Comparative Analysis of Molecular Profiles of Sporadic Odontogenic Keratocyst and Bilateral Odontogenic Keratocyst: A Next Generation Sequencing Study

Abstract

Aim:

To comparatively analyse and interpret the molecular profiles of sporadic odontogenic keratocysts (OKC) with bilateral non-syndromic odontogenic keratocysts employing next-generation sequencing (NGS).

Materials and Methods:

All histopathologically confirmed cases were processed for 50 hotspot gene panel using NGS, followed by protein-protein analysis using the STRING Consortium 2023.

Results:

Except for 1 case, which was seen in the maxilla in a female patient, all included cases affected the mandible in males. In sporadic cases, a missense mutation was frequently found with either gain/ loss of function (GOF/LOF). TP53 showed a missense mutation with LOF at exon 5 and a nonsense mutation with LOF at exon 10. Other mutations were noted in the MET gene exon 19 and BRAF gene exon 11. Contrariwise, an identical mutation was seen in the left and right lesions of bilateral OKC, which was a mutation of TP53 with LOF at exon 8. Additionally OKC of the right side showed a gain-of-function (missense mutation) of the NRAS gene at exon 3.

Conclusion:

The TP53 gene mutation plays a significant role in the pathogenesis of OKC and supports its neoplastic nature. Bilateral OKC showed additional NRAS mutation, and sporadic cases demonstrated MET and BRAF mutations.

Keywords

cancer disease gene sequencing non-syndromic OKC medicine TP53

Introduction

Odontogenic keratocyst (OKC), alternatively regarded as keratocystic odontogenic tumour (KCOT), is the third most common odontogenic cyst of the jaws, with a high potential for recurrence.^1-3 Depending on various factors, especially the type of treatment modality, the recurrence rate of OKC has been reported to range from 8% to as high as 71%.^4,5 It has been observed that lesions treated with conservative enucleation without ostectomy tend to recur more than those managed aggressively. Likewise, several histopathological features are significantly associated with a higher recurrence potential.^6-8 These features include satellite cysts in the wall, basal budding, juxtaepithelial hyalinisation, friable epithelium, epithelial dysplasia, chronic inflammation in the wall, and basal/parabasal mitoses. Apoptotic/antiapoptotic proteins, as well as various cytokeratins, are also expressed in OKCs and have been linked to the recurrence potential and a possible role in the pathogenesis.⁹

There is a robust association between multilocular OKC and Nevoid Basal Cell Carcinoma Syndrome (NBCC/Gorlin).¹⁰ However, there are reported cases of non-syndromic multiple OKC, bilateral OKC, and syndromic bilateral OKC.^11-14 Several genetic alterations have been identified in OKC, out of which the aberration in the PTCH1 gene is the most common alteration. In rare instances, viral aetiology is proposed in odontogenic pathologies; however, their role in OKC is questionable.¹⁵ An allelic loss in p16, p53, PTCH, TSLC1, LTAS2, MCC, and FHIT genes supports a neoplastic origin, which are tumour-suppressor genes and are coincidentally associated with many malignancies, indicating an aggressive behaviour.¹⁶

Ambele et al,¹⁷ in a comparative molecular analysis between sporadic and non-syndromic cases of OKC, demonstrated similar alterations except that the alterations on 1p13.3, 2q22.1, and 6p21.33 were detected in sporadic cases and were absent in all the studied syndromic cases. The data about the gene sequencing of OKCs is limited and could provide important insight into the pathogenesis of OKCs based on their association/non-association with the syndrome, or their number. The present study was designed to analyse and interpret the molecular profiles of sporadic odontogenic keratocysts in comparison with bilateral odontogenic keratocysts employing next-generation sequencing (NGS), a high-throughput sequencing technique used to sequence billions of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

Methodology

Study Design

Sample Preparation

The present prospective study was conducted in the Department of Oral Pathology and Microbiology after seeking clearance from the institutional human ethical clearance committee (IHEC/SDC/UG-2214/25/OPATH/108) and included 3 cases of sporadic odontogenic keratocyst and 1 case of non-syndromic bilateral odontogenic keratocyst. The bilateral case was classified as non-syndromic based on a comprehensive clinical examination, radiographic evaluation, and review of the medical and family histories. The patient did not exhibit clinical features suggestive of nevoid basal cell carcinoma syndrome (Gorlin syndrome). Germline genetic testing was not performed, and classification was based solely on clinical criteria. All cases were initially histopathologically confirmed on incisional biopsy and were later enucleated with peripheral ostectomy. The tissues were processed routinely for routine histopathology and next-generation sequencing (NGS) to facilitate final diagnosis. The procurement of the samples for the NGS study did not affect the final histopathological diagnosis. Briefly, after fixation for 24 hours in 10% neutral buffered formalin, the tissues were dehydrated in isopropyl alcohol for 30 minutes, followed by 2 changes of acetone (30 minutes each). The following steps involved clearing in 2 changes of xylene for 30 minutes each and impregnation in paraffin wax overnight. The processed tissue was embedded in wax to prepare formalin-fixed paraffin-embedded (FFPE) blocks, sectioned, stained, and permanently mounted. The final diagnosis was made according to the essential and desired criteria of the World Health Organisation (WHO) classification of head and neck tumours 2024. The slides, which showed an adequate amount of epithelium, were sent for further evaluation.

Next-Generation Sequencing

Formalin-fixed paraffin-embedded (FFPE) blocks of histopathologically confirmed bilateral OKC (2 blocks – 1 right, and 1 left) and 3 blocks of sporadic OKCs were sent for NGS. Fragments from an in-house developed gene panel were sequenced, with the extracted deoxyribonucleic acid from the submitted blocks. Burrows-Wheeler Aligner was employed to align these fragments with the human reference genome (GRCh37), and LoFreq (version 4.0) and the Mutect variant caller were used for the detection of somatic mutations. We assessed the mutation status of ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53, and VHL, which were further annotated and filtered using the GENEYX analysis workflow implementing the ACMG, AMP-ASCO CAP guidelines for the interpretation of sequence variants. For evaluation of the impact of detected variants in human disease, OMIM, ClinVar, 1000 genomes, SIFT, gnomAD, NCIB RefSeq Genes, LRT PRED, Civic, dbSNP, GERP, and PolyPhen2 were used. HGVS nomenclature (www.hgvs.org/mutnomen) was used for final assessment and evaluation. Variant allele frequencies were reported as generated by the bioinformatics analysis pipeline, following standard variant calling and rounding conventions.

Protein-Protein Interaction

Using STRING Consortium 2023 (STRING: functional protein association networks [string-db.org]), we further analysed Cancer-omics data and multilevel protein association networks.¹⁸

Results

Patient Characteristics

The clinical and radiological features of the included cases are shown in Table 1. All but 1 cases affected the mandible, with a male preponderance. Bilateral OKC affected a 13-year-old boy with impacted bilateral mandibular third molars near the condyles (Figure 1).

Table 1.

Clinicodemographic Data of the Included Cases in the Present Study.

Case number	Age (in years)	Gender	Location	Radiographic features
1 (Bilateral)	12	M	Ramus bilateral	WD RL with impacted 38 and 48 in a DC like relationship
2 (Sporadic)	38	F	Anterior right maxilla	WD unilocular RL in between tooth number #5 and #6
3 (Sporadic)	35	M	Left Ramus	Sub-condylar WD RL in the left ramus
4 (Sporadic)	39	M	Left Mandible	Radiolucency in the PA region of teeth number # 18-21

Abbreviations: M, male; F, female; WD, well defined; RL, radiolucency; DC, dentigerous cyst; PA, periapical.

Histological Features

All cases showed 4 to 8 cell-thick parakeratinised stratified squamous epithelium with flat epithelium-connective tissue interface and multiple areas of subepithelial split. The cyst wall was devoid of inflammatory reaction, with no evidence of satellite cysts or dental rests in the multiple deeper sections studied, except for the right side lesion of bilateral OKC. Additionally, the bilateral case showed subepithelial hyalinisation with basal and parabasal mitoses (Figure 1).

Mutational Landscape of Sporadic OKC

The most common mutation was a missense mutation with either gain/ loss of function (Figure 2). TP53 showed a missense mutation with loss of function (LOF) at exon 5 (variant-chr17:7578460 [A>G], and CDS/AA change at c.470T>C/p.Val157Ala) and a nonsense mutation with loss of function at exon 10 (variant- chr17:7574003[G>A], and CDS/AA change at c.1024C>T/p.Arg342). Other mutations were noted in MET gene exon 19 (pathogenic, chr7:116423414[A>G]) and BRAF gene exon 11 (likely pathogenic, chr7:140481417[C>T]). The mutation on exon 2 of MET was designated as a variant of unknown significance (VUS, chr7:116340207[A>G]; Table 2).

Table 2.

Molecular Analysis of Sporadic Odontogenic Keratocysts as Analysed by Next-generation Sequencing.

Gene	Variant	CDS/AA change	Effect	CVG (%VAF)	Pathogenicity
BRAF Exon 11	chr7:140481417 (C > T)	c.1391G>A/ p.Gly464Glu	MISSENSE GOF	557 (7.54)	Likely pathogenic
TP53 Exon 5	chr17:7578460 (A > G)	c.470T>C/ p.Val157Ala	MISSENSE LOF	1610 (14.78)	Pathogenic
TP53 Exon 10	chr17:7574003 (G > A)	c.1024C>T/ p.Arg342	NONSENSE LOF	279 (25.81)	Pathogenic
MET Exon 19	chr7:116423414 (A > G)	c.3689A>G/ p.Tyr1230Cys	MISSENSE GOF	600 (5.83)	Pathogenic
MET Exon 2	chr7:116340207 (A > G)	c.1069A>G/ p.Met357Val	MISSENSE	56753 (33.78)	VUS

Mutational Landscape of Bilateral Non-Syndromic OKC

The left and right OKCs were assessed and showed identical missense mutations of TP53 with LOF at exon 8 (chr17:7577142 [C>TA]); in addition, the OKC of the right side showed a gain-of-function (missense mutation) of the NRAS gene at exon 3 and was marked as likely pathogenic (Table 3). The identical TP53 variants observed in both lesions, with high variant allele frequencies, may represent either a shared somatic event or a potential underlying germline alteration; however, this could not be confirmed due to the absence of germline testing.

Table 3.

Molecular Analysis of Bilateral Odontogenic Cyst as Analysed by Next-generation Sequencing.

Left
Gene	Variant	CDS/AA change	Effect	CVG (%VAF)	Pathogenicity
TP53 Exon 8	chr17:7577142 (C>TA)	c.796G>T/p.Gly266	MISSENSE LOF	1507 (59.79)	Pathogenic
Right
TP53 Exon 8	chr17:7577142 (C>TA)	c.796G>T/p.Gly266	MISSENSE LOF	1507 (59.79)	Pathogenic
NRAS Exon 3	chr1:115256507 (T>CG)	c.204A>C/p.Arg68Ser	MISSENSE GOF	560 (52.32)	Likely pathogenic

Protein-Protein Network Analyses

Using the STRING website, the interaction between the mutated genes was predicted. The results showed that TP53, BRAF, MET, and NRAS were associated with each other in OKC, with predicted functional partners as TENT5C, RGL3, EML4, SOS1, and SHC4 genes. The PPI network contained 9 nodes, 22 edges, an average node degree of 4.89, avg. local clustering coefficient of 0.757, the expected number of edges of 9, and PPI enrichment P-value of .000156 (Figure 3).

Discussion

Odontogenic keratocysts are rather common cystic odontogenic lesions, yet bear many controversies regarding their nature, nomenclature, and position in the classification.¹⁹ Further, these cysts show an aggressive clinical course and are often detected late, at the time when the cyst has already caused marked bone destruction. The treatment options are complicated by dysplasia in the epithelium, varied histological features and their strong association with NBCC syndrome.^7,19 It has been demonstrated previously that, unlike sporadic cases, syndromic cases show a robust relationship with mutation in the PTCH1 gene, and are noted in 40% to 85% of the cases diagnosed as NBCC syndrome.^17,20 There are limited studies in the literature focussing specifically on gene sequencing of sporadic cases.^20,21 In a recent paper, Stojanov et al,²¹ showed a biallelic inactivation in 80% of sporadic OKCs and 9q copy-neutral loss of heterozygosity targeting the PTCH1 locus in 15% of sporadic cases. In the present study, we aimed to perform gene sequencing of 3 sporadic cases of OKCs as compared with a case of bilateral OKC in a 13-year-old Indian male.

In line with the literature, we found that all the cases affected the lower jaw with a preponderance to the male gender.^22-24 Interestingly, the bilateral non-syndromic variant had impacted molars within the radiolucencies, as previously reported.¹⁴ All cases showed a classic parakeratinised odontogenic epithelium with an uninflamed cyst wall, irrespective of the focal nature of the lesions. It must be emphasised that orthokeratinisation of the lining should be reported as orthokeratinised odontogenic cyst, which may also present as bilateral lesions and are always non-syndromic. In one of the previous papers, a 32-year-old male with bilateral radiolucencies was presented as OKC; however, the photomicrographs demonstrated orthokeratinised epithelium.²⁵ This distinction is important as both lesions are histologically and genetically different, unlike once believed not so.

Most of the previous studies on molecular analysis of sporadic or syndromic OKC concentrated either on the PTCH1 gene or the related pathways.^20-22,26 Other studies have reported mutations in PTCH2 and SUFU. The frequency of BRAF V600E mutation in OKCs is variable. While analysing 18 OKCs using next-generation sequencing, França et al,²⁷ could not find BRAF mutation even in a single case. The authors believed that BRAF does not play any role in the pathogenesis of OKC.²⁷ Missense mutations of ATM p.Ser333Phe, SMO p.Gly416Glu, PIK3CA p.Ser326Phe, FBXW7 p.Ser438Phe, JAK2 p.Ser605Phe, PTEN p.Arg173His, ATM p.Cys353Arg, PTEN p.Ser294Arg, and MET p.His1112Tyr were detected.

Contrariwise, Shimura et al,²⁸ showed a missense mutation in 2/7 studied cases of OKCs utilising whole genome sequencing. Apart, PTCH1 and SMO were detected in other OKC cases. They questioned the neoplastic nature of OKC and supported the prevailing concept to classify it under the category of odontogenic cysts. In the present study, using a 50-gene panel, we found a BRAF missense mutation (p.Gly464Glu) in sporadic OKC; however, the bilateral OKC did not reveal a BRAF mutation. But this may not be generalised as only a single case of bilateral sporadic OKC was included. Irrespective of the laterality, missense mutation of the TP53 gene with loss of function was noted in all cases (chromosome 17). Bilateral OKC also showed MET p.Tyr1230Cys and MET p.Met357Val mutations. Missense mutation of MET has been reported before.²⁷ NRAS mutation was seen in sporadic cases. The results of the present study point towards the plausible role of TP53, BRAF, NRAS, and MET gene mutations in OKCs. Clonal loss of heterozygosity of tumour suppressor genes such as p53, p16, PTCH1, and MCC in OKC supports a neoplastic origin rather than merely a developmental cyst.¹⁶ We also found mutation in MET, BRAF, and NRAS, in addition to TP53, which are also noted in neoplasms such as ameloblastoma, adenomatoid odontogenic tumour, malignant melanoma, and papillary thyroid carcinoma.^29-31 The STRING analysis showed that all 4 genes were related to each other directly or indirectly through TENT5C, RGL3, EML4, SOS1, and SHC4 genes, suggesting their plausible role in the pathogenesis of OKC beyond the PTCH1 gene.

The identical TP53 mutations with high variant allele frequencies observed in the bilateral case raise the possibility of a germline TP53 alteration. However, the present study was limited to the sequencing of tumour tissue, and matched normal tissue or peripheral blood samples were not available for germline analysis. Although the patient did not demonstrate clinical features suggestive of known cancer predisposition syndromes, the absence of germline testing represents an important limitation. Future studies incorporating germline analysis will be essential to distinguish somatic from inherited TP53 alterations, particularly in bilateral odontogenic keratocysts.

Although the present study was limited by a small sample size, owing to the cost sensitivity of next-generation sequencing techniques, we present preliminary molecular data comparing sporadic and clinically non-syndromic bilateral odontogenic keratocysts, highlighting the potential role of TP53 and other oncogenic pathways.

Conclusion

Within the limitations of the study, it can be concluded that the TP53 gene mutation plays an important role in the pathogenesis of OKC and supports its neoplastic nature. Bilateral OKC showed additional NRAS mutation, and sporadic cases demonstrated MET and BRAF mutations. Further studies with larger sample sizes are needed to confirm the findings.

Footnotes

ORCID iD

Deepak Pandiar

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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