ijms232213774 - 09 Nov 2022

Cited by 10 | Viewed by 2354

Abstract

Fascaplysin is a natural product isolated from sponges with a wide range of anticancer activities. However, the mechanism of fascaplysin against NSCLC has not been clearly studied. In this study, fascaplysin was found to inhibit migration by regulating the wnt/β-catenin signaling pathway and reversing the epithelial–mesenchymal transition phenotype. Further research showed that the anti-NSCLC effect of fascaplysin was mainly through the induction of ferroptosis and apoptosis. Fascaplysin-induced ferroptosis in lung cancer cells, evidenced by increased levels of ROS and Fe²⁺ and downregulation of ferroptosis-associated protein and endoplasmic reticulum stress, was involved in fascaplysin-induced ferroptosis. In addition, ROS was found to mediate fascaplysin-induced apoptosis. Fascaplysin significantly upregulated the expression of PD-L1 in lung cancer cells, and enhanced anti-PD-1 antitumor efficacy in a syngeneic mouse model. Therefore, these results suggest that fascaplysin exerts anticancer effects by inducing apoptosis and ferroptosis in vitro, and improving the sensitivity of anti-PD-1 immunotherapy in vivo. Fascaplysin is a promising compound for the treatment of NSCLC. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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19 pages, 1959 KiB

Open AccessArticle

Landscape of Genomic Alterations and PD-L1 Expression in Early-Stage Non-Small-Cell Lung Cancer (NSCLC)—A Single Center, Retrospective Observational Study

by Susann Stephan-Falkenau, Anna Streubel, Thomas Mairinger, Jens Kollmeier, Daniel Misch, Sebastian Thiel, Torsten Bauer, Joachim Pfannschmidt, Manuel Hollmann, Michael Wessolly and Torsten Gerriet Blum

Int. J. Mol. Sci. 2022, 23(20), 12511; https://doi.org/10.3390/ijms232012511 - 19 Oct 2022

Cited by 3 | Viewed by 2392

Abstract

Precision oncology and immunotherapy have revolutionized the treatment of advanced non-small-cell lung cancer (NSCLC). Emerging studies show that targeted therapies are also beneficial for patients with driver alterations such as epidermal growth factor receptor (EGFR) mutations in early-stage NSCLC (stages I–IIIA). Furthermore, patients with elevated programmed death-ligand 1 (PD-L1) expression appear to respond favorably to adjuvant immunotherapy. To determine the frequency of genomic alterations and PD-L1 status in early-stage NSCLC, we retrospectively analyzed data from 2066 unselected, single-center patients with NSCLC diagnosed using next-generation sequencing and immunohistochemistry. Nine-hundred and sixty-two patients (46.9%) presented with early-stage NSCLC. Of these, 37.0% had genomic alterations for which targeted therapies have already been approved for advanced NSCLC. The frequencies of driver mutations in the early stages were equivalent to those in advanced stages, i.e., the rates of EGFR mutations in adenocarcinomas were 12.7% (72/567) and 12.0% (78/650) in early and advanced NSCLC, respectively (p = 0778). In addition, 46.3% of early-stage NSCLC cases were PD-L1-positive, with a tumor proportion score (TPS) of ≥1%. With comparable frequencies of driver mutations in early and advanced NSCLC and PD-L1 overexpression in nearly half of patients with early-stage NSCLC, a broad spectrum of biomarkers for adjuvant and neoadjuvant therapies is available, and several are currently being investigated in clinical trials. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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11 pages, 1820 KiB

Open AccessArticle

Monitoring Circulating Tumor DNA in Untreated Non-Small-Cell Lung Cancer Patients

by Woo Kyung Ryu, Sekyung Oh, Jun Hyeok Lim, Seung Jae Lee, Hyun-Tae Shin and Jeong-Seon Ryu

Int. J. Mol. Sci. 2022, 23(17), 9527; https://doi.org/10.3390/ijms23179527 - 23 Aug 2022

Cited by 4 | Viewed by 1948

Abstract

Circulating tumor DNA (ctDNA) has been utilized to monitor the clinical course of patients of non-small-cell lung cancer (NSCLC) who receive therapies targeting druggable mutations. However, despite providing valuable information on how NSCLC would naturally progress, the clinical utility of ctDNA for clinical-course monitoring and prediction of treatment-naïve NSCLC patients without druggable mutations remain unknown. We longitudinally followed a total of 12 treatment-naïve NSCLC patients, who did not harbor EGFR and ALK mutations, by collecting clinical information, radiological data, and plasma samples. Changes in ctDNA levels and tumor burden (TB) were compared with each other. New metastasis development, volume doubling time (VDT), and overall survival (OS) were analyzed regarding ctDNA detection at diagnosis. ctDNA was detected in the plasma of seven (58.3%) patients. Changes in ctDNA levels correlated with those in TB in a substantial fraction (57.1%) of patients and was also associated with brain metastasis, tumor necrosis, or pneumonia in other patients. All patients with ctDNA detection developed new metastasis during follow-ups in the organs that had been devoid of metastasis at diagnosis. The patients without ctDNA detection did not develop new metastasis (median duration of follow-ups: 9.8 months). In addition, patients with ctDNA detection had shorter VDT (p = 0.039) and worse OS (p = 0.019) than those without ctDNA detection. The natural course of NSCLC progression can be monitored by measuring ctDNA levels. Detection of ctDNA at diagnosis can predict development of new metastasis, rapid tumor growth and poor survival of NSCLC patients. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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13 pages, 30676 KiB

Open AccessArticle

PD-L1 Expression in Non-Small Cell Lung Cancer Specimens: Association with Clinicopathological Factors and Molecular Alterations

by Mohammed S. I. Mansour, Karina Malmros, Ulrich Mager, Kajsa Ericson Lindquist, Kim Hejny, Benjamin Holmgren, Tomas Seidal, Annika Dejmek, Katalin Dobra, Maria Planck and Hans Brunnström

Int. J. Mol. Sci. 2022, 23(9), 4517; https://doi.org/10.3390/ijms23094517 - 19 Apr 2022

Cited by 6 | Viewed by 2400

Abstract

Immune checkpoint inhibitors (ICI) targeting programmed cell death-1 or its ligand (PD-L1) have improved outcomes in non-small cell lung cancer (NSCLC). High tumor PD-L1 expression, detected by immunohistochemistry (IHC) typically on formalin-fixed paraffin-embedded (FFPE) histological specimens, is linked to better response. Following our previous investigation on PD-L1 in cytological samples, the aim of this study was to further explore the potential impacts of various clinicopathological and molecular factors on PD-L1 expression. Two retrospective NSCLC cohorts of 1131 and 651 specimens, respectively, were investigated for PD-L1 expression (<1%/1–49%/≥50%), sample type, sample site, histological type, and oncogenic driver status. In both cohorts, PD-L1 was positive (≥1%) in 55% of the cases. Adenocarcinomas exhibited lower PD-L1 expression than squamous cell carcinomas (p < 0.0001), while there was no difference between sample types, tumor locations, or between the two cohorts in multivariate analysis (all p ≥ 0.28). Mutational status correlated significantly with PD-L1 expression (p < 0.0001), with the highest expression for KRAS-mutated cases, the lowest for EGFR-mutated, and the KRAS/EGFR wild-type cases in between. There was no difference in PD-L1 levels between different prevalent KRAS mutations (all p ≥ 0.44), while mucinous KRAS-mutated adenocarcinomas exhibited much lower PD-L1 expression than non-mucinous (p < 0.0001). Our data indicate that cytological and histological specimens are comparable for PD-L1 evaluation. Given the impact of KRAS mutations and the mucinous growth pattern on PD-L1 expression, these factors should be further investigated in studies on ICI response. Full article

(This article belongs to the Special Issue Lung Cancer: From Molecular Basis to Genome-Guided Therapy and Immunotherapy)

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