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Genetic Changes in Sporadic Keratocystic Odontogenic Tumors (Odontogenic Keratocysts)
K. Heikinheimo1,2, ,*,
K.J. Jee3,,
P.R. Morgan4,
B. Nagy5,
S. Knuutila3 and
I. Leivo3
1 Department of Oral and Maxillofacial Surgery, Institute of Dentistry, University of Turku, Lemminkäisenkatu 2, FIN-20520 Turku, Finland;
2 Department of Oral Diseases, Turku University Hospital, Lemminkäisenkatu 2, FIN-20500 Turku, Finland;
3 Haartman Institute, Department of Pathology, FIN-00014 University of Helsinki, Finland;
4 Department of Oral Pathology, GKT Dental Institute, King’s College London, United Kingdom; and
5 Genetic Laboratory, 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary
Correspondence: * corresponding author, heikinhe{at}netlife.fi
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ABSTRACT
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Little is known about the genetic background of keratocystic odontogenic tumors (KCOT, odontogenic keratocysts). Our aim was to characterize genomic aberrations in sporadic KCOT using cDNA-expression arrays and array-comparative genomic hybridization. For cDNA-expression arrays, 10 KCOT specimens and 20 fetal tooth germs were studied. Quantitative real-time reverse-transcription/polymerase chain-reaction and immunohistochemical studies were also undertaken. Several genes were over-expressed in 12q13, including cytokeratin 6B (KRT6B) ( 10-fold), epidermal growth factor receptor ERBB3 (~ 4.7-fold), and glioma-associated oncogene homologue 1 (GLI1) (~ 5- to 12-fold). One amplicon (~ 0.7 Mega base pairs [Mbp]), covering several genes involved in the regulation of cell growth, was found in 12q13.2. Deletions were found in 3q13.1, 5p14.3, and 7q31.3, including the cell-adhesion-related gene cadherin 18 (CDH18) and leukocyte cell adhesion molecule (ALCAM, MEMD). Over-expressed and amplified genes in 12q13, also reported in several other tumors and cell lines, may contribute to the persistent growth characteristics of KCOT.
Key Words: genomic aberrations • gene expression • keratocystic odontogenic tumor • odontogenic keratocyst
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INTRODUCTION
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The keratocystic odontogenic tumor (KCOT, odontogenic keratocyst) is a frequently aggressive and recurrent cystic jaw lesion (see reviews by Shear, 2002a,b,c). It is considered to be neoplastic under the new WHO classification (Philipsen, 2005). It is thought to arise from epithelial cells of the developing tooth, especially cells of the dental lamina. Histopathologically, the tumor is lined by a thin, stratified squamous epithelium with a palisade-like layer of basal cells. Epithelial cells of sporadic KCOT exhibit high rates of cell proliferation. KCOT associated with the inherited nevoid basal-cell carcinoma syndrome (NBCCS; also known as the Gorlin syndrome) display even higher rates of cell growth (see review by Shear, 2002b). Little is known about genetic aberrations in KCOT, except that point mutations occur in the tumor suppressor gene, patched (PTCH), in both the sporadic and syndrome-associated forms of the tumor (Lench et al., 1996; Barreto et al., 2000). Epithelial-mesenchymal cell signaling in the sonic hedgehog (SHH)/PTCH pathway is essential in early tooth development (see review by Cobourne and Sharpe, 2005), and it has been suggested that abnormal regulation of the pathway is involved in the origination of a wide range of neoplasms (see review by Villavicencio et al., 2000). Results of genome-wide studies for genetic aberrations are needed if the biological nature of KCOT is to be better understood, but no such results have been reported.
cDNA-expression array and array-comparative genomic hybridization are powerful tools for large-scale genetic studies (Todd and Wong, 2002; Oostlander et al., 2004). cDNA-expression arrays allow for the detection of abnormally regulated genes—in particular, tumor entities—through comparisons with normal counterpart tissues (Heikinheimo et al., 2002). Array-comparative genomic hybridization is a high-resolution method for the study of genetic aberrations in specific genomic locations (Albertson and Pinkel, 2003; Oostlander et al., 2004). Results obtained by both methods can help with the differential diagnosis of human tumors, and with assessments of prognoses (Knuutila, 2004).
In the study described here, we compared gene-expression patterns in sporadic KCOT with those in developing human tooth germs, by means of cDNA-expression arrays. We also screened the whole KCOT genome by means of array-comparative genomic hybridization, to detect amplifications and deletions.
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MATERIALS & METHODS
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Fetal Teeth
Twenty deciduous human tooth germs at cap and bell stages were collected as previously described (Heikinheimo et al., 2002). The study had been approved by the Ethical Committee of Helsinki Maternity Hospital, and by the Finnish National Authority for Medicolegal Affairs.
Keratocystic Odontogenic Tumors (KCOT)
Twelve sporadic KCOT (odontogenic keratocyst) specimens, numbered 1–12, were obtained during surgery in the Department of Oral Diseases, Turku University Central Hospital, Turku, Finland (three cases), and in the Department of Oral Medicine and Pathology, KCL Dental Institute, Guy’s Hospital, London, UK (nine cases). The specimens were snap-frozen in isopentane/liquid nitrogen and stored at –70°C. Seven KCOT were primary (1 maxillary and 6 mandibular) and 5 were recurrent (3 maxillary and 2 mandibular). The study had been approved by the Ethical Committee of the Hospital District of Varsinais-Suomi, Finland, and by the Guy’s Hospital Research Ethics Committee, UK, and informed patient consent was obtained.
RNA Isolation
Total RNA was isolated from 12 fresh-frozen tissues by means of the RNeasy Total RNA kit (Qiagen GmbH, Hilden, Germany), in accordance with the manufacturer’s instructions. To remove genomic DNA contamination, we treated RNA with RNase-free DNase 1 (Clontech Laboratories Inc., Palo Alto, CA, USA). The quality and integrity of the RNA were checked by means of spectrophotometry and agarose-gel electrophoresis.
cDNA-expression Array and Analysis
cDNA expression arrays were performed with cases 1–10 and a pooled control sample containing 20 fetal tooth germs. Atlas Human Cancer cDNA Expression Array Filters containing 588 cancer-related human cDNA fragments (Clontech Laboratories Inc.) were used as previously described (Heikinheimo et al., 2002). To identify relationships between gene-expression patterns and the samples, we undertook complete-linkage hierarchical clustering (Eisen et al., 1998).
Quantitative Real-time Reverse-transcription/ Polymerase Chain-reactions
Quantitative real-time reverse-transcription/polymerase chain-reactions were carried out in duplicate with cases 1–4, 6, 11, and 12, with fetal tooth germ RNA reference as previously described (Heikinheimo et al., 2002). Gene-specific primers (APPENDIX 1) for 4 annotated genes on 12q13 (ITGA7, KRT6, DDIT3, ERBB3) and the housekeeping gene phospholipase 2A (PL2A) were designed with the use of LightCycler Probe Design Software (Version 1.0; Roche, GmbH, Mannheim, Germany). GLI1, a downstream signaling molecule for tumor suppressor gene patched (PTCH), localized near the amplified region in 12q13, was included in the analysis. PTCH is point-mutated in KCOT (Lench et al., 1996; Barreto et al., 2000). A negative control without cDNA template was run simultaneously. Standard curves were obtained with serial dilutions of the PL2A gene and DNA Control kits (Roche). The concentration of each gene product was determined by a kinetic approach and LightCycler software (Roche).
Immunohistochemistry
The following antibodies were used: mouse monoclonal antibody (Mab) to cytokeratin 6B (dilution 1:50; gift of Dr. I.M. Leigh), mouse Mab to human c-erbB-3 oncoprotein (clone RTJ1; dilution 1:150; Novocastra Laboratories Ltd, Newcastle, UK), goat polyclonal antibody (Pab) to human heparin-binding-EGF (concentration 6.3 µg/mL; R&D Systems, Minneapolis, MN, USA), and rabbit Pab to mouse/human glioma-associated oncogene homolog (dilution 1:100; Biodesign International, Saco, ME, USA). Frozen sections of cases 2, 3, 8, 11, and 12 were cut and stained with Biotin-Streptavidin detection kits (Rabbit IgG and Mouse IgG Vectastain Elite ABC Kits, Vector Laboratories, Burlingame, CA, USA, and HRP-DAB Anti-goat Cell and Tissue Staining Kit, R&D Systems, Minneapolis, MN, USA), as described previously (Heikinheimo et al., 1999).
Array-comparative Genomic Hybridization Labeling, Hybridization, and Data Analysis
Genome-wide array-comparative genomic hybridization was performed with oligonucleotide-based human genome CGH microarray 44A (Agilent Technologies, Palo Alto, CA, USA). In brief, genomic DNA was extracted from samples 8, 11, and 12, pooled, and fragmented. The digested DNA was purified with a QIAprep mini-kit (Qiagen, Valencia, CA, USA), and the quality of the DNA was checked. A total of 3 µg of DNA was generated with Cy3-dUTP and Cy5-dUTP (Perkin-Elmer, Wellesley, MA, USA). Hybridization was performed at 65°C for 40 hrs. Slides were scanned in Agilent microarray scanner G2565AA (Agilent Technologies). Images were analyzed with Agilent G2567AA Feature Extraction software (v7.5; Agilent Technologies), with intensity-dependent linear normalization to remove experimental biases for fluorescent dyes (Cy5/Cy3). The signal intensity ratio of Cy5/Cy3 was corrected by standard deviation and coefficient in all clones. Pooled DNA extracted from lymphocytes of ten healthy individuals was used as normal reference DNA. Genome-wide aberrations were identified by Agilent CGH Analytics (v3.2) software (Agilent Technologies). Genomic regions for amplifications and deletions were defined by Z-score algorithm, with a moving average of 2 Mb and the threshold set at 2.0.
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RESULTS
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Gene Expression Profiles
We found 106 genes in which expression was different in KCOT from expression in the normal tooth germ. Forty-three were up-regulated and 63 down-regulated. Only the 20 most substantially over- and under-expressed genes were therefore selected for further consideration (Fig. 1 , Table). Hierarchical clustering revealed no significant expression differences within the samples (APPENDIX 2).
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Figure 1. Distribution of gene expression in sporadic KCOT determined by cDNA array and visualized in Treeview. Cases 1–10 are shown in columns and genes in rows. Data of the 20 most highly over- and under-expressed genes are shown. Difference in gene expression from controls (normal human tooth germ) is displayed in descending order (over-expressed genes), and in ascending order (under-expressed genes). Over-expressed genes are shown in red, under-expressed genes in green. The most over-expressed gene is KRT6B, and the most under-expressed is CSPG2.
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Confirmation of Gene Expression by Quantitative Real-time Reverse-transcription/Polymerase Chain-reaction
The quantitative real-time reverse-transcription/polymerase chain-reaction data for KRT6B, DDIT3, ERBB3, and ITGA7 were in agreement with the cDNA array result, except for two cases (case 6 for ERBB3 and case 4 for ITGA7) (Fig. 2A). GLI1 was over-expressed in six out of seven KCOT cases. One case (case 3) did not show differential gene expression compared with the reference.
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Figure 2. Relative expression of genes in 12q as observed by quantitative real-time reverse-transcription/polymerase chain-reaction (QRT-PCR), and immunolocalization of protein products by immunohistochemistry. (A) X-axis indicates cases (1–4, 6, 11, and 12) analyzed. Normalized ratios (obtained with the housekeeping gene PL2A) of gene expression for each gene are plotted on the Y-axis. The graph shows over-expression of KRT6, DDIT3, ERBB3, and GLI1 in all seven cases (except for ERBB3 in case 6, and GLI1 in case 3). ITGA7 was under-expressed in all seven cases, except case 4. (B) Positive immunoreactivity with KRT6B and ERBB3 antibodies was seen in suprabasal cell layers of tumor epithelium. When stained, HBEGF antibodies showed positive reactivity in basal epithelial cells and a few suprabasal epithelial cells. GLI1 antibodies showed positive reactivity in all epithelial cell layers. Scale bars, A–D, 50 µm.
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Detection of Selected Polypeptides by Immunohistochemistry
Immunolocalization of KRT6B, ERBB3, HBEGF, and GLI1 confirmed expression of the corresponding proteins in KCOT (Fig. 2B ). Staining of all 4 polypeptides was confined to the tumor epithelium. KRT6B and ERBB3 immunoreactivity was detected in suprabasal epithelial cell layers, HBEGF in basal cell layers and some suprabasal epithelial cell layers, and GLI1 in all epithelial cell layers.
Genomic Aberrations Detected by Array-comparative Genomic Hybridization
We found gains corresponding to amplicon on 12q13.2 (Fig. 3) and losses on 3q13.1, 5p14.3, and 7q31.3 (APPENDIX 3) in DNA pooled from cases 8, 11, and 12, in comparison with normal reference DNA. The size of the amplicon on 12q13.2 was approximately 0.7 Mbp, spanning nucleotides between 55348922 Kb and 56056484 Kb of the human genome. This region contains many genes known to be involved in gene transcription and growth regulation (Fig. 3). The deleted region on 3q13.1 was approximately 2.5 Mbp in genomic length and annotated, e.g., the activated leukocyte cell adhesion molecule (ALCAM). The deletion on 5p14.3 was found to be small in genomic nucleotide length, spanning only the CDH18 gene family. 7q31.3 deleted regions were approximately 1 Mbp in genomic length (spanning from 121933120 to 122917363 Mbp), containing several known genes (APPENDIX 4).
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Figure 3. Array-comparative genomic hybridization profile of gene amplifications in pooled DNA from cases 8, 11, and 12. Gene amplifications in 12q13.2 reveal amplicon (0.7 Mbp) of 15 consecutive amplified genes. CI = chromosomal idiogram, P = composite of oligo probe dots. Color indicates ratio of gene copy number to normal reference DNA, AG = region of gene amplification indicated by blue bar, M = magnification of amplified genomic region. Some known genes are plotted in the amplified region. N = genomic nucleotide scale bar.
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DISCUSSION
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Cytokeratin 6B (KRT6B; localized in the type II keratin gene domain on chromosome 12q13.13) was the most substantially over-expressed gene (up to 10-fold) in KCOT (Rogers et al., 2005). Immunohistochemistry showed the corresponding cytokeratin 6B protein to be localized in suprabasal epithelial cells of KCOT, with a distribution similar to that reported for its partner protein, cytokeratin 16 (Shear, 2002c). The KRT6/16 pair is typically found in suprabasal cell layers of stratified epithelia with fast cell turnovers, e.g., in oral mucosa, the genital tract, and the outer root sheath of the hair follicle, and in carcinomas of the head and neck (Navarro et al., 1995; Komine et al., 2000; Sesterhenn et al., 2005). Transcription of the KRT6B gene is induced by growth factors and cytokines. In proliferative processes in the epidermis, KRT6B gene expression is enhanced by epidermal growth factor (Komine et al., 2000). It may be surmised that over-expression of KRT6B in KCOT is a cytoskeletal response to increased proliferation of epithelial cells.
Other over-expressed genes found in the 12q13 region include epidermal growth factor receptor 3 (ERBB3, average 4.6-fold) and glioma-associated oncogene homologue 1 (GLI1, 5- to 12-fold). ERBB3 and GLI1 are members of a large signal transduction network that regulate development and are amplified and/or over-expressed in many human malignancies (Villavicencio et al., 2000; Vivekanand and Rebay, 2006). GLI1 is a downstream signaling molecule of the sonic hedgehog (SHH/PTCH) pathway (Arheden et al., 1989). It has been reported that PTCH is mutated in sporadic and syndrome-related KCOT, resulting in dysregulated GLI1 signaling (Lench et al., 1996; Barreto et al., 2000; Villavicencio et al., 2000; Shear, 2002b). Immunohistochemistry showed GLI1 protein in all epithelial cell layers and ERBB3 protein in the suprabasal epithelial cells, which are the predominantly proliferating cells in KCOT (Li et al., 1995). It may be speculated that defective integration and cross-talk of both sonic hedgehog and epidermal growth factor receptor pathways may be part of the pathogenesis of KCOT.
With genome-wide array-comparative genomic hybridization, only 1 amplicon was detected in the KCOT in this study. It was located at 12q13.2, covering at least 15 consecutive genes amplified at a distinct level (4- to 6-fold). Most of these genes are involved in the regulation of cell growth (Gough et al., 1998; Chen et al., 2002; Mazzocchi et al., 2004). However, our findings cannot be considered conclusive, because of the small number of cases involved. Interestingly, the over-expressed genes KRT6B and ERBB3 are located near this amplicon. Recently, amplicons spanning the 12q13 region have been reported in several human tumors and transformed cell lines (Simon et al., 2002; Su et al., 2004; Or et al., 2005; Di Palma et al., 2006). Interestingly, also, this chromosomal band is known to harbor 1 homeobox (HOX) gene cluster, which is an important master regulator of normal development (Lappin et al., 2006).
The results reported here also revealed several aberrations, particularly deletions, in epithelial cell adhesion molecules, including cadherins 5 and 18. Cadherins are implicated in, e.g., cell-cell recognition, and in interactions, migration, and apoptosis. Cadherin-5 (CDH5), which has been shown to be involved in angiogenesis, tumor progression, and metastasis, was one of the most over-expressed genes (6-fold). We believe that this finding could reflect the aggressive growth potential of KCOT. In contrast, using array-comparative genomic hybridization, we detected deletion of CDH18 at 5p14.3. Cadherin-18 is a relatively unknown member of the type-II cadherins, but it is thought to be concerned in cell-cell and cell-extracellular matrix interactions, possibly also in synaptic adhesions (Shibata et al., 1997). A deletion in 5p harboring a cadherin gene cluster has been reported in connection with malignant transformation (Chalmers et al., 1999).
The results of the study reported here show that the significantly under-expressed genes included many extracellular matrix protein genes, such as collagen VI, vitronectin, tenascin, procollagens I and III, versican, basement membrane component laminin  4, and cell-adhesion-related integrin 7B. Our findings indicate that gene expression of structural connective tissue molecules deposited in the stroma surrounding KCOT is down-regulated. Such down-regulation could result in disturbances of stromal functions, and be involved in the origination of KCOT.
It is possible that the over-expression of interleukin genes IL-2, IL-3, IL-12β, and IL-1β convertase in the present study may relate to an inflammatory response that is sometimes seen in KCOT. However, these cytokines may also be expressed by epithelial and stromal cells in the absence of inflammation. They mediate, e.g., processes of matrix metalloproteinase activation (Kubota et al., 2000) that could contribute to the growth potential of KCOT. Recently, it has been shown that the activated leukocyte cell adhesion molecule (ALCAM/MEMD) plays a signaling role in pro-MMP2 activation and MT1-MMP processing (Lunter et al., 2005). Truncation of ALCAM severely impaired MMP-2 activation through reduced transcription. The deletion of ALCAM at 3q13.1 observed in the study described here may therefore enhance a matrix metalloproteinase-mediated proteolytic cascade, contributing to the growth potentials of KCOT (Lunter et al., 2005).
In conclusion, we report here several over-expressed and amplified genes of the 12q13 region that may be relevant in relation to the aggressive and recurrent characteristics of KCOT. We also report several gene aberrations related to cell adhesion. These may play roles in disturbances of cell-cell and cell-stromal functions, and their existence could explain one of the microscopic hallmarks of KCOT, namely, detachment of lining epithelium from the stroma.
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ACKNOWLEDGMENTS
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The work was supported by the Finnish Dental Society Apollonia, the Finnish Cancer Society, Helsinki University Central Hospital Fund, the Maritza and Reino Salonen Foundation, and COST Action B23 (EU).
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FOOTNOTES
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A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.
 authors contributing equally to the work 
Received for publication June 30, 2006.
Revision received January 19, 2007.
Accepted for publication January 30, 2007.
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Journal of Dental Research, Vol. 86, No. 6,
544-549 (2007)
DOI: 10.1177/154405910708600611
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ABSTRACT
INTRODUCTION