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Oral cancer with special reference to virus detection and quantitative gene expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Oral and Maxillofacial Surgery.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background. Head and neck cancers (HNC) are among the most common malignancies worldwide, and about 90–92% of oral neoplasias are oral squamous cell carcinomas (OSCC). Alcohol and tobacco consumption have been recognized as the main risk factors for OSCC development. Oncogenic viruses, such as human papillomavirus (HPV) or Epstein-Barr virus (EBV), as well as genetic alterations may also contribute to tumour formation. 

Aims. To study the prevalence of HPV, EBV, Herpes simplex type-1 (HSV-1), and HPV-16 and their integration status as well as the molecular mechanisms that can serve as a basis for the development of OSCC.

Results. In Paper I we reported a statistically significant increase in the prevalence of HPV-16 in oral epithelial dysplasia (OED) and OSCC samples compared to controls. A statistically significant increase was also seen in integrated HPV-16 compared to episomal viral forms when comparing OED and OSCC samples. Paper II reported the detection of HSV-1 in 54% of healthy samples, in 36% of oral leukoplakia samples, and 52% of OSCC samples. However, these differences were not statistically significant. In Paper III we reported a statistically significant increase in the detection of HPV-positive samples when comparing nested polymerase chain reaction (PCR) with single-PCR results in OSCC and fresh oral mucosa. Paper IV reported that the highest prevalence of HPV (65%) was seen in Sudan, while an HSV-1 prevalence of 55% and an EBV prevalence of 80% were seen in the UK. Finally, Paper V reported that the mRNA levels of Bcl-2, keratin 1, keratin 13, and p53 were significantly lower and that the level of survivin was significantly higher in the OSCC samples of the toombak users than in their paired control samples. Significant downregulation in keratin 1 and keratin 13 expression levels was found in the OSCC samples of the non-toombak users relative to their normal control samples.

Conclusion. HPV-16 integration was increased in oral epithelial dysplasia and OSCC compared to normal oral mucosa. Nested PCR is a more accurate method of establishing HPV prevalence in samples containing low copy numbers of HPV DNA. HPV and EBV may be a risk factor in OSCC development. Our findings confirmed the role of survivin in OSCC carcinogenesis and survivin might be interesting as a biomarker to be monitored. The results presented here provide both clinical and biological insights that will bring us closer to the goal of managing this disease and improving treatment and outcomes for future patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1179
Keyword [en]
HPV, EBV, HSV-1, Oral Squamous Cell Carcinoma, Leukoplakia, apopto-sis, cell cycle regulation, intermediate filament proteins.
National Category
Natural Sciences Medical and Health Sciences
Research subject
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-275516ISBN: 978-91-554-9476-6 (print)OAI: oai:DiVA.org:uu-275516DiVA: diva2:900444
Public defence
2016-03-18, Skoog-salen, Akademiska sjukhuset, Ingång 79, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-02-26 Created: 2016-02-04 Last updated: 2016-03-09
List of papers
1. Association of Human Papilloma Virus infection in healthy oral mucosa, oral dysplasia and oral squamous cell carcinoma
Open this publication in new window or tab >>Association of Human Papilloma Virus infection in healthy oral mucosa, oral dysplasia and oral squamous cell carcinoma
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2015 (English)In: Journal of Oral Health and Dental Management, ISSN 1583-5588, Vol. 14, no 5Article in journal (Refereed) Published
Abstract [en]

Aims: Human papillomavirus (HPV) is an important risk factor for development of oral cancer; however, the integrational status of the virus into the host DNA association between HPV infection and oral squamous cell carcinoma (OSCC) is still uncertain has not been investigated to the same extent. The objective of the present study was to investigate the prevalence of consensus HPV, and HPV-16 and its integration status, in healthy oral mucosa, oral epithelial dysplasia (OED), and OSCC samples.Materials and Methods: The study material consisted of 26 fresh, normal oral mucosa samples, and 53 and 27 paraffin-embedded OED and OSCC samples, respectively. The specimens were DNA extracted and investigated for the presence of HPV, and HPV-16 and its integration status, by polymerase chain reaction (PCR) and DNA sequencing.Results: Thirty-eight (72%) of the 53 paraffin-embedded OED samples, 16 (59%) of the 27 OSCC samples, and 12 (46%) of the 26 control samples were found to be HPV-DNA positive, with nested PCR (NPCR). Further, HPV-16 was detected in 31 (82%), 15 (94%), and 0 (0%) HPV-positive OED cases, HPV-positive OSCC cases, and controls, respectively. Integration was observed in 26/31 (84%) and 13/15 (87%) of the HPV-16-positive OED and OSCC cases, respectively. A statistically significant difference was found comparing prevalence of HPV-16 in controls with that in both OED and OSCC samples (P<0.005). A statistically significant difference was also found comparing prevalence of integrated and episomal viral forms comparing OED and OSCC samples (P<0.005).Conclusion: The high prevalence of HPV and high-risk HPV-16 in OED and OSCC samples suggests a potential aetiologic role for the virus in OSCC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-265748 (URN)
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-12-01
2. Nested PCR for detection of HSV-1 in oral mucosa
Open this publication in new window or tab >>Nested PCR for detection of HSV-1 in oral mucosa
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2015 (English)In: Medicina Oral, ISSN 1698-4447, E-ISSN 1698-6946, Vol. 20, no 6, E664-E669 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: It has been estimated that 15%-20% of human tumours are driven by infection and inflammation, and viral infections play an important role in malignant transformation. The evidence that herpes simplex virus type 1 (HSV-1) could be involved in the aetiology of oral cancer varies from weak to persuasive. This study aimed to investigate by nested PCR (NPCR) the prevalence of HSV-1 in samples from normal oral mucosa, oral leukoplakia, and oral squamous cell carcinoma (OSCC).

MATERIAL AND METHODS: We investigated the prevalence of HSV-1 in biopsies obtained from 26 fresh, normal oral mucosa from healthy volunteers as well as 53 oral leukoplakia and 27 OSCC paraffin-embedded samples. DNA was extracted from the specimens and investigated for the presence of HSV-1 by nested polymerase chain reaction (NPCR) and DNA sequencing.

RESULTS: HSV-1 was detected in 14 (54%) of the healthy samples, in 19 (36%) of the oral leukoplakia samples, and in 14 (52%) of the OSCC samples. The differences were not statistically significant.

CONCLUSIONS: We observed a high incidence of HSV-1 in healthy oral mucosa, oral leukoplakia, and OSCC tissues. Thus, no connection between OSCC development and presence of HSV-1 was detected.

Keyword
HSV-1; nested PCR; PCR
National Category
Dentistry
Identifiers
urn:nbn:se:uu:diva-265746 (URN)10.4317/medoral.20630 (DOI)000369435500004 ()26449432 (PubMedID)
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2017-12-01Bibliographically approved
3. Comparison Between Single PCR and Nested PCR in Detection of Human Papilloma Viruses in Paraffin-embedded OSCC and Fresh Oral Mucosa
Open this publication in new window or tab >>Comparison Between Single PCR and Nested PCR in Detection of Human Papilloma Viruses in Paraffin-embedded OSCC and Fresh Oral Mucosa
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2015 (English)In: In Vivo, ISSN 0258-851X, E-ISSN 1791-7549, Vol. 29, no 1, 65-70 p.Article in journal (Refereed) Published
Abstract [en]

Background: Infection with human papilloma virus (HPV) has been implicated as one of the risk factors for the development of oropharyngeal cancer. Many different HPV tests exist, and information regarding their specific technical, analytical, and clinical properties is increasing. Aim: This study aimed to compare the level of detection of HPV using two reliable polymerase chain reaction (PCR) methods, nested PCR (NPCR) and single PCR (SPCR), in archival paraffin-embedded oral squamous cell carcinoma (OSCC) samples and fresh oral mucosa specimens. Materials and Methods: The presence of HPV genome in two groups of tissue samples was analyzed: (i) 57 paraffin-embedded OSCC samples from Sudan and (ii) eight healthy fresh oral mucosal samples from Swedish volunteers. The specimens were tested by SPCR with primer pair MY9/MY11 and NPCR using GP5+/GP6+ primer sets. Results: Eighteen (32%) out of the 57 paraffin-embedded OSCC samples, and five (62%) out of the eight fresh clinically healthy samples were found to be HPV-positive with NPCR. With SPCR, four (7%) out of the paraffin-embedded OSCC samples were HPV-positive. A statistically significant difference between HPV-positive and -negative samples was found when comparing NPCR and SPCR in OSCC and fresh oral mucosa (p<0.0001). The comparative test between SPCR and NPCR showed 100% sensitivity and 69% specificity for OSCC. Conclusion: The use of the GP5+/GP6+ nested PCR increased the positivity rate, efficiency rate and sensitivity of HPV detection in oral samples significantly and should be considered as the method of choice.

Keyword
HPV, nested PCR, single PCR, paraffin embedded, OSCC, fresh oral mucosa
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-245198 (URN)000348134300011 ()25600532 (PubMedID)
Available from: 2015-02-25 Created: 2015-02-25 Last updated: 2017-12-04Bibliographically approved
4. Human Papilloma Virus, Herpes Simplex Virus and Epstein Barr Virus in Oral Squamous Cell Carcinoma from Eight Different Countries
Open this publication in new window or tab >>Human Papilloma Virus, Herpes Simplex Virus and Epstein Barr Virus in Oral Squamous Cell Carcinoma from Eight Different Countries
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2012 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 2, 571-580 p.Article in journal (Refereed) Published
Abstract [en]

Oral squamous cell carcinoma (OSCC) is a major health problem in many parts of the world, and the major causative agents are thought to he the use of alcohol and tobacco. Oncogenic viruses have also been suggested to be involved in OSCC development. This study investigated the prevalence of human papillomaviruses (HPV), herpes simplex virus (HSV) and Epstein-Barr virus (EBV) in 155 OSCC from eight different countries from different ethnic groups, continents and with different socioeconomic backgrounds. 41 A total of OSCCs were diagnosed in the tongue (26%) and 23 in the floor of the mouth (15%); the other 91 OSCCs were diagnosed in other locations (59%). The patients were also investigated regarding the use of alcohol and smoking and smokeless tobacco habits. Tissue samples were obtained from formalin-fixed, paraffin-embedded samples of the OSCC. DNA was extracted and the viral genome was examined by single, nested and seminested PCR assays. Sequencing of double-stranded DNA from the PCR product was carried out. Following sequencing of the HPV-, HSV- and EBV-positive PCR products, 100% homology between the sampels was found. Of all the 155 OSCCs examined, 85 (55%) were positive for EBV, 54 (35%) for HPV and 24 (15%) for HSV. The highest prevalence of HPV was seen in Sudan (65%), while HSV (55%) and EBV (80%) were most prevalent in the UK. In 34% (52/155) of all the samples examined, co-infection by two (46/155=30%) or three (6/155=4%) virus specimens was detected. The most frequent double infection was HPV with EBV in 21% (32/155) of all OSCCs. There was a statistically significant higher proportion of samples with HSV (p=0.026) and EBV (p=0.015) in industrialized countries (Sweden, Norway, UK and USA) as compared to developing countries (Sudan, India, Sri Lanka and Yemen). Furthermore, there was a statistically significant higher co-infection of HSV and EBV in samples from industrialized countries (p=0.00031). No firm conclusions could be drawn regarding the relationship between alcohol, tobacco and virus infections. The significance of our findings must be put in relation to other risk factors and these observations warrant further studies to determine the possible role of viral infections and co-infections with HPV, EBV and HSV as risk markers for the development of OSCC.

Keyword
Epstein Barr virus, herpes simplex virus, human papilloma virus, oral squamous cell carcinoma
National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-169954 (URN)000299985800023 ()22287747 (PubMedID)
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved
5. Differential Expression of Apoptosis, Cell Cycle Regulation and Intermediate Filament Genes in Oral Squamous Cell Carcinomas Associated with Toombak Use in Sudan
Open this publication in new window or tab >>Differential Expression of Apoptosis, Cell Cycle Regulation and Intermediate Filament Genes in Oral Squamous Cell Carcinomas Associated with Toombak Use in Sudan
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2011 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 31, no 10, 3345-3351 p.Article in journal (Refereed) Published
Abstract [en]

Previously we used microarray genomic hybridization technology to explore genome-wide profiles of chromosomal aberrations in samples of oral squamous cell carcinomas (OSCCs) and paired normal controls. Based on these findings, 9 genes related to apoptosis, cell cycle regulation and intermediate filament proteins were selected and their differential expression status was examined by real-time quantitative RT-PCR in 26 samples of Sudanese OSCCs and their matched normal controls. The findings were correlated with the habit of toombak use. The mRNA levels of Bcl2, keratin 1, keratin 13 and p53 were significantly lower and the level of survivin was significantly higher in the OSCC samples of the toombak users compared to their paired control samples. A significant down-regulation in keratin I and keratin 13 expression levels was found in the OSCC samples of the non-toombak users compared to their normal control samples. The differential expression of genes related to apoptosis, cell cycle regulation and types I and II keratin could be useful diagnostic markers and provide valuable information for the understanding of oral malignancy in relation to toombak use.

Keyword
Oral squamous cell carcinomas, toombak, genes, apoptosis, cell cycle regulation, intermediate filament proteins, Sudan
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-160724 (URN)000295667700030 ()21965745 (PubMedID)
Available from: 2011-11-01 Created: 2011-10-31 Last updated: 2017-12-08Bibliographically approved

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