Molecular Mechanisms in Laryngeal Cancer: A Review of Genetic and Epigenetic Alterations

Laryngeal cancer is among the most prevalent cancers that impact the upper aerodigestive tract, with laryngeal squamous cell carcinoma (LSCC) being the primary subtype. Recent advances have sparked significant attention to the molecular mechanisms of the disease. The stages of LSCC typically progress gradually, starting with precursor lesions in the laryngeal epithelium. The larynx plays a crucial role in breathing, swallowing, and speaking, therefore, its cancer can lead to significant quality-of-life concerns. Globally, laryngeal cancer is the second most common malignancy in the upper aerodigestive tract, after lung cancer. Its incidence and prevalence are increasing, with an estimated yearly rate of ۲.۷۶ and ۱۴.۳۳ cases per ۱۰۰,۰۰۰ population, respectively, with an annual death rate of ۱.۶۶. The burden of disease is higher in men and represents an age-related increase in individuals over ۶۵ years. There are also geographic variations, with the highest incidence in Europe and the lowest in Africa. Understanding the risk factors for laryngeal cancer is crucial for its prevention and treatment. Approximately ۹۰% of global deaths from laryngeal cancer are attributed to the use of tobacco and alcohol, which have a synergistic effect on disease promotion. Other risk factors include opium use, high-risk human papillomavirus (HPV) infection, and potential EBV co-infections. Epigenetic changes, especially abnormal DNA methylation, including both hypo- and hyper-methylation, contributes to the initiation and progression of laryngeal cancer. Hypomethylation involves removing a methyl group from a DNA strand, commonly seen in repetitive sequences such as LINE-۱ or ALU elements, which can trigger cancer-causing pathways. Conversely, hypermethylation in tumor suppressor genes such as p۱۶, PTEN, DAPK, MGMT, E-cadherin, and RASSF۱ can result in gene silencing, allowing for unregulated cell proliferation and cancer metastasis. These epigenetic alterations are linked to cancer progression, prognosis, and spread, and have been evaluated as indicators for disease diagnosis and prediction. While DNA methylation patterns show promise for clinical use, additional research is necessary to explore novel therapeutic approaches targeting abnormal methylation in larynx cancer. Genetic changes in the larynx are also a defining feature of LSCC, causing disturbances in normal cell function and leading to the proliferation and metastasis of tumors. Mutations in the TP۵۳ gene, observed in over ۵۰% of LSCC cases, weaken its ability as a tumor suppressor. In addition, the loss of heterozygosity at the chromosome ۹p۲۱ locus affects the CDKN۲A gene, which encodes a crucial cell cycle regulator, p۱۶INK۴a, which can lead to unregulated cell proliferation. The PI۳K/AKT pathway is frequently disrupted by PIK۳CA amplification and PTEN loss, leading to increased tumor cell survival. Moreover, overexpression of EGFR-associated cyclin D۱ is connected with a rise in tumor invasiveness. Additional genetic alterations, such as mutations in NOTCH۱ and HRAS, along with different chromosomal abnormalities, contribute to the advancement of the illness and negative outcomes. While our understanding of LSCC's genetics has advanced, further investigation is needed to completely grasp the complex relationship between these mutations and their possible medical applications. The complicated nature of these genetic mutations highlights the difficulties in developing successful treatments for LSCC.

کلیدواژه ها:

Laryngeal cancer ، Laryngeal squamous cell carcinoma (LSCC) ، Epigenetics ، Genetic alterations ، Molecular mechanisms