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Prognostic Biomarkers of Lung Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Biomarkers".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 24823

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Special Issue Editors

Dr. Jelena Knezevic

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Guest Editor

Institute Ruder Boskovic, 10000 Zagreb, Croatia
Interests: genetic diversity of innate immunity; molecular and genetic background of different disorders; functional characterization of genetic variants; naturally occurring variants of PRRs; chronic inflammation; COPD; lung cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Luka Brcic

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Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
Interests: mesothelioma; pathogenetic mechanisms of lung and pleural tumors; lung and pleural pathology; mediastinal pathology; fibrosing lung diseases
Special Issues, Collections and Topics in MDPI journals

Dr. András Khoór

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Department of Laboratory Medicine and Pathology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
Interests: lung cancer; pulmonary and breast pathology; adenocarcinoma of the lung

Special Issue Information

Dear Colleagues,

Lung cancer is the leading cause of death, responsible for almost 20% of all cancer-related deaths worldwide. The majority of lung cancer patients are diagnosed at later stages (stages III/IV) when the tumor has already spread to multiple lymph nodes and distant organs, which consequently impacts the median survival time. Prognostic biomarkers, in general, are defined as molecular characteristics that are associated with long-term outcomes or courses of disease. Identifying prognostic biomarkers in lung cancer patients is important because it allows the recognition of patient subpopulations that might anticipate different outcomes or might benefit from different types of therapies. Prognostic biomarkers can be genes (somatic mutations), changes in DNA methylation, mRNA and micro-RNA levels, or protein changes. Advancements in technology, such as mass spectrometry or next-generation sequencing influence a growing number of studies focusing on the identification of the tumor-specific signature. There is no doubt that molecular tumor profiling is a very promising and productive research area that has arisen in the last decade, with numerous emerging biomarkers reported to date. Even though current biomarkers notably improved lung cancer treatment, there is still a need for novel predictors and targeted therapies that could help to achieve better outcomes and cost-effectiveness in treating patients with lung cancer.

In this Special Issue, we invite Authors to discuss different aspects of techniques, approaches and lung cancer tumor types and contribute to a better understanding of disease mechanism and outcomes, especially in the patients diagnosed with advanced stages of disease. We welcome reviews, mini-reviews, new methods, and original research articles.

Dr. Jelena Knezevic
Dr. Luka Brcic
Dr. András Khoór
Guest Editors

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Keywords

lung cancer
EGFR
prognostic biomarkers
mRNA
molecular tumor profiling
ALK
BRAF V600E
PD-L1

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Published Papers (9 papers)

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Research

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20 pages, 3285 KiB

Open AccessArticle

Transcriptomic Profiling for Prognostic Biomarkers in Early-Stage Squamous Cell Lung Cancer (SqCLC)

by Maja Šutić, Branko Dmitrović, Antonia Jakovčević, Feđa Džubur, Nada Oršolić, Željko Debeljak, Asta Försti, Sven Seiwerth, Luka Brčić, Goran Madzarac, Miroslav Samaržija, Marko Jakopović and Jelena Knežević

Cancers 2024, 16(4), 720; https://doi.org/10.3390/cancers16040720 - 8 Feb 2024

Viewed by 2108

Abstract

Squamous cell lung carcinoma (SqCLC) is associated with high mortality and limited treatment options. Identification of therapeutic targets and prognostic biomarkers is still lacking. This research aims to analyze the transcriptomic profile of SqCLC samples and identify the key genes associated with tumorigenesis, overall survival (OS), and a profile of the tumor-infiltrating immune cells. Differential gene expression analysis, pathway enrichment analysis, and Gene Ontology analysis on RNA-seq data obtained from FFPE tumor samples (N = 23) and healthy tissues (N = 3) were performed (experimental cohort). Validation of the results was conducted on publicly available gene expression data using TCGA LUSC (N = 225) and GTEx healthy donors’ cohorts (N = 288). We identified 1133 upregulated and 644 downregulated genes, common for both cohorts. The most prominent upregulated genes were involved in cell cycle and proliferation regulation pathways (MAGEA9B, MAGED4, KRT, MMT11/13), while downregulated genes predominately belonged to immune-related pathways (DEFA1B, DEFA1, DEFA3). Results of the survival analysis, conducted on the validation cohort and commonly deregulated genes, indicated that overexpression of HOXC4 (p < 0.001), LLGL1 (p = 0.0015), and SLC4A3 (p = 0.0034) is associated with worse OS in early-stage SqCLC patients. In contrast, overexpression of GSTZ1 (p = 0.0029) and LILRA5 (p = 0.0086) was protective, i.e., associated with better OS. By applying a single-sample gene-set enrichment analysis (ssGSEA), we identified four distinct immune subtypes. Immune cell distribution suggests that the memory T cells (central and effector) and follicular helper T cells could serve as important stratification parameters. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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27 pages, 9765 KiB

Open AccessArticle

A 15-Gene-Based Risk Signature for Predicting Overall Survival in SCLC Patients Who Have Undergone Surgical Resection

by Sevcan Atay

Cancers 2023, 15(21), 5219; https://doi.org/10.3390/cancers15215219 - 30 Oct 2023

Viewed by 1462

Abstract

Small cell lung cancer (SCLC) is a malignancy with a poor prognosis whose treatment has not progressed for decades. The survival benefit of surgery and the selection of surgical candidates are still controversial in SCLC. This study is the first report to identify transcriptomic alterations associated with prognosis and propose a gene expression-based risk signature that can be used to predict overall survival (OS) in SCLC patients who have undergone potentially curative surgery. An integrative transcriptome analysis of three gene expression datasets (GSE30219, GSE43346, and GSE149507) revealed 1734 up-regulated and 2907 down-regulated genes. Cox-Mantel test, Cox regression, and Lasso regression analyses were used to identify genes to be included in the risk signature. EGAD00001001244 and GSE60052-cohorts were used for internal and external validation, respectively. Overall survival was significantly poorer in patients with high-risk scores compared to the low-risk group. The discriminatory performance of the risk signature was superior to other parameters. Multivariate analysis showed that the risk signature has the potential to be an independent predictor of prognosis. The prognostic genes were enriched in pathways including regulation of transcription, cell cycle, cell metabolism, and angiogenesis. Determining the roles of the identified prognostic genes in the pathogenesis of SCLC may contribute to the development of new treatment strategies. The risk signature needs to be validated in a larger cohort of patients to test its usefulness in clinical decision-making. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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11 pages, 268 KiB

Open AccessArticle

The Challenges and Opportunities of the Implementation of Comprehensive Genomic Profiling in Everyday Clinical Practice with Non-Small Cell Lung Cancer: National Results from Croatia

by Dora Čerina, Kristina Krpina, Marko Jakopović, Natalija Dedić Plavetić, Fran Seiwerth, Snježana Tomić, Jasna Radić, Ingrid Belac Lovasić, Ivana Canjko, Marijo Boban, Miroslav Samaržija and Eduard Vrdoljak

Cancers 2023, 15(13), 3395; https://doi.org/10.3390/cancers15133395 - 28 Jun 2023

Cited by 1 | Viewed by 1758

Abstract

Non–small cell lung cancer (NSCLC) has become the best example of precision oncology’s impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1–3) CRGA per patient. From the panel of recommended tests, KRAS, MET, and EGFR were the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

14 pages, 2823 KiB

Open AccessArticle

Prognostic Value of Chromatin Structure Typing in Early-Stage Non-Small Cell Lung Cancer

by Luning Mao, Jianghua Wu, Zhongjie Zhang, Lijun Mao, Yuejin Dong, Zufeng He, Haiyue Wang, Kaiwen Chi, Yumeng Jiang and Dongmei Lin

Cancers 2023, 15(12), 3171; https://doi.org/10.3390/cancers15123171 - 13 Jun 2023

Cited by 1 | Viewed by 1193

Abstract

(1) Background: Chromatin structure typing has been used for prognostic risk stratification among cancer survivors. This study aimed to ascertain the prognostic values of ploidy, nucleotyping, and tumor–stroma ratio (TSR) in predicting disease progression for patients with early-stage non-small cell lung cancer (NSCLC), and to explore whether patients with different nucleotyping profiles can benefit from adjuvant chemotherapy. (2) Methods: DNA ploidy, nucleotyping, and TSR were measured by chromatin structure typing analysis (Matrix Analyser, Room4, Kent, UK). Cox proportional hazard regression models were used to assess the relationships of DNA ploidy, nucleotyping, and TSR with a 5-year disease-free survival (DFS). (3) Results: among 154 early-stage NSCLC patients, 102 were non-diploid, 40 had chromatin heterogeneity, and 126 had a low stroma fraction, respectively. Univariable analysis suggested that non-diploidy was associated with a significantly lower 5-year DFS rate. After combining DNA ploidy and nucleotyping for risk stratification and adjusting for potential confounders, the DNA ploidy and nucleotyping (PN) high-risk group and PN medium-risk group had a 4- (95% CI: 1.497–8.754) and 3-fold (95% CI: 1.196–6.380) increase in the risk of disease progression or mortality within 5 years of follow-up, respectively, compared to the PN low-risk group. In PN high-risk patients, adjuvant therapy was associated with a significantly improved 5-year DFS (HR = 0.214, 95% CI: 0.048–0.957, p = 0.027). (4) Conclusions: the non-diploid DNA status and the combination of ploidy and nucleotyping can be useful prognostic indicators to predict long-term outcomes in early-stage NSCLC patients. Additionally, NSCLC patients with non-diploidy and chromatin homogenous status may benefit from adjuvant therapy. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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13 pages, 1863 KiB

Open AccessArticle

Regulation of VEGFR2 and AKT Signaling by Musashi-2 in Lung Cancer

by Igor Bychkov, Iuliia Topchu, Petr Makhov, Alexander Kudinov, Jyoti D. Patel and Yanis Boumber

Cancers 2023, 15(9), 2529; https://doi.org/10.3390/cancers15092529 - 28 Apr 2023

Cited by 2 | Viewed by 2029

Abstract

Lung cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) represents most of the diagnoses of lung cancer. Vascular endothelial growth factor receptor-2 (VEGFR2) is a member of the VEGF family of receptor tyrosine kinase proteins, which are expressed on both endothelial and tumor cells, are one of the key proteins contributing to cancer development, and are involved in drug resistance. We previously showed that Musashi-2 (MSI2) RNA-binding protein is associated with NSCLC progression by regulating several signaling pathways relevant to NSCLC. In this study, we performed Reverse Protein Phase Array (RPPA) analysis of murine lung cancer, which suggests that VEGFR2 protein is strongly positively regulated by MSI2. Next, we validated VEGFR2 protein regulation by MSI2 in several human lung adenocarcinoma cell line models. Additionally, we found that MSI2 affected AKT signaling via negative PTEN mRNA translation regulation. In silico prediction analysis suggested that both VEGFR2 and PTEN mRNAs have predicted binding sites for MSI2. We next performed RNA immunoprecipitation coupled with quantitative PCR, which confirmed that MSI2 directly binds to VEGFR2 and PTEN mRNAs, suggesting a direct regulation mechanism. Finally, MSI2 expression positively correlated with VEGFR2 and VEGF-A protein levels in human lung adenocarcinoma samples. We conclude that the MSI2/VEGFR2 axis contributes to lung adenocarcinoma progression and is worth further investigations and therapeutic targeting. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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18 pages, 1712 KiB

Open AccessArticle

LC-MS/MS Based Volatile Organic Compound Biomarkers Analysis for Early Detection of Lung Cancer

by Shuaibu Nazifi Sani, Wei Zhou, Balarabe B. Ismail, Yongkui Zhang, Zhijun Chen, Binjie Zhang, Changqian Bao, Houde Zhang and Xiaozhi Wang

Cancers 2023, 15(4), 1186; https://doi.org/10.3390/cancers15041186 - 13 Feb 2023

Cited by 15 | Viewed by 4419

Abstract

(1) Background: lung cancer is the world’s deadliest cancer, but early diagnosis helps to improve the cure rate and thus reduce the mortality rate. Annual low-dose computed tomography (LD-CT) screening is an efficient lung cancer-screening program for a high-risk population. However, LD-CT has often been characterized by a higher degree of false-positive results. To meet these challenges, a volatolomic approach, in particular, the breath volatile organic compounds (VOCs) fingerprint analysis, has recently received increased attention for its application in early lung cancer screening thanks to its convenience, non-invasiveness, and being well tolerated by patients. (2) Methods: a LC-MS/MS-based volatolomics analysis was carried out according to P/N 5046800 standard based breath analysis of VOC as novel cancer biomarkers for distinguishing early-stage lung cancer from the healthy control group. The discriminatory accuracy of identified VOCs was assessed using subject work characterization and a random forest risk prediction model. (3) Results: the proposed technique has good performance compared with existing approaches, the differences between the exhaled VOCs of the early lung cancer patients before operation, three to seven days after the operation, as well as four to six weeks after operation under fasting and 1 h after the meal were compared with the healthy controls. The results showed that only 1 h after a meal, the concentration of seven VOCs, including 3-hydroxy-2-butanone (TG-4), glycolaldehyde (TG-7), 2-pentanone (TG-8), acrolein (TG-11), nonaldehyde (TG-19), decanal (TG-20), and crotonaldehyde (TG-22), differ significantly between lung cancer patients and control, with the invasive adenocarcinoma of the lung (IAC) having the most significant difference. (4) Conclusions: this novel, non-invasive approach can improve the detection rate of early lung cancer, and LC-MS/MS-based breath analysis could be a promising method for clinical application. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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Review

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16 pages, 2244 KiB

Open AccessReview

Rictor—A Mediator of Progression and Metastasis in Lung Cancer

by Fatime Szalai, Dániel Sztankovics, Ildikó Krencz, Dorottya Moldvai, Judit Pápay, Anna Sebestyén and Andras Khoor

Cancers 2024, 16(3), 543; https://doi.org/10.3390/cancers16030543 - 26 Jan 2024

Cited by 2 | Viewed by 1873

Abstract

Lung carcinoma is one of the most common cancer types for both men and women. Despite recent breakthroughs in targeted therapy and immunotherapy, it is characterized by a high metastatic rate, which can significantly affect quality of life and prognosis. Rictor (encoded by the RICTOR gene) is known as a scaffold protein for the multiprotein complex mTORC2. Among its diverse roles in regulating essential cellular functions, mTORC2 also facilitates epithelial–mesenchymal transition and metastasis formation. Amplification of the RICTOR gene and subsequent overexpression of the Rictor protein can result in the activation of mTORC2, which promotes cell survival and migration. Based on recent studies, RICTOR amplification or Rictor overexpression can serve as a marker for mTORC2 activation, which in turn provides a promising druggable target. Although selective inhibitors of Rictor and the Rictor-mTOR association are only in a preclinical phase, they seem to be potent novel approaches to reduce tumor cell migration and metastasis formation. Here, we summarize recent advances that support an important role for Rictor and mTORC2 as potential therapeutic targets in the treatment of lung cancer. This is a traditional (narrative) review based on Pubmed and Google Scholar searches for the following keywords: Rictor, RICTOR amplification, mTORC2, Rictor complexes, lung cancer, metastasis, progression, mTOR inhibitors. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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30 pages, 994 KiB

Open AccessReview

Advances in Genomic Data and Biomarkers: Revolutionizing NSCLC Diagnosis and Treatment

by Juan Carlos Restrepo, Diana Dueñas, Zuray Corredor and Yamil Liscano

Cancers 2023, 15(13), 3474; https://doi.org/10.3390/cancers15133474 - 3 Jul 2023

Cited by 19 | Viewed by 6414

Abstract

Non-small cell lung cancer (NSCLC) is a significant public health concern with high mortality rates. Recent advancements in genomic data, bioinformatics tools, and the utilization of biomarkers have improved the possibilities for early diagnosis, effective treatment, and follow-up in NSCLC. Biomarkers play a crucial role in precision medicine by providing measurable indicators of disease characteristics, enabling tailored treatment strategies. The integration of big data and artificial intelligence (AI) further enhances the potential for personalized medicine through advanced biomarker analysis. However, challenges remain in the impact of new biomarkers on mortality and treatment efficacy due to limited evidence. Data analysis, interpretation, and the adoption of precision medicine approaches in clinical practice pose additional challenges and emphasize the integration of biomarkers with advanced technologies such as genomic data analysis and artificial intelligence (AI), which enhance the potential of precision medicine in NSCLC. Despite these obstacles, the integration of biomarkers into precision medicine has shown promising results in NSCLC, improving patient outcomes and enabling targeted therapies. Continued research and advancements in biomarker discovery, utilization, and evidence generation are necessary to overcome these challenges and further enhance the efficacy of precision medicine. Addressing these obstacles will contribute to the continued improvement of patient outcomes in non-small cell lung cancer. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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17 pages, 1070 KiB

Open AccessReview

Phospholipase Family Enzymes in Lung Cancer: Looking for Novel Therapeutic Approaches

by Sara Salucci, Beatrice Aramini, Anna Bartoletti-Stella, Ilaria Versari, Giovanni Martinelli, William Blalock, Franco Stella and Irene Faenza

Cancers 2023, 15(12), 3245; https://doi.org/10.3390/cancers15123245 - 19 Jun 2023

Cited by 4 | Viewed by 2379

Abstract

Lung cancer (LC) is the second most common neoplasm in men and the third most common in women. In the last decade, LC therapies have undergone significant improvements with the advent of immunotherapy. However, the effectiveness of the available treatments remains insufficient due to the presence of therapy-resistant cancer cells. For decades, chemotherapy and radiotherapy have dominated the treatment strategy for LC; however, relapses occur rapidly and result in poor survival. Malignant lung tumors are classified as either small- or non-small-cell lung carcinoma (SCLC and NSCLC). Despite improvements in the treatment of LC in recent decades, the benefits of surgery, radiotherapy, and chemotherapy are limited, although they have improved the prognosis of LC despite the persistent low survival rate due to distant metastasis in the late stage. The identification of novel prognostic molecular markers is crucial to understand the underlying mechanisms of LC initiation and progression. The potential role of phosphatidylinositol in tumor growth and the metastatic process has recently been suggested by some researchers. Phosphatidylinositols are lipid molecules and key players in the inositol signaling pathway that have a pivotal role in cell cycle regulation, proliferation, differentiation, membrane trafficking, and gene expression. In this review, we discuss the current understanding of phosphoinositide-specific phospholipase enzymes and their emerging roles in LC. Full article

(This article belongs to the Special Issue Prognostic Biomarkers of Lung Cancer)

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