Lung cancer stands as the leading cause of cancer-related deaths worldwide, presenting a major public health challenge. It is primarily classified into two main types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), each with distinct clinical and pathological features. Recent decades have seen remarkable advancements in the diagnosis, treatment, and understanding of lung cancer, particularly with the development of targeted therapies and immune checkpoint inhibitors for NSCLC, which have significantly improved survival rates for certain patient groups. The role of genetic mutations and molecular profiling has become central to selecting the most effective treatments, marking a shift towards personalized medicine in lung cancer care. Screening programs, especially those utilizing low-dose CT scans, have proven effective in early detection among high-risk populations, thereby enhancing the potential for curative treatment interventions. Despite advances, the five-year survival rate remains dismally low, largely due to late diagnoses. Early detection, therefore, is paramount to improving outcomes, highlighting the critical role of biomarkers in non-invasive screening and diagnosis. These biomarkers, found in body fluids like blood and sputum, offer hope for early intervention, potentially revolutionizing lung cancer management and patient survival rates.
Figure 1 Currently explored biomarker candidates for lung cancer screening. (Seijo, 2019)
Keratin 19 (KRT19) is a member of the keratin family, which comprises a diverse group of fibrous proteins that form the intermediate filament network providing structural support to epithelial cells. KRT19 is particularly noted for its expression in epithelial tissues and is recognized as the smallest human keratin. Its expression is associated with epithelial cell integrity and dynamics, playing a critical role in cell structure, stress response, and signaling pathways. KRT19 is frequently overexpressed in lung cancer cells, particularly in non-small cell lung cancer (NSCLC), where its levels can correlate with tumor aggressiveness, metastatic potential, and patient prognosis. The utility of KRT19 as a biomarker in circulating tumor cells (CTCs) has been explored for early detection, monitoring treatment response, and predicting disease recurrence. Its roles in lung cancer also extend to molecular mechanisms including involvement in epithelial-mesenchymal transition (EMT), a process crucial for cancer metastasis, where KRT19 expression may modulate cell adhesion, migration, and invasiveness. Thus, KRT19 serves as a key molecule at the intersection of cellular biology and oncology, offering insights into tumor behavior and avenues for targeted therapies in lung cancer.
The Epidermal Growth Factor Receptor (EGFR) is a transmembrane glycoprotein that is part of the ErbB family of tyrosine kinase receptors, which play a crucial role in the regulation of cell growth, survival, proliferation, and differentiation. It is activated by binding to its specific ligands, such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), leading to a cascade of downstream signaling pathways that promote cellular responses pivotal for development and homeostasis. In the context of lung cancer, particularly non-small cell lung cancer (NSCLC), EGFR is of significant interest due to its overexpression or mutation in a substantial fraction of cases, driving tumor growth and survival. EGFR mutations, predominantly found in the tyrosine kinase domain, alter receptor function, leading to increased kinase activity and uncontrolled cell division. Such mutations are more common in specific populations, including non-smokers, women, and individuals of East Asian descent. Targeted therapies against EGFR, including tyrosine kinase inhibitors (TKIs) like erlotinib and gefitinib, have been developed, offering a personalized treatment approach that has significantly improved outcomes for patients with EGFR-mutant NSCLC.
Enolase 2 (ENO2), also known as neuron-specific enolase (NSE), is a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate, a critical step in the glycolytic pathway. This isoform of enolase is predominantly expressed in neuronal and neuroendocrine tissues, reflecting its name. However, its expression is not limited to the nervous system; ENO2 has been implicated in various cancers, including lung cancer, where it plays a multifaceted role. In lung cancer, ENO2 is considered a biomarker for diagnosis and prognosis, as elevated levels of ENO2 are often found in patients with lung cancer, particularly in small cell lung cancer (SCLC), a subtype known for its aggressive behavior and poor prognosis. Beyond its function in metabolism, ENO2 is involved in cancer pathophysiology through promoting tumor growth, proliferation, and metastasis. It supports the high glycolytic demands of cancer cells (the Warburg effect), contributing to the tumor's growth and survival under hypoxic conditions. Moreover, ENO2's role in lung cancer extends to mediating resistance to therapy, making it a potential target for therapeutic intervention.
Biomarker | Alternative Names | Gene ID | UniProt ID | Roles |
ATAD2 | ATPase Family, AAA Domain Containing 2; AAA Nuclear Coregulator Cancer-Associated Protein; ANCCA; EC 3.6.1.3; PRO2000; CT137 | 29028 | A0A024R9G7 | A large family of ATPases has been described, whose key feature is that they share a conserved region of about 220 amino acids that contains an ATP-binding site. The proteins that belong to this family either contain one or two AAA (ATPases Associated with diverse cellular Activities) domains. AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes. The protein encoded by this gene contains two AAA domains, as well as a bromodomain. |
CEACAM5 | CEACAM-5; CD66e; CEA; Meconium antigen 100 | 1048 | P06731 | This gene encodes a cell surface glycoprotein that represents the founding member of the carcinoembryonic antigen (CEA) family of proteins. The encoded protein is used as a clinical biomarker for gastrointestinal cancers and may promote tumor development through its role as a cell adhesion molecule. Additionally, the encoded protein may regulate differentiation, apoptosis, and cell polarity. This gene is present in a CEA family gene cluster on chromosome 19. Alternative splicing results in multiple transcript variants. |
EGFR | Epidermal Growth Factor Receptor; Receptor Tyrosine-Protein Kinase ErbB-1; Erb-B2 Receptor Tyrosine Kinase 1; Proto-Oncogene C-ErbB-1; EC 2.7.10.1; ERBB1; ERBB; HER1; Epidermal Growth Factor Receptor (Avian Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog); Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog (Avian) | 1956 | P00533 | The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor. Binding of the protein to a ligand induces receptor dimerization and tyrosine autophosphorylation and leads to cell proliferation. Mutations in this gene are associated with lung cancer. [provided by RefSeq, Jun 2016] |
ENO2 | Enolase 2; 2-Phospho-D-Glycerate Hydro-Lyase; Enolase 2 (Gamma, Neuronal); Neuronal Enriched Enolase; Neuron-Specific Enolase; Neural Enolase; Gamma-Enolase; EC 4.2.1.11; | 2026 | P09104 | This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme, a homodimer, is found in mature neurons and cells of neuronal origin. A switch from alpha enolase to gamma enolase occurs in neural tissue during development in rats and primates. |
KRT19 | Keratin 19; 40-KDa Keratin Intermediate Filament; Keratin, Type I Cytoskeletal 19; Keratin, Type I, 40-Kd; Keratin 19, Type I; Cytokeratin 19; CK-19 | 3880 | P08727 | The protein encoded by this gene is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. Unlike its related family members, this smallest known acidic cytokeratin is not paired with a basic cytokeratin in epithelial cells. It is specifically expressed in the periderm, the transiently superficial layer that envelopes the developing epidermis. The type I cytokeratins are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2008] |
LDHA | L-lactate dehydrogenase; EC 1.1.1.27; ldh# | 3939 | P00338 | Catalytic activity: (S)-lactate + NAD+ = H+ + NADH + pyruvate |
LDHB | HEL-S-281; LDH-B; LDH-H; LDHBD; TRG-5 | 3945 | P07195 | LDHB is the B subunit of lactate dehydrogenase enzyme, which catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH and NAD+ in a post-glycolysis process. Recent studies have shown that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is localized in the peroxisomes. Mutations in this gene are associated with lactate dehydrogenase B deficiency. |
NAPSA | Napsin A Aspartic Peptidase; Kidney-Derived Aspartic Protease-Like Protein; Aspartyl Protease 4; TA01/TA02; Napsin-1; Asp 4; NAP1; ASP4; NAPA; EC 3.4.23.15 | 9476 | O96009 | This gene encodes a member of the peptidase A1 family of aspartic proteases. The encoded preproprotein is proteolytically processed to generate an activation peptide and the mature protease. The activation peptides of aspartic proteinases function as inhibitors of the protease active site. These peptide segments, or pro-parts, are deemed important for correct folding, targeting, and control of the activation of aspartic proteinase zymogens. The encoded protease may play a role in the proteolytic processing of pulmonary surfactant protein B in the lung and may function in protein catabolism in the renal proximal tubules. This gene has been described as a marker for lung adenocarcinoma and renal cell carcinoma. [provided by RefSeq, Feb 2016] |
PDGFRL | PDGFRL; Platelet-Derived Growth Factor Receptor-Like Protein; PDGRL; Platelet-Derived Growth Factor Receptor-Like; Platelet-Derived Growth Factor-Beta-Like Tumor Suppressor; PDGFR-Like Protein | 5157 | Q15198 | This gene encodes a protein with significant sequence similarity to the ligand binding domain of platelet-derived growth factor receptor beta. Mutations in this gene, or deletion of a chromosomal segment containing this gene, are associated with sporadic hepatocellular carcinomas, colorectal cancers, and non-small cell lung cancers. This suggests this gene product may function as a tumor suppressor. |
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