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Molecular and Genetic Pathogenesis of Oral Cancer: A Basis for Customized Diagnosis and Treatment
Leonor Barroso1, Pedro Veiga2, Joana Barbosa Melo2,3,4
1Maxillofacial Surgery Department, Unidade Local de Saúde de Coimbra, 3000-075 Coimbra, Portugal.
Abstract:
Oral cancer, the most common form of head and neck cancer, is worldwide a serious public health problem. Most patients present a locally advanced disease, and face poor prognosis, even with multimodality treatment. They may also develop second primary tumors in the entirety of their upper aerodigestive tract. The most altered signaling pathways are the PI3K/AKT/mTOR, TP53, RB, and the WNT/β-catenin pathways. Genomic and molecular cytogenetic analyses have revealed frequent losses at 3p, 8p, 9p, and 18q, along with gains at 3q, 7p, 8q, and 11q, and several genes frequently affected have been identified, such as TP53, CCND1, CTTN, CDKN2A, EGFR, HRAS, PI3K, ADAM9, MGAM, SIRPB1, and FAT1, among others. Various epigenetic alterations were also found, such as the global hypomethylation and hypermethylation of CDKN2A, APC, MGMT, PTEN, CDH1, TFP12, SOX17, GATA4, ECAD, MGMT, and DAPK. Several microRNAs are upregulated in oral cancer, including miR-21, miR-24, miR-31, miR-184, miR-211, miR-221, and miR-222, while others are downregulated, such as miR-203, miR-100, miR-200, miR-133a, miR-133b, miR-138, and miR-375. The knowledge of this molecular pathogenesis has not yet been translated into clinical practice, apart from the use of cetuximab, an EGFR antibody. Oral tumors are also genetically heterogenous and affect several pathways, which means that, due to the continuous evolution of these genetic alterations, a single biopsy is not sufficient to fully evaluate the most adequate molecular targets when more drugs become available. Liquid biopsies, either resorting to circulating tumor cells, extracellular vesicles or cell-free nucleic acids, have the potential to bypass this problem, and have potential prognostic and staging value. We critically review the current knowledge on the molecular, genetic and epigenetic alterations in oral cancer, as well as the applications and challenges of liquid biopsies in its diagnosis, follow-up, and prognostic stratification.
Insights
Oral cancer presents significant challenges due to genetic heterogeneity and poor prognosis. Liquid biopsies offer a promising approach for improved diagnosis and monitoring of this complex disease.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
- Epigenetics
Background:
- Oral cancer is a major global health concern, often diagnosed at advanced stages with poor patient outcomes.
- Patients with oral cancer face a high risk of developing secondary primary tumors within the upper aerodigestive tract.
- Current treatments are often insufficient due to the complex molecular landscape of oral tumors.
Purpose of the Study:
- To review the current understanding of molecular, genetic, and epigenetic alterations in oral cancer.
- To explore the potential applications and challenges of liquid biopsies in managing oral cancer.
- To highlight the need for advanced diagnostic tools to address tumor heterogeneity.
Main Methods:
- Comprehensive review of existing literature on oral cancer molecular pathogenesis.
- Analysis of genomic, cytogenetic, and epigenetic alterations.
- Evaluation of signaling pathway dysregulation, including PI3K/AKT/mTOR, TP53, RB, and WNT/β-catenin.
- Assessment of microRNA expression profiles.
- Review of liquid biopsy technologies (circulating tumor cells, extracellular vesicles, cell-free nucleic acids).
Main Results:
- Identified frequent genomic alterations (losses at 3p, 8p, 9p, 18q; gains at 3q, 7p, 8q, 11q) and affected genes (e.g., TP53, EGFR, PI3K).
- Documented diverse epigenetic changes, including global hypomethylation and specific gene hypermethylation (e.g., CDKN2A, APC, MGMT).
- Observed altered expression of numerous microRNAs, with specific miRNAs being upregulated (e.g., miR-21, miR-222) or downregulated (e.g., miR-203, miR-375).
- Highlighted the genetic heterogeneity of oral tumors, complicating single-biopsy molecular profiling.
- Recognized the potential of liquid biopsies to overcome limitations of traditional biopsies for diagnosis, follow-up, and prognostic stratification.
Conclusions:
- Significant molecular and genetic alterations underpin oral cancer development and progression.
- Liquid biopsies represent a promising tool for overcoming the challenges posed by oral tumor heterogeneity and evolution.
- Further research and clinical integration of liquid biopsies are crucial for improving oral cancer patient management.
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