|Year : 2016 | Volume
| Issue : 1 | Page : 16-22
Molecular biology of head and neck cancers
Deepa Philip, Vanita Noronha, Amit Joshi, Vijay Patil, Anant Ramaswamy, Anuradha Chougule, Kumar Prabhash
Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||23-May-2016|
Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Head and Neck cancers constitute a real challenge for oncologists across the globe, with one person dying every hour of every day. It can distort and disfigure the face, strip away the voice and rob one of his basic abilities to eat, drink and swallow. The psychosocial impact can be extremely devastating. From previously being considered a homogenous entity, it is now a well recognized fact that Head and Neck cancer is rightly called “Head and neck cancers” in view of their genetic and molecular heterogeneity despite sharing histological and etiological homogeneity. The present review discusses recent insights as well as established principles of the molecular biology of Head and Neck Cancers.
Keywords: Head and neck cancer, HPV, molecular biology
|How to cite this article:|
Philip D, Noronha V, Joshi A, Patil V, Ramaswamy A, Chougule A, Prabhash K. Molecular biology of head and neck cancers. J Head Neck Physicians Surg 2016;4:16-22
|How to cite this URL:|
Philip D, Noronha V, Joshi A, Patil V, Ramaswamy A, Chougule A, Prabhash K. Molecular biology of head and neck cancers. J Head Neck Physicians Surg [serial online] 2016 [cited 2021 Jan 21];4:16-22. Available from: https://www.jhnps.org/text.asp?2016/4/1/16/182856
| Introduction|| |
Head and neck cancers constitute a real challenge for oncologists across the globe, with one person dying every hour of every day. It can distort and disfigure the face, strip away the voice, and rob one of his basic abilities to eat, drink, and swallow. The psychosocial impact can be so devastating that Sir. Sigmund Freud, the father of modern psychiatry, who was diagnosed with oral cavity cancer in 1930's underwent 30 surgeries on him and finally died at a personal request of being euthanized by his physician. In this present chapter, we will discuss recent insights into the molecular biology of this malignancy.
Head and neck cancer is rightly called “Head and neck cancers” in view of their genetic and molecular heterogeneity despite sharing histological and etiological homogeneity.
| Molecular Basis of Risk Factors|| |
Genetic factors contributing to increased risk of carcinogenesis
The most important risk factor for developing head and neck cancer is tobacco with its effects linked to p53 mutations. Alcohol and betel nut ,, chewing have synergistic effect with tobacco. Tobacco smoke contains many known carcinogens of which benzo[a] pyrenediol epoxide, induces DNA adducts throughout the genome. These DNA damages are repaired by the human DNA repair machinery which includes nucleotide excision repair (NER) and base excision repair (BER),,, pathways. Genetic polymorphisms  in the genes involved in NER ,,,,, such as ERCC-1 and XPD and in the genes involved in BER such as XRCC-1 and ADPRT may contribute to increased risk and susceptibility to head and neck squamous cell carcinoma (HNSCC).
Infections: Human papillomavirus-infected head and neck squamous cell carcinoma
Human papillomavirus (HPV) is a strictly epitheliotropic, double-stranded DNA virus that has been studied since 1980's in the etiopathogenesis of HNSCC.,, HPV-positive and HPV-negative tumors represent different clinicopathological and genetic/molecular entities. This subgroup is unique in that it has a favorable prognosis, affects the younger population, has a site predilection for the tonsils/oropharynx., The oropharyngeal cancer increase began in the late 1970s and is attributed to increased rates of infection with high-risk HPVs secondary to changing sexual practices that are traceable to widespread use of oral contraceptives, reduced use of condoms, and freedom to have more sexual partners, without the fear of an unwanted pregnancy. The virus contains two oncogenes, E6 and E7, the expression of which inactivates p53 and retinoblastoma (RB), respectively, causing alterations of cell cycle regulation in the infected cells.
As HPV-related tumors seem to respond well to both chemotherapy and radiation, the question arises as to whether we are overtreating patients and exposing them to unnecessary long-term treatment-related toxicity. Trials are ongoing to determine how to treat these patients with maximal efficacy while limiting treatment-related toxicities. The role of vaccines in preventing HPV-related HNSCC-like cervical cancers, time can only prove.
Genetic cancer syndromes
There are many genetic cancer syndromes that have been postulated as contributing to increased risk of HNSCC such as Fanconi's anemia, Bloom syndrome, Ataxia Telangiectasia, and Xeroderma Pigmentosa, which are characterized usually by early age of onset of malignancy and specific and unusual patterns of clinical presentation and multiple malignancies in the same individual sometimes of different histologies. There are familial head and neck cancers  associated with inherited defects in CDKN2A locus  (also known as multiple tumor suppressor gene 1) and in hMDM2 regulator p14ARF. This relatively rare but a mysterious subset of patient population with young patients without known risk factors provide a valuable and rich area for studies at molecular level [Table 1].
| Field Cancerization|| |
The concept of field cancerization was first elucidated by Slaughter et al. in 1953 in his classic paper. This concept formed the basis for the logical explanation for second primary tumors and local recurrences. Many years later, the concept was revisited in the molecular era, and molecular basis of multistep process of carcinogenesis was studied.
The concept can be summarized as the multistep process of patch-field carcinoma process [Figure 1] and [Figure 2].
|Figure 2: Integrated model of multi.step molecular carcinogenesis in head and neck squamous cell carcinoma.|
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The initial step is when normal stem cell acquires genetic alterations leading to the formation of clonal unit  of altered daughter cells known as the patch, which has mutations in TP53.
The next logical and critical step is to acquire more genetic changes that give additional survival and proliferative advantage to these cells, leading to the formation of a field.
Further clonal divergence leads to the development of tumors within a contiguous field of premalignant cells. The importance of this concept lies in the fact that these fields remain despite tacking the primary tumor. This results in second primary tumors or in local recurrences. Hence, it is vital to tackle the field as well during therapy and to keep under close surveillance.
| Hallmarks of Cancer|| |
The hallmarks of cancer  constitute the biological capabilities acquired by human tumors in their multi-step process of carcinogenesis. It forms the framework for rationalizing the complexities involved in neoplasia. Here, we review the most promising pathways, receptors, and proteins from this inventory, implicated in the initiation, promotion, and progression of human HNSCC with relation to each of these hallmarks of cancer [Figure 3].
Hallmark-1: Enabling replicative immortality
The key feature acquired by cancer cells to evade senescence and to acquire replicative immortality is to regulate the cell cycle.,,,,
- HPV-negative head and neck squamous cell carcinoma: TP53, CCND1, and CDKN2A are established cancer genes in HPV-negative
- HPV-positive head and neck squamous cell carcinoma: TP53 and the genes encoding the Rb family (comprising RB1,RBL1 [which encodes p107], and RBL2 [which encodes p130]) are established cancer genes in HPV-positive HNSCC
- Ectopic expression of telomerase reverse transcriptase (TERT, the catalytic subunit of telomerase)
- Cancer stem cells (CSCs): CSCs constitute a highly tumorogenic subpopulation of cells within the tumor (constituting <10% of the whole tumor) characterized by the ability of self-renewal, differentiation, and proliferation. They play a pivotal role in cancer progression, treatment failure, growth of primary tumor, and metastasis. They are postulated to play a role in treatment failures and recurrences after treatment. The important genes and transcription factors deciphered so far in the molecular biology of stem cells include NANOG (inhibitor of self-differentiation and chemotherapy resistance), OCT-4 (for self-renewal and pluripotency), BMI1 (in self-renewal), and Snail and Twist and Wnt signaling (in epithelial to mesenchymal transition, which is important in metastasis) and ABC (in drug efflux and chemotherapy resistance).
Thus, CSC plays a pivotal role in treatment resistance and in recurrence after therapy.,,
[Table 2] gives a summary of important genes/transcription factors considered important in CSC Biology [Table 2].
Hallmark-2: Changes in growth factor signaling: The epidermal growth factor receptor pathway
Epidermal growth factor receptor (EGFR) signaling plays an important role in carcinogenesis, progression, and treatment responses. In HNSCC, EGFR is overexpressed in up to 80–100% of tumors, some of the highest rates of any human carcinoma.,, There are regional differences among sites in the head and neck that express EGFR, with relatively lower levels associated with laryngeal tumors compared with those of the oral cavity and oropharynx.
When extracellular ligands bind to EGFR it leads to dimerization of receptors, which causes autophosphorylation, which in turn leads to the activation of many intracellular downstream oncogenic signal transduction pathways such as Ras, Raf, MAP-kinase-pathway, JAK-STAT, and PI3K/AKT pathways as depicted in flowchart below, which leads to increased cell proliferation, activation of angiogenesis, and inhibition of apoptosis.,,
Important features of EGFR overexpressing tumors are as follows:,
- More advanced stage of disease
- Poorly differentiated tumors
- Poor chemo/targeted therapy sensitivity
- Increased treatment resistance
- Radiation sensitivity.
The prominent role that EGFR plays in HNSCC tumourogenesis has prompted intense research in the development of targeted therapies based on EGFR. The search for molecular predictive and prognostic factors based on EGFR is an area of active and intense investigation today [Table 3].
Insulin-like growth factor type-1 receptor
Insulin-like growth factor type-1 receptor is a transmembrane tyrosine kinase receptor, whose activation leads to intracellular signal transduction cascade activation, through Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase protein kinase, which leads to increased cell proliferation and resistance to apoptosis., This is a potential therapeutic target for the future.
Hallmark-3: Insensitivity to growth inhibitory signals: The transforming growth factor-beta pathway
An important growth inhibitory pathway associated with HNSCC is the transforming growth factor-beta (TGF-β) pathway.
It acts through the TGF-β receptors  and then through the intracellular signal transduction mediators SMAD2 and SMAD3 and SMAD4,, which regulate target gene transcription and thus downregulates proliferation and increases apoptosis. TGF-β downregulation also activates the NF-KB pathway which provided survival signal to the cells.
Hallmark-4: Evading apoptosis: PI3K-PTEN-AKT
This is an important signal transduction pathway that is implicated in 10–20% of HNSCC. Besides activating PIK3CA mutations, inactivating mutations or deletions of PTEN have also been described that once activated cannot turn off the PI3K pathway.
Hallmark-5: Invasion and metastasis
HNSCC like all other classic solid tumors is associated with lymph node metastasis, which is an important prognostic factor. Metastatic dissemination requires extracellular matrix degradation, which requires the activation of a cascade of matrix metalloproteinases. The CSMD1 gene on chromosome 8p has been intensively studied for its involvement in the invasion and metastasis of especially in supraglottic laryngeal cancer.
This is a particularly dangerous and pathological form of reprogramming of cells that leads to tissue invasion and metastasis, one of the most important hallmarks of malignancy. Epithelial-to-mesenchymal transition is the culmination of a series of transcriptional and translational events and modifications that lead to reprogramming of cells. Cells lose their cell-cell adherence through tight junctions/cadherins/desmosomes and acquire increasing cell mobility and become more migratory, thus leading to tissue invasion and metastasis.,, This has been shown to play a pivotal role in high-risk HNSCC, though its complete clinical significance is yet to be deciphered.
Tumor growth is usually limited by the requirement of oxygen and nutrient supply to the interior of the tumor and the elimination of catabolites from the tumor., This requires growth factors like VEGF to induce sprouting of endothelial cells and new vessel formation to feed the tumor. There have been many studies that have linked VEGF expression by IHC to prognosis in HNSCC including a meta-analysis that reported a higher risk of. However, studies with adjustments for other confounders such as HPV status are needed. Anti-VEGF targeted therapies in pipeline included sunitinib, sorafenib, and bevacizumab, which are being explored in HNSCC, though conclusive evidence from studies is awaited.
| Epigenetic Modification|| |
Tumourogenesis need not always be due to direct damage to the genome. It could be due to changes in gene expression without altering the gene sequence. It could be due to the methylation of base sequences/modification of histone proteins by acetylation/ubiquitination or methylation. Hypermethylation of tumor suppressor genes has been studied as a probable mechanism of development of HNSCC without altering the genetic information/DNA sequence.
| Driver and Passenger Genes in Head and Neck Squamous Cell Carcinoma-Candidate Genes/established Genes|| |
HNSCC has a paucity of driver oncogenes, so targeting these pathways forms a critical challenge in the success of our therapeutic armamentarium against this malignancy  [Table 4].
|Table 4: Driver and passenger genes in head and neck squamous cell carcinoma-candidate genes/established genes|
Click here to view
| Conclusions|| |
It has been rightly said that HNSCC is a malignancy where we have no regimen of choice; instead, we have a choice of regimens. Hence, the success of therapy of such a genetically heterogeneous malignancy would lie in prompt identification of prognostic and predictive factors of therapeutic response at the molecular level; so that personalized and precision medicine can be provided and neither the good risk group is overtreated nor is the poor risk group undertreated. The integration of molecular diagnostics and the molecular risk–based approach to cancer treatment that is pathway-driven is the challenge for the years to come.
“Bench to bedside and back to bench” is the way forward in the era of molecular diagnostics and personalized precision medicine.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]