Expanding fields of genetically altered cells in head and neck squamous carcinogenesis

doi:10.1016/j.semcancer.2004.08.004

Seminars in Cancer Biology

Volume 15, Issue 2, April 2005, Pages 113-120

https://doi.org/10.1016/j.semcancer.2004.08.004 Get rights and content

Abstract

Recent molecular pathology studies in head and neck cancer support a carcinogenesis model in which the development of a field with genetically altered cells plays a central role. This preneoplastic field is of monoclonal origin and expands non-invasively superseding normal epithelium. Clonal divergence and selection within the field ultimately leads to the development of cancer. These fields can be large (over 7 cm diameter) and are often not visible for the surgeon explaining that they may remain after resection of the primary tumor. When not removed, a field is an important risk factor for secondary cancer.

Section snippets

Head and neck squamous cell carcinoma: the clinical problem

Head and neck squamous cell carcinoma (head and neck cancer) develops in the mucosal linings of the upper respiratory and digestive tract. Despite significant advances in head and neck cancer treatment, long-term survival of cancer patients has only moderately improved during the last 20 years [1]. A major problem of head and neck cancer is that most patients present with advanced cancer as the disease often progresses without clear clinical symptoms. Early detection of this type of cancer

Field cancerization: a genetic basis

The development of locally recurrent cancer and second primary tumors has frequently been explained by the concept of ‘field cancerization’. In their classical paper of 1953, Slaughter et al., used the term field cancerization for the first time, when studying 783 patients with oral cancer [9]. After performing extensive histological examinations, field cancerization was described as: (i) oral cancer develops in multifocal areas of precancerous change; (ii) histologically abnormal tissue

A field with genetically altered cells as precursor lesion

A field can be defined as an epithelial sheet of cells with cancer-associated genetic alterations, but without invasive growth. In fact, it is a lesion with molecularly defined preneoplastic characteristics. As stated above, it is known that the presence of a field also has consequences for the risk of another cancer development. In addition, we now discuss the evidence that is at present available in support of the concept that a field can be considered a precursor lesion, preceding invasive

Molecular basis of the origin of a field

The squamous epithelium of the mucosal linings of the upper respiratory and digestive tract is maintained throughout adult life by stem cells, defined as cells with the capacity to self-renew and to generate daughter cells that can differentiate to form all of the cell types found in the mature tissue [38]. No definitive identification of stem cells in the head and neck mucosal epithelium has been made, but the principles of the studies obtained in skin are likely to be valid [39]. Stem cells

The patch-field-carcinoma model

Based on the present information we propose the following progression model for head and neck cancer (Fig. 1). In the initial phase, a stem cell acquires one (or more) genetic alterations, one of which is likely to be a mutation in the p53 gene and forms a patch in the mucosal epithelium with genetically altered daughter cells. As a result of subsequent genetic alterations the stem cell escapes the normal control mechanisms and gains growth advantage: the patch starts to expand in a lateral

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Methylation status of SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes in patients with oral squamous cell carcinoma
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Our study assessed the methylation status of the SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes, which are associated with epigenetic silencing in cancers. In a group of 75 patients with oral squamous cell carcinoma, aberrant methylation was detected using methylation-specific PCR in tumours and matched margins. Our results showed significantly higher methylation frequency in tumours than in surgical margin of SFRP2 (26.6% vs 11.9%, p < 0.05) and DAPK1 (65.3% vs 41.3%, p < 0.01) genes. Moreover, methylation of the SFRP1 and DAPK1 genes was associated with older age. Advanced tumour stages were associated with lower rates of SFRP1 gene methylation. Decreased methylation levels of the SFRP2 and RASSF1A genes were associated with positive N stage. On the contrary, lymph node metastasis were associated with higher methylation rates of RARβ and DAPK1 genes. Patients with a familial history of cancer were associated with more frequently methylated SFRP1, SFRP2 and DAPK1 genes. Hypermethylation of DAPK1 was associated with decreased risk of death in patients. Our results are suggestive, although not conclusive, that some epigenetic changes, especially frequent hypermethylation of SFRP2 and DAPK1 genes, can be useful as potential diagnostic biomarkers of oral cavity cancer. Moreover, estimating the methylation status in surgical margins could become an additional strategy for more accurate treatment methods. Further efforts are needed to identify and validate this finding on a larger patient group and using new advanced methylation testing methods.
A comprehensive study of smoking-specific microRNA alterations in head and neck squamous cell carcinoma
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While tobacco smoking is a well-known risk factor for head and neck squamous cell carcinoma (HNSCC), the molecular mechanisms underlying tobacco-induced HNSCC remain unclear. This study sought to comprehensively identify microRNA (miRNA) alterations and evaluate their clinical relevance in smoking-induced HNSCC pathogenesis and progression.
Using small RNA-sequencing data and clinical data from 145 HNSCC patients, we performed a series of differential expression and correlation analyses to identify a panel of tobacco-dysregulated miRNAs associated with key clinical characteristics in HNSCC. We then examined the expression patterns of these miRNAs in normal epithelial cell lines following exposure to cigarette smoke extract.
Our analyses revealed distinct panels of miRNAs to be dysregulated with smoking status and associated with additional clinical features, including tumor stage, metastasis, anatomic site, and patient survival. The differential expression of key miRNAs, including miR-101, miR-181b, miR-486, and miR-1301, was verified in cigarette-treated epithelial cell lines, suggesting their potential roles in the early development of smoking-related HNSCCs.
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Local recurrence and the development of second primary tumors (SPT) are important factors that can influence the survival rate of oral squamous cell carcinoma (OSCC) patients. We investigate the concept of field cancerization which proposes that normal tissue adjacent to the primary tumor harbor pre-neoplastic alterations that can lead to the development of local recurrence and SPTs.
To examine the concept of field cancerization, we applied whole-exome and targeted ultra-deep sequencing on 5 freshly frozen samples from a stage III OSCC patient from three tumor sites, lymph node metastasis and blood. Lastly, we sequenced one formalin-fixed paraffin-embedded recurrence biopsy that was collected approximately a year and half later located in the same area as before.
Sequencing identified 126 somatic mutations. We identified 24 mutations in the recurrence biopsy and 14 mutations are shared by the primary tumor.
The low number of shared mutations indicates that either these mutations represent a very early clone in the primary tumor’s evolution, or that these mutations represent a pre-neoplastic field, in which the primary tumor and recurrence are derived from. In both instances, the clinical recurrence is of a monoclonal origin which suggests either field cancerization by migration of mutated cells in the adjacent mucosa, or that the recurrence developed out of remaining tumor tissue.
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Citation Excerpt :
There was no association of dysplasia, recurrence or OKD with the analyzed clinicopathologic variables, except for OKD with granular cell layer and orthokeratin presence (Table 4). Although OL is clinically visible and detectable, it is known that mutations in the oral mucosa form a cancerization field that could lead to epithelial precursor lesions or OSCC in other sites of the mouth in a susceptible patient [13–15]. Aside from that, oral carcinoma can appear from the apparently normal mucosa [4].
Oral leukoplakia is the most common potentially malignant disorder in the oral cavity and can precede carcinoma. This study aimed to identify possible oral leukoplakia salivary biomarkers.
Unstimulated saliva was collected from participants and protein concentration was determined. Proteins were then precipitated with cold acetone and separated using 2DE over a pH range of 3–10. Spot demarcation and matching were performed and protein identification was done through MS analysis. Oral leukoplakia tissues were submitted to immunohistochemistry analysis for keratin 10 (CK10). A complementary analysis of oral leukoplakias that were not included previously was performed in addition.
226 ± 10 spots were identified in oral leukoplakia 2DE gels, and 262 ± 12 spots were identified in volunteers. Twenty-two spots were highly abundant in oral leukoplakias or not detected in the control group, such as apolipoprotein A1, alpha amylase, cystatins, keratin 10, and lysozyme precursor. All were identified. All oral leukoplakia cases were immunopositive for CK10, mainly in the superficial epithelial layers.
The 2DE salivary protein profiles of individuals with and without oral leukoplakia were observably different. CK10 appears to be an interesting protein and should be further studied in oral carcinogenesis.
MS-based proteomics enables large-scale analysis of proteins. Proteomics can provide detailed descriptions of proteomes of cells and tissues, including body fluids, and appears as a powerful tool to study human disorders. Saliva is readily accessible through non invasive collection and can mirror diverse disease states. Saliva from both diseased and healthy subjects can be analyzed through 2DE and differences between groups could be found. Routine immunohistochemistry analysis confirmed one of these findings, with CK10 being positive tissues from individuals with oral leukoplakia. Therefore, the present study allows insights into development of an important potential oral cancer precursor, named oral leukoplakia. However, the results can be extrapolated and tested in other precancer states, such as proliferative verrucous leukoplakia, patients at risk of oral cancer due to lifestyle behavior and/or cancer history in the family or even those who are under surveillance after a treated primary oral cancer.

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ReviewExpanding fields of genetically altered cells in head and neck squamous carcinogenesis

Abstract

Section snippets

Head and neck squamous cell carcinoma: the clinical problem

Field cancerization: a genetic basis

A field with genetically altered cells as precursor lesion

Molecular basis of the origin of a field

The patch-field-carcinoma model

Int. J. Oral. Maxillofac. Surg.

Cell

J. Invest. Dermatol.

Eur. J. Cancer

Oral Oncol.

Oral Oncol.

Oral Oncol.

J. Invest. Dermatol.

J. Invest. Dermatol.

Medical progress—head and neck cancer

N. Engl. J. Med.

Recurrence at the primary site in head and neck cancer and the significance of neck lymph node metastases as a prognostic factor

Cancer

Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions

Head Neck

Multiple primary tumors in patients with head and neck cancer

Laryngorhinootologie

Second neoplasm in patients with head and neck cancer

Head Neck

Multiple primary malignant tumorsA survey of the literature and a statistical study

Am. J. Cancer

Distinguishing second primary tumors from lung metastases in patients with head and neck squamous cell carcinoma

J. Natl. Cancer Inst.

“Field cancerization” in oral stratified squamous epithelium

Cancer

Chromosomal alterations in squamous cell carcinomas of the head and neck: window to the biology of disease

Head Neck

Multiple molecular alterations of FHIT in betel-associated oral carcinoma

J. Pathol.

Cyclin D1 amplification in chromosomal band 11q13 is associated with overrepresentation of 3q21–q29 in head and neck carcinomas

Int. J. Cancer

A case–control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization

Cancer Res.

Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications

Clin. Cancer Res.

Detection of chromosome instability of tissue fields at risk: in situ hybridization

J. Cell Biochem.

Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck

N. Engl. J. Med.

Genetic instability in epithelial tissues at risk for cancer

Ann. N. Y. Acad. Sci.

Detection of minimal residual cancer to investigate why oral tumors recur despite seemingly adequate treatment

Clin. Cancer Res.

Multiple head and neck tumors: evidence for a common clonal origin

Cancer Res.

Multiple head and neck tumors frequently originate from a single preneoplastic lesion

Am. J. Pathol.

Review
Expanding fields of genetically altered cells in head and neck squamous carcinogenesis