Genetic variants influencing the emergence and progression of lung cancer: a comprehensive review

Introduction

Lung cancer is unequivocally the prominent cause of cancer deaths, responsible for an alarming 18% of all cancer fatalities (1). In the world, lung cancer is the top cause of cancer-related death (2). Lung cancer poses a significant and complex challenge in contemporary oncology, marked by its wide-ranging genetic diversity and frequently severe clinical repercussions (3). Within this intricate landscape, a remarkable and potentially life-threatening complication known as superior vena cava syndrome (SVCS) occasionally arises. SVCS arises when lung cancer, specifically non-small cell lung cancer (NSCLC), invades the superior vena cava (SVC), a vital pathway for deoxygenated blood’s return from the upper body to the heart (4). Due to this physical blockage, individuals affected by SVCS frequently exhibit a combination of troubling symptoms, such as facial puffiness, neck swelling, and difficulty breathing, demanding immediate medical attention (5). SVC syndrome was described by William Hunter in 1757 after a patient’s death from an aortic aneurysm (6).

Although the blockage of the SVC is primarily a mechanical outcome of tumor growth, the genetic foundations of lung cancer can significantly impact the emergence, advancement, and clinical ramifications of SVCS (7). As our comprehension of the genetics of lung cancer has expanded with time, an increasing volume of research has elucidated the complex interaction between genetic elements and the onset of SVCS (8). The classical representation of veristic sculptures dates to antiquity and is often used to depict two well-known conditions that are associated with advancing age: SVCS and gynecomastia (9). This comprehensive review endeavours to illuminate this fascinating yet complex relationship, aiming to unravel the genetic factors and mechanisms underlying lung cancer.

Within these pages, we embark on a journey through the genetic landscape of lung cancer, exploring common mutations and alterations that have been associated with this formidable disease. As we navigate the intricate landscape of lung cancer genetics, our attention progressively shifts toward the precise genetic elements that might render individuals susceptible to SVCS. This exploration illuminates potential genetic indicators and biomarkers for assessing SVCS risk (10). Several mechanisms contribute to the development of SVC obstruction, with an emphasis on tumor growth, invasion, and angiogenesis (11).

The most prevalent extrinsic cause of SVCS is lung cancer, which accounts for up to 85–90% of malignancy-related SVCS. In up to 60% of cases, SVCS can be the first sign of an undetected tumor. Lung cancer and non-Hodgkin lymphoma account for 85–90% of malignancy-related SVCS, while metastatic tumors account for the remaining 10% (12). SVC syndrome affects 2–4% of lung cancer patients, with small-cell lung carcinoma causing it in about 10% of cases (13). From 2010 to 2017, there were approximately 1.5 million novel cases of lung cancer reported in Surveillance, Epidemiology, and End Results (SEER)-National Program of Cancer Registries (NPCR), out of which around 1.28 million were NSCLC (14). As per the American Cancer Society, it is projected that in 2023, about 238,340 new incidences of lung cancer will be identified in the US, resulting in 127,070 deaths (15). Researchers recently found that men are slightly more likely to be identified with invasive cancer (40.9%) than women (39.1%). This is believed to be because men are exposed to a more significant number of carcinogenic environmental and behavioral factors, such as smoking. However, the study revealed that other factors also play a significant role in determining cancer risk (16).

Furthermore, we scrutinize the clinical manifestations associated with SVCS in the context of lung cancer, emphasizing the pivotal significance of early identification and genetic analysis in directing patient care (17). Additionally, we investigate the significance of genetic analysis and molecular profiling in shaping treatment modalities for lung cancer patients, especially those at risk of SVCS, thanks to the advent of precision medicine (18).

As we navigate this intricate genetic landscape, we not only aim to deliver a comprehensive identification of the genetic aspects and mechanisms underlying SVCS in lung cancer but also to shed light on potential avenues for future research and clinical management. The insights gathered here not only underscore the significance of interdisciplinary collaboration among oncologists, geneticists, and researchers but also emphasize the profound impact that genetic research can have on the prognosis and personalized treatment of patients affected by this dual challenge of lung cancer and SVCS.

Genes associated with lung cancer

Lung cancer is a serious disease that arises due to the uncontrolled growth of abnormal cells in the lungs, resulting in the formation of a tumor. It is caused by genetic mutations that occur within the lung cells (19). Extensive research has identified several genes that are often transmuted in individuals with lung cancer. These genes are critical in regulating gene expression, cell growth, differentiation, and apoptosis. It is imperative to take this disease seriously and seek immediate medical attention if any symptoms arise (20). Three genes, EGFR, KRAS, and ALK, are commonly assessed for genetic transmutations in lung cancer. EGFR is found to be mutated in approximately 10% of persons with NSCLC and over 50% of lung cancer cases in individuals who have not smoked. Patients whose tumors do not have EGFR or KRAS mutations may have other abnormalities including the ALK gene. This occurs when ALK combines with another gene, most commonly EML4 (21). In rare cases, genes are correlated to lung cancer. Cell division, development, and death are all regulated by genes (22). Genetic alterations that increase lung cancer risk mostly occur during a person’s lifetime and are not inherited. Lung adenocarcinomas are more likely to be caused by genetic mutations, seen in around 60% of cases (23). These genes play significant roles in the development of lung cancer. Several other genetic mutations are also implicated in lung cancer, including those in cyclin-dependent kinase inhibitor 2A (CDKN2A), liver kinase B1 (LKB1), neurofibromin 1 (NF1), RET proto-oncogene (RET), and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), illustrated in Figure 1 and Table 1.

Figure 1 Mechanism of genes associated with lung cancer. CDKN2A, cyclin-dependent kinase inhibitor 2A; LKB1, liver kinase B1; NF1, neurofibromin 1; RET, RET proto-oncogene; NSCLC, non-small cell lung cancer.

CDKN2A

The P16 gene, formally known as CDKN2A, is a vital tumor suppressor gene responsible for controlling the cell cycle. In the context of lung cancer, CDKN2A inactivation is a frequent occurrence, typically brought about by homozygous deletions, promoter region methylation, or point mutations (28). In NSCLC, homozygous deletion is the most common type of CDKN2A inactivation (29). Even though methylation of the p16 promoter has been related to KRAS mutations and smoking, the association between p16 deactivation mechanisms and additional prevalent genetic alterations remains debated or unclear (30). Research has demonstrated that the loss of CDKN2A function is indicative of resistance to immunotherapy in NSCLC (31). Furthermore, CDKN2A exhibits elevated expression levels in tumor tissue when compared to normal tissue, and this expression pattern is indicative of the prognosis in patients with tumors (32). This gene is situated on chromosome 9 and codes for approximately 156 amino acids (24).

LKB1

The LKB1 gene is a tumor suppressor that regulates cellular functions, including metabolism, proliferation, polarity, and immunology. Tumors lacking LKB1 (LKB1-null tumors) display a high degree of aggressiveness and demonstrate resistance to chemotherapy, targeted therapies, as well as immune checkpoint inhibitors (33). In around one-third of NSCLC cases, LKB1 is rendered inactive due to bi-allelic mutations, resulting in the loss of the LKB1 protein and the absence of a feasible target for drug intervention (34). LKB1 governs the AMP-activated protein kinase (AMPK) pathway, which, in turn, overwhelms the mTOR pathway. This reticence of the mTOR pathway results in reduced protein synthesis and constrains the uptake of adenosine triphosphate (ATP) (35). During periods of metabolic stress, LKB1 becomes active and triggers the activation of AMPK. This activation, in turn, promotes catabolic pathways and helps re-establish cellular energy balance. Alterations in LKB1 have been linked to unfavorable prognoses and decreased survival rates among patients with NSCLC (36). Targeting LKB1 in the context of cancer represents a promising therapeutic strategy. Several approaches are currently under investigation, including the exploration of AMPK activators, mTOR inhibitors, and immunotherapy as potential treatment options (37). Located on chromosome 19, this gene encodes 433 amino acids (25).

NF1

NF1 is a gene that serves as a tumor suppressor by regulating RAS signaling, a critical pathway implicated in various cancers like melanoma and lung cancer (38). In lung cancer, NF1 mutations are common and lead to reduced neurofibromin levels, a pivotal RAS controller. The NF1 gene produces neurofibromin, a central regulator of the RAS protein (39). Neurofibromin activates RAS’s GTPase activity, essentially flipping the switch from an active guanosine triphosphate (GTP)-bound state to an inactive guanosine diphosphate (GDP)-bound state through its GTPase-activating protein-related domain (GRD) (40). In essence, neurofibromin functions as a universal “off” switch for vertebrate RAS GTPases. These mutations can contribute to treatment resistance across different cancer types (41). In lung cancer specifically, NF1 mutations frequently co-occur with mutations in genes such as TP53, KEAP1, and STK11. Notably, in NSCLC, NF1 mutations have been linked to poorer responses to immune checkpoint inhibitors, which can significantly impact treatment outcomes (42). Located on chromosome 17, this gene encodes 2,839 amino acids (40).

RET

The RET gene is an oncogene implicated as a key driver in NSCLC. RET rearrangements arise from the fusion of the RET gene’s C-terminal region with the N-terminal region of associate genes like CCDC6, and KIF5B, among others (43). This fusion event generates chimeric cytosolic proteins with a constitutively active RET kinase domain, resulting in uncontrolled cell growth and cancer development (44). In non-squamous NSCLC patients, RET gene fusions are observed in 1–2% of cases, making it a significant biomarker of interest for physicians diagnosing this type of lung cancer (45). Traditional treatment approaches offer limited benefits to NSCLC patients with RET fusion-positive tumors, and the consequences of immunotherapy are generally unfavorable. However, there are promising options in the form of pralsetinib (BLU-667) and selpercatinib (LOXO-292), both of which are potent and discriminating inhibitors designed to mark various RET alterations, comprising fusions (46). RET alterations are most commonly found in lung cancer (NSCLC), and their prevalence is substantial, accounting for approximately 37,500 cases worldwide and 4,000 cases in the United States (constituting 2% of all NSCLC cases) (47). RET alterations are also frequently observed in various forms of inherited and sporadic thyroid cancers and may occur in other tumor types as well (48). This gene is situated on chromosome 10 and is responsible for encoding a protein consisting of 1,114 amino acids (26).

ROS1

ROS1-positive lung cancer is a rare but extremely hostile form of NSCLC that affects 1–2% of patients. This kind of lung cancer is characterized by a genetic fusion event in the ROS1 gene, which promotes abnormal cell growth and can result in cancer spreading to other parts of the body, including the brain and bones (49). As an oncogene, ROS1 normally plays a role in regulating cell growth, but when it undergoes a mutation, it can become a driver of cancer development. It is crucial to understand the nature of ROS1-positive lung cancer, as early detection and targeted treatment can significantly improve patient outcomes (50). By raising awareness about this condition, we can increase funding for research and improve the chances of finding a cure. It is currently possible to treat ROS1-positive NSCLC by using specific tyrosine kinase inhibitors such as crizotinib and entrectinib. These targeted therapies have shown promising results in managing this type of lung cancer (51). It is important to note that when a lung cancer patient is ROS1-positive, the cancer is usually more aggressive due to the influence of the ROS1 protein, which promotes the growth of abnormal cells within the tumor (52). Located on chromosome 6, this gene is responsible for encoding a protein comprising 2,347 amino acids (27).

SVCS in lung cancer

SVCS, or superior vena cava syndrome, is a condition that occurs when the SVC vein is partly blocked or condensed (53). This major vein transports blood from the head, neck, upper chest, and arms to the heart. It is often caused by lung cancer, which accounts for 70–90% of cases, as well as non-Hodgkin lymphoma or other cancers (12). SVCS symptoms include swelling of the face, arms, and neck, cough, shortness of breath, chest pain, and difficulty swallowing (5). Treatment options depend on the underlying cause and severity of symptoms. For patients with lung cancer, medication may comprise chemotherapy, radiation therapy, or surgery to remove the tumor causing the blockage (54). Venous stenting, a minimally invasive procedure, can also be used to relieve the blockage and improve blood flow (55).

Pathophysiology

SVCS is a medical emergency characterized by the partial or broad obstruction of blood flow through the SVC, a major vein responsible for returning deoxygenated blood from the upper body to the heart (56). In the context of lung cancer, SVCS typically occurs due to specific mechanisms related to the tumor’s growth and its impact on the SVC (57). Figure 2 illustrates the pathophysiology of SVCS.

Figure 2 Pathophysiology of SVCS in lung cancer. SVCS, superior vena cava syndrome; SVC, superior vena cava.

Extrinsic compression

One of the primary mechanisms underlying SVCS in lung cancer is the external pressure exerted on the SVC. This pressure arises from the growth of the primary lung tumor or nearby structures, such as enlarged mediastinal lymph nodes (58). As these tumors or lymph node masses expand, they compress the SVC, gradually narrowing its lumen and impeding the normal flow of blood (59).

Intravascular invasion

In certain instances, lung cancer can directly invade the wall of the SVC. The tumor can extend into the SVC, physically blocking the vein and disrupting blood flow. This invasion of cancer cells into the vein exacerbates the development of SVCS (4).

Thrombus formation

Lung cancer patients face an elevated risk of developing blood clots (thrombi) within the SVC. These clots can partially or completely obstruct the vein, leading to the disruption of blood flow. The hypercoagulability associated with cancer, or the tendency to form blood clots, contributes to this phenomenon (60).

The block of blood flow through the SVC results in a range of clinical signs and symptoms, including swelling of the face, neck, and upper extremities due to increased venous pressure (61). Coughing, shortness of breath, and difficulty swallowing due to compromised venous return from the head and upper body. Chest pain may occur due to heightened pressure and stress on the heart. In severe cases, patients may exhibit signs such as cyanosis (bluish skin discoloration), plethora (a flushed or reddish appearance), and distended subcutaneous vessels due to impaired circulation (62).

SVCS is a medical condition described by the obstruction or compression of the SVC; a major vein responsible for returning deoxygenated blood from the upper body to the heart. SVCS can result from various underlying conditions, including tumors (most commonly lung cancer), infections, and thrombosis (blood clots) (17) (Figure 3). While there are no specific genes directly linked to SVCS, genetic factors can influence the development of the underlying conditions that lead to SVCS (6).

Figure 3 Superior vena cava syndrome.

Genetic factors may contribute to the risk of developing conditions that can lead to SVCS. However, SVCS is primarily caused by an underlying condition that obstructs or compresses the SVC. The focus of SVCS treatment is to identify and manage the underlying condition. If you suspect SVCS, seek advice from a healthcare professional for an accurate diagnosis and treatment plan.

Conclusions

Lung cancer remains a formidable challenge in contemporary oncology, responsible for a significant portion of cancer-related deaths globally. Within this complex landscape, SVCS emerges as a life-threatening complication, primarily related to lung cancer, especially NSCLC. While SVCS itself lacks direct genetic associations, the genetic underpinnings of lung cancer significantly influence its occurrence, progression, and clinical impact. This comprehensive review has explored the intricate relationship between genetics and SVCS in lung cancer. Genetic mutations, such as those in EGFR, KRAS, ALK, CDKN2A, LKB1, NF1, RET, and ROS1, play pivotal roles in lung cancer development, progression, and treatment responses. CDKN2A inactivation is frequent and indicative of poor prognosis and immunotherapy resistance. LKB1 mutations lead to aggressive tumor behavior and therapy resistance, while NF1 mutations disrupt RAS signaling, affecting therapeutic outcomes. RET rearrangements define a rare NSCLC subtype, and ROS1 gene fusions drive aggressive lung cancer. SVCS, primarily caused by lung cancer, demands early detection and genetic analysis for tailored treatments. Precision medicine, guided by genetic profiling, holds great promise in personalizing therapies for SVCS-affected individuals. Furthermore, understanding the genetic factors influencing SVCS risk sheds light on potential biomarkers and risk assessment. The review has also delved into the pathophysiology of SVCS, emphasizing the roles of tumor growth, compression, invasion, and thrombus formation in obstructing the SVC. Recognizing the clinical manifestations and the genetic factors contributing to SVCS is crucial for prompt diagnosis and management, enhancing patient outcomes. In conclusion, the intricate interplay between genetics and SVCS in lung cancer underscores the importance of interdisciplinary collaboration among oncologists, geneticists, and researchers. As genetic research continues to advance, it offers new avenues for improving patient prognosis and tailoring treatments for those confronted by the dual challenge of lung cancer and SVCS. This knowledge not only enriches our understanding but also highlights the transformative potential of genetics in the battle against this devastating complication of lung cancer.

Acknowledgments

The authors would like to thank the Chettinad Academy of Research and Education for their continuous support and encouragement.

Funding: None.

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-23-36/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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