Objectives: p16INK4a is a key gatekeeper for multiple biological processes that are associated wi... more Objectives: p16INK4a is a key gatekeeper for multiple biological processes that are associated with protection from cancer, including cell cycle control and senescence. Elevated expression of this gene is strongly correlated with biological activity of HPV infection and cancer development in uterine cervix and tonsil. Although HPV DNA has been found in a small portion of oral cavity cancers and dysplasia, the relevance of its presence to cancer development at this site is unclear, as is the significance of an expression change in p16INK4a as a predictor of HPV status, tissue behavior and outcome. Methods: Formalin-fixed, paraffin-embedded biopsies from 164 patients with mild, moderate and severe oral dysplasia in the “Oral Cancer Prediction Longitudinal study” (OCPL), British Columbia, Canada, were analyzed for HPV DNA using a semi-quantitative viral load Luminex technology. Expression of p16INK4a was assessed and categorized into 3 staining patterns (diffuse, focal, and negative). Results: HPV DNA was found in 13 (8%) lesions, 7 had HPV-16 infection and 1 HPV-18. Of the 164 samples, diffuse p16INK4a expression was present in 18%, focal in 56% and no p16 staining in 23% of samples. There was no significant correlation between HPV DNA-positivity and p16INK4a staining. Different p16 staining patterns showed significantly different progression rates (P < 0.0001): progression occurred in 1/92 (1.1%) focally stained, 1/29 (3.5%) diffusely stained and 10/43 (23.3%) with no staining. Conclusion: HPV DNA-positivity occurs in a small proportion of oral dysplasia but is poorly associated with p16INK4a expression. Future assessment of these samples for HR-HPV oncogene transcripts will provide information on its biological activity. The low likelihood of progression of p16INK4a focally stained lesions suggests a value of this marker in identification of low-risk cases. Acknowledgements: Supported by Else Kröner-Fresenius-Stiftung Foundation, Germany Citation Format: Tarinee Lubpairee, Elena Prigge, Magnus von Knebel Doeberitz, Miriam Reuschenbach, Lewei Zhang, Miriam P. Rosin. p16INH4a status helps predict clinical outcome of dysplasia in the oral cavity irrespective of HPV status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5306. doi:10.1158/1538-7445.AM2017-5306
Fishermen from Kerala (India) who chewed tobacco-containing betel quids daily (17.2 ± 9.6 quids p... more Fishermen from Kerala (India) who chewed tobacco-containing betel quids daily (17.2 ± 9.6 quids per day) and had well-developed oral leukoplakias with elevated frequencies of micronucleated cells participated in a short-term intervention trial. Beta-carotene (180 mg/week) (Group I), ...
Many factors contribute to socioeconomic status (SES), yet in most survival studies only income i... more Many factors contribute to socioeconomic status (SES), yet in most survival studies only income is used as a measure for determining SES. We used a complex, composite, census-based metric for socioeconomic deprivation to better distinguish individuals with lower SES and assess its impact on survival and staging trends of oral cancers. Oropharyngeal (OPC) and oral cavity cancer (OCC) cases were identified from the British Columbia cancer registry between 1981-2009 and placed into affluent and deprived neighborhoods using postal codes linked to VANDIX (a composite SES index based on 7 census variables encompassing income, housing, family structure, education, and employment). Stage and cancer-specific survival rates were examined by sex, SES, and time period. Approximately 50 % of OPC and OCC cases of both sexes resided in SES deprived neighborhoods. Numbers of cases have increased in recent years for all but OCC in men. The deprivation gap in survival between affluent and deprived ne...
The distinction between a new primary oral tumor and recurrence may bear significant prognostic i... more The distinction between a new primary oral tumor and recurrence may bear significant prognostic implications. Currently, this differentiation relies mainly on tumor location: when both lesions are at or near the same site, the new one is regarded as a recurrence; when the two are at different sites, the second lesion is regarded as a new primary. Recent investigations using molecular analysis have demonstrated that some oral squamous cell carcinomas (SCC) arising from different sites show the same clonogenical changes. In this case report, we studied the clonality of three SCC (one primary, two apparent recurrences) from the right lateral tongue of a young, non-smoking woman by using microsatellite analysis for loss of heterozygosity. The results showed that while the first two tumors were clonogenically similar, the third tumor was clonogenically different and was consistent with the development of a new primary. This result indicates that location of tumors alone is not always reliable in determining whether a new tumor is a recurrence or a new primary lesion.
BACKGROUND. Two staging systems for oral leukoplakias have been proposed to better predict progno... more BACKGROUND. Two staging systems for oral leukoplakias have been proposed to better predict prognosis. Although one system includes site as an independent determinant, its use is controversial.
There will be an increasing need of methods for assessing the suitability of specimens for geneti... more There will be an increasing need of methods for assessing the suitability of specimens for genetic-based assays as DNA markers become an integral part of molecular diagnosis. The targeting of specimens for specific analyses will require the ability to rapidly screen for DNA quality. Conventional methods such as Southern analysis and gene specific-polymerase chain reaction (PCR) often require quantities of material that represent a significant portion of the specimen, especially in microdissected samples. Here we describe a novel application of a commonly used PCRbased DNA-fingerprinting technology that requires minimal quantities of DNA to simultaneously assess multiple regions throughout the genome for DNA quality. Randomly amplified polymorphic DNA (RAPD) PCR generates DNA fragments of a broad size range with the product size reflecting the degree of sample fragmentation. Fourteen DNA samples extracted from cells microdissected from seven formalin-fixed, paraffin-embedded oral cancer biopsies were assessed for DNA quality using gene-specific PCR and RAPD-PCR. Although the more conventional assay required 2-ng DNA (or 300-cell equivalents) to examine DNA quality at a single locus, RAPD-PCR provided a more informative profile of DNA quality from the same microdissected archival specimens. KEY WORDS: DNA quality, Formalin-fixed archival biopsy, Microdissection, Randomly amplified polymorphic DNA-polymerase chain reaction. Mod Pathol 2002;15(8):889 -892
Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This ... more Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This is mainly due to the diculty in predicting outcome for this heterogeneous group of lesions. In this study, we constructed a detailed clinical history of 66 mild and moderate dysplasias in order to determine how treatment aected outcome, and to evaluate the eect of treatment on lesions with dierent genetic pro®les, which are de®ned by patterns of loss of heterozygosity (LOH) associated with low, intermediate and high risk of progression [Clin. Cancer Res., 6, 357-62, 2000]. The results showed that although treatment guided by clinical removal of leukoplakia reduced cancer progression risk in all three risk groups, the amount of reduction in our study group did not reach statistical signi®cance. To assess whether completeness of lesion removal was a major factor in recurrence, repeat biopsies at the primary sites were analyzed for persistent LOH status on chromosomes 3p, 4q, 8p, 9p, 11q, 13q and 17p. Strikingly, eight of 17 cases judged clinically removed contained the same molecular clones in the initial and subsequent biopsies, suggesting incomplete removal. When molecular information was included in the assessment of lesion removal, treatment signi®cantly reduced the risk of progression for cases with intermediate (P=0.043) and high risk (P=0.001) genetic pro®les, but not cases with low-risk pro®les. A 9.1-fold decrease in progression risk was observed for those with high-risk pro®le. Altogether, these data suggest the use of molecular pro®les to guide the treatment of low-grade dysplasia. Our data also suggest that currently an inadequate margin may in part be responsible for the high rate of recurrence, especially in high-risk lesions. #
JAMA otolaryngology-- head & neck surgery, Jan 14, 2016
The prevalence of genetically altered cells in oral cancers has a negative influence on the locor... more The prevalence of genetically altered cells in oral cancers has a negative influence on the locoregional recurrence rate and lowers survival. Fluorescence visualization (FV) can identify clinically occult, high-risk oral lesions by allowing health care professionals and surgeons to visualize and map occult disease. This process may improve overall survival by decreasing rates of locoregional recurrence. To assess the efficacy of FV-guided surgery in reducing locoregional recurrence and improving overall survival. A retrospective, case-control observational study was conducted on patients registered at a single oral oncology clinic from September 1, 2004, to August 31, 2009. The study included 246 patients 18 years or older with a diagnosis of a high-grade lesion (severe dysplasia or carcinoma in situ) or squamous cell carcinoma of less than 4 cm who underwent curative surgical treatment with at least 1 follow-up visit. Among these patients, 154 underwent surgery with FV guidance (FV...
1. J Can Dent Assoc. 2008 Apr;74(3):237-8. Voices from the community--the voice of an oral cancer... more 1. J Can Dent Assoc. 2008 Apr;74(3):237-8. Voices from the community--the voice of an oral cancer patient. Biggar H, Poh CF, Rosin M, Williams PM. University of British Columbia and BC Oral Cancer Prevention Program, BC ...
Dentists may encounter pigmented lesions in routine clinical practice. In most cases, the lesions... more Dentists may encounter pigmented lesions in routine clinical practice. In most cases, the lesions are asymptomatic and benign in nature; however, rarely, a pigmented lesion can be a sign of malignancy. We report a case of malignant melanoma of the maxillary gingiva to highlight the importance of biopsy and periodic follow-up of patients with unusual focal pigmented lesions in the oral cavity.
Most human breast cancers have diversified genomically and biologically by the time they become c... more Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as...
Human palatine tonsils are oropharyngeal lymphoid tissues containing multiple invaginations (cryp... more Human palatine tonsils are oropharyngeal lymphoid tissues containing multiple invaginations (crypts) in which the continuity of the outer surface epithelium is disrupted and the isolated epithelial cells intermingle with other cell types. We now show that primitive epithelial cells detectable in vitro in 2D colony assays and in a 3D culture system are CD44(+)NGFR(+) and present in both surface and crypt regions. Transcriptome analysis indicated a high similarity between CD44(+)NGFR(+) cells in both regions, although those isolated from the crypt contained a higher proportion of the most primitive (holo)clonogenic cells. Lentiviral transduction of CD44(+)NGFR(+) cells from both regions with human papillomavirus 16-encoded E6/E7 prolonged their growth in 2D cultures and caused aberrant differentiation in 3D cultures. Our findings therefore reveal a shared, site-independent, hierarchical organization, differentiation potential, and transcriptional profile of normal human tonsillar epit...
01ra lichen pLanus (OLP) is a common mucosal condition that is considered premalignant by some, a... more 01ra lichen pLanus (OLP) is a common mucosal condition that is considered premalignant by some, although others argue that only lichenoid lesions with dysplasia are precancerous. To address the question of whether OLP without dysplasia is premalignant, we used microsatellite analysis to examine 33 cases of OLP for allelic loss at nine loci located on chromosomes 3p, 9p, and 17p. Loss of heterozygosity (LOH) on these three arms occurs frequently in oral tumors, and the presence of these alterations in premalignant lesions suggests that they may play an important role in tumor progression. Results were compared with those observed in oral dysplasias (10 mild, 11 moderate, 16 severe/carcinoma in situ), 22 oral squamous cell carcinomas, and 29 reactive lesions. LOH was present in 6% of OLP, 14% of reactve lesions, 400/o of mild dysplasia, 46% of moderate dysplasia, 81% of severe dysplasia/carcinoma in situ, and 91% of squamous cell carcinomas. LOH was detected on only a single arm in OLP and reactive lesions but occurred on more than one chromosome in dysplasia and cancer, and the frequency of this multiple loss correlated significantly with increasing degrees of dysplasia and progression into squamous cell carcinoma (P = 0.0028). Although these findings do not support OLP as a lesion at risk for malignant transformation, such results need to be confirmed by use of other genetic markers as OLP may undergo malignant transforation through genetic pathways different from those of oral dysplasia. (AmJPathol 1997, 151:323-327) Oral lichen planus (OLP) is one of the most common oral mucosa diseases, occurring in approximately 1 % of the general population.1'2 Clinically, OLP frequently presents as multiple white lacy lesions that occur most commonly on the buccal mucosa and tongue. The lesions may become erosive or atrophic or may present in other clinical patterns. Unlike cutaneous LP, OLP tends to be chronic. It has been suggested that complete remission of OLP is either nonexistent or infrequent (see review in Ref.
Although it is widely accepted that clonal genetic alterations are an essential component of tumo... more Although it is widely accepted that clonal genetic alterations are an essential component of tumor progression, little is known of the distnbu tion of such changes in high-risk lesions or how such clones are altered overtime.Weexploredthefeasibilityofusing exfoliativecellscollectedby scraping the mucosal surface to detect allelic loss in oral lesions of 22 patients (14 squamous cell carcinomas, 2 carcinomas in situ, and 6 dys plasias). The data show that the patterns of allelic loss observed in these samples closely represent those observed In biopsies of the same region.
Loss of 3p has been associated with oral cancer progression and is common in many cancers. Howeve... more Loss of 3p has been associated with oral cancer progression and is common in many cancers. However, regions of alteration on 3p are poorly defined. We have constructed a high-resolution chromosomal array using a tiling set of 535 human bacterial artificial chromosomes that provides near complete coverage of 3p. Array comparative genomic hybridization analysis of 20 microdissected oral squamous cell carcinomas showed multiple and recurrent segments of copy number changes. These include a deletion containing the FHIT gene; novel segments of copy decrease at 3p22, 3p24, and 3p26; and an unexpected ϳ0.7 Mbp segmental increase at 3p21. These data strongly support the value of using chromosomal array comparative genomic hybridization for detailed profiling of oral squamous cell carcinomas.
Objectives: p16INK4a is a key gatekeeper for multiple biological processes that are associated wi... more Objectives: p16INK4a is a key gatekeeper for multiple biological processes that are associated with protection from cancer, including cell cycle control and senescence. Elevated expression of this gene is strongly correlated with biological activity of HPV infection and cancer development in uterine cervix and tonsil. Although HPV DNA has been found in a small portion of oral cavity cancers and dysplasia, the relevance of its presence to cancer development at this site is unclear, as is the significance of an expression change in p16INK4a as a predictor of HPV status, tissue behavior and outcome. Methods: Formalin-fixed, paraffin-embedded biopsies from 164 patients with mild, moderate and severe oral dysplasia in the “Oral Cancer Prediction Longitudinal study” (OCPL), British Columbia, Canada, were analyzed for HPV DNA using a semi-quantitative viral load Luminex technology. Expression of p16INK4a was assessed and categorized into 3 staining patterns (diffuse, focal, and negative). Results: HPV DNA was found in 13 (8%) lesions, 7 had HPV-16 infection and 1 HPV-18. Of the 164 samples, diffuse p16INK4a expression was present in 18%, focal in 56% and no p16 staining in 23% of samples. There was no significant correlation between HPV DNA-positivity and p16INK4a staining. Different p16 staining patterns showed significantly different progression rates (P < 0.0001): progression occurred in 1/92 (1.1%) focally stained, 1/29 (3.5%) diffusely stained and 10/43 (23.3%) with no staining. Conclusion: HPV DNA-positivity occurs in a small proportion of oral dysplasia but is poorly associated with p16INK4a expression. Future assessment of these samples for HR-HPV oncogene transcripts will provide information on its biological activity. The low likelihood of progression of p16INK4a focally stained lesions suggests a value of this marker in identification of low-risk cases. Acknowledgements: Supported by Else Kröner-Fresenius-Stiftung Foundation, Germany Citation Format: Tarinee Lubpairee, Elena Prigge, Magnus von Knebel Doeberitz, Miriam Reuschenbach, Lewei Zhang, Miriam P. Rosin. p16INH4a status helps predict clinical outcome of dysplasia in the oral cavity irrespective of HPV status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5306. doi:10.1158/1538-7445.AM2017-5306
Fishermen from Kerala (India) who chewed tobacco-containing betel quids daily (17.2 ± 9.6 quids p... more Fishermen from Kerala (India) who chewed tobacco-containing betel quids daily (17.2 ± 9.6 quids per day) and had well-developed oral leukoplakias with elevated frequencies of micronucleated cells participated in a short-term intervention trial. Beta-carotene (180 mg/week) (Group I), ...
Many factors contribute to socioeconomic status (SES), yet in most survival studies only income i... more Many factors contribute to socioeconomic status (SES), yet in most survival studies only income is used as a measure for determining SES. We used a complex, composite, census-based metric for socioeconomic deprivation to better distinguish individuals with lower SES and assess its impact on survival and staging trends of oral cancers. Oropharyngeal (OPC) and oral cavity cancer (OCC) cases were identified from the British Columbia cancer registry between 1981-2009 and placed into affluent and deprived neighborhoods using postal codes linked to VANDIX (a composite SES index based on 7 census variables encompassing income, housing, family structure, education, and employment). Stage and cancer-specific survival rates were examined by sex, SES, and time period. Approximately 50 % of OPC and OCC cases of both sexes resided in SES deprived neighborhoods. Numbers of cases have increased in recent years for all but OCC in men. The deprivation gap in survival between affluent and deprived ne...
The distinction between a new primary oral tumor and recurrence may bear significant prognostic i... more The distinction between a new primary oral tumor and recurrence may bear significant prognostic implications. Currently, this differentiation relies mainly on tumor location: when both lesions are at or near the same site, the new one is regarded as a recurrence; when the two are at different sites, the second lesion is regarded as a new primary. Recent investigations using molecular analysis have demonstrated that some oral squamous cell carcinomas (SCC) arising from different sites show the same clonogenical changes. In this case report, we studied the clonality of three SCC (one primary, two apparent recurrences) from the right lateral tongue of a young, non-smoking woman by using microsatellite analysis for loss of heterozygosity. The results showed that while the first two tumors were clonogenically similar, the third tumor was clonogenically different and was consistent with the development of a new primary. This result indicates that location of tumors alone is not always reliable in determining whether a new tumor is a recurrence or a new primary lesion.
BACKGROUND. Two staging systems for oral leukoplakias have been proposed to better predict progno... more BACKGROUND. Two staging systems for oral leukoplakias have been proposed to better predict prognosis. Although one system includes site as an independent determinant, its use is controversial.
There will be an increasing need of methods for assessing the suitability of specimens for geneti... more There will be an increasing need of methods for assessing the suitability of specimens for genetic-based assays as DNA markers become an integral part of molecular diagnosis. The targeting of specimens for specific analyses will require the ability to rapidly screen for DNA quality. Conventional methods such as Southern analysis and gene specific-polymerase chain reaction (PCR) often require quantities of material that represent a significant portion of the specimen, especially in microdissected samples. Here we describe a novel application of a commonly used PCRbased DNA-fingerprinting technology that requires minimal quantities of DNA to simultaneously assess multiple regions throughout the genome for DNA quality. Randomly amplified polymorphic DNA (RAPD) PCR generates DNA fragments of a broad size range with the product size reflecting the degree of sample fragmentation. Fourteen DNA samples extracted from cells microdissected from seven formalin-fixed, paraffin-embedded oral cancer biopsies were assessed for DNA quality using gene-specific PCR and RAPD-PCR. Although the more conventional assay required 2-ng DNA (or 300-cell equivalents) to examine DNA quality at a single locus, RAPD-PCR provided a more informative profile of DNA quality from the same microdissected archival specimens. KEY WORDS: DNA quality, Formalin-fixed archival biopsy, Microdissection, Randomly amplified polymorphic DNA-polymerase chain reaction. Mod Pathol 2002;15(8):889 -892
Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This ... more Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This is mainly due to the diculty in predicting outcome for this heterogeneous group of lesions. In this study, we constructed a detailed clinical history of 66 mild and moderate dysplasias in order to determine how treatment aected outcome, and to evaluate the eect of treatment on lesions with dierent genetic pro®les, which are de®ned by patterns of loss of heterozygosity (LOH) associated with low, intermediate and high risk of progression [Clin. Cancer Res., 6, 357-62, 2000]. The results showed that although treatment guided by clinical removal of leukoplakia reduced cancer progression risk in all three risk groups, the amount of reduction in our study group did not reach statistical signi®cance. To assess whether completeness of lesion removal was a major factor in recurrence, repeat biopsies at the primary sites were analyzed for persistent LOH status on chromosomes 3p, 4q, 8p, 9p, 11q, 13q and 17p. Strikingly, eight of 17 cases judged clinically removed contained the same molecular clones in the initial and subsequent biopsies, suggesting incomplete removal. When molecular information was included in the assessment of lesion removal, treatment signi®cantly reduced the risk of progression for cases with intermediate (P=0.043) and high risk (P=0.001) genetic pro®les, but not cases with low-risk pro®les. A 9.1-fold decrease in progression risk was observed for those with high-risk pro®le. Altogether, these data suggest the use of molecular pro®les to guide the treatment of low-grade dysplasia. Our data also suggest that currently an inadequate margin may in part be responsible for the high rate of recurrence, especially in high-risk lesions. #
JAMA otolaryngology-- head & neck surgery, Jan 14, 2016
The prevalence of genetically altered cells in oral cancers has a negative influence on the locor... more The prevalence of genetically altered cells in oral cancers has a negative influence on the locoregional recurrence rate and lowers survival. Fluorescence visualization (FV) can identify clinically occult, high-risk oral lesions by allowing health care professionals and surgeons to visualize and map occult disease. This process may improve overall survival by decreasing rates of locoregional recurrence. To assess the efficacy of FV-guided surgery in reducing locoregional recurrence and improving overall survival. A retrospective, case-control observational study was conducted on patients registered at a single oral oncology clinic from September 1, 2004, to August 31, 2009. The study included 246 patients 18 years or older with a diagnosis of a high-grade lesion (severe dysplasia or carcinoma in situ) or squamous cell carcinoma of less than 4 cm who underwent curative surgical treatment with at least 1 follow-up visit. Among these patients, 154 underwent surgery with FV guidance (FV...
1. J Can Dent Assoc. 2008 Apr;74(3):237-8. Voices from the community--the voice of an oral cancer... more 1. J Can Dent Assoc. 2008 Apr;74(3):237-8. Voices from the community--the voice of an oral cancer patient. Biggar H, Poh CF, Rosin M, Williams PM. University of British Columbia and BC Oral Cancer Prevention Program, BC ...
Dentists may encounter pigmented lesions in routine clinical practice. In most cases, the lesions... more Dentists may encounter pigmented lesions in routine clinical practice. In most cases, the lesions are asymptomatic and benign in nature; however, rarely, a pigmented lesion can be a sign of malignancy. We report a case of malignant melanoma of the maxillary gingiva to highlight the importance of biopsy and periodic follow-up of patients with unusual focal pigmented lesions in the oral cavity.
Most human breast cancers have diversified genomically and biologically by the time they become c... more Most human breast cancers have diversified genomically and biologically by the time they become clinically evident. Early events involved in their genesis and the cellular context in which these events occur have thus been difficult to characterize. Here we present the first formal evidence of the shared and independent ability of basal cells and luminal progenitors, isolated from normal human mammary tissue and transduced with a single oncogene (KRAS(G12D)), to produce serially transplantable, polyclonal, invasive ductal carcinomas within 8 weeks of being introduced either subrenally or subcutaneously into immunodeficient mice. DNA barcoding of the initial cells revealed a dramatic change in the numbers and sizes of clones generated from them within 2 weeks, and the first appearance of many 'new' clones in tumours passaged into secondary recipients. Both primary and secondary tumours were phenotypically heterogeneous and primary tumours were categorized transcriptionally as...
Human palatine tonsils are oropharyngeal lymphoid tissues containing multiple invaginations (cryp... more Human palatine tonsils are oropharyngeal lymphoid tissues containing multiple invaginations (crypts) in which the continuity of the outer surface epithelium is disrupted and the isolated epithelial cells intermingle with other cell types. We now show that primitive epithelial cells detectable in vitro in 2D colony assays and in a 3D culture system are CD44(+)NGFR(+) and present in both surface and crypt regions. Transcriptome analysis indicated a high similarity between CD44(+)NGFR(+) cells in both regions, although those isolated from the crypt contained a higher proportion of the most primitive (holo)clonogenic cells. Lentiviral transduction of CD44(+)NGFR(+) cells from both regions with human papillomavirus 16-encoded E6/E7 prolonged their growth in 2D cultures and caused aberrant differentiation in 3D cultures. Our findings therefore reveal a shared, site-independent, hierarchical organization, differentiation potential, and transcriptional profile of normal human tonsillar epit...
01ra lichen pLanus (OLP) is a common mucosal condition that is considered premalignant by some, a... more 01ra lichen pLanus (OLP) is a common mucosal condition that is considered premalignant by some, although others argue that only lichenoid lesions with dysplasia are precancerous. To address the question of whether OLP without dysplasia is premalignant, we used microsatellite analysis to examine 33 cases of OLP for allelic loss at nine loci located on chromosomes 3p, 9p, and 17p. Loss of heterozygosity (LOH) on these three arms occurs frequently in oral tumors, and the presence of these alterations in premalignant lesions suggests that they may play an important role in tumor progression. Results were compared with those observed in oral dysplasias (10 mild, 11 moderate, 16 severe/carcinoma in situ), 22 oral squamous cell carcinomas, and 29 reactive lesions. LOH was present in 6% of OLP, 14% of reactve lesions, 400/o of mild dysplasia, 46% of moderate dysplasia, 81% of severe dysplasia/carcinoma in situ, and 91% of squamous cell carcinomas. LOH was detected on only a single arm in OLP and reactive lesions but occurred on more than one chromosome in dysplasia and cancer, and the frequency of this multiple loss correlated significantly with increasing degrees of dysplasia and progression into squamous cell carcinoma (P = 0.0028). Although these findings do not support OLP as a lesion at risk for malignant transformation, such results need to be confirmed by use of other genetic markers as OLP may undergo malignant transforation through genetic pathways different from those of oral dysplasia. (AmJPathol 1997, 151:323-327) Oral lichen planus (OLP) is one of the most common oral mucosa diseases, occurring in approximately 1 % of the general population.1'2 Clinically, OLP frequently presents as multiple white lacy lesions that occur most commonly on the buccal mucosa and tongue. The lesions may become erosive or atrophic or may present in other clinical patterns. Unlike cutaneous LP, OLP tends to be chronic. It has been suggested that complete remission of OLP is either nonexistent or infrequent (see review in Ref.
Although it is widely accepted that clonal genetic alterations are an essential component of tumo... more Although it is widely accepted that clonal genetic alterations are an essential component of tumor progression, little is known of the distnbu tion of such changes in high-risk lesions or how such clones are altered overtime.Weexploredthefeasibilityofusing exfoliativecellscollectedby scraping the mucosal surface to detect allelic loss in oral lesions of 22 patients (14 squamous cell carcinomas, 2 carcinomas in situ, and 6 dys plasias). The data show that the patterns of allelic loss observed in these samples closely represent those observed In biopsies of the same region.
Loss of 3p has been associated with oral cancer progression and is common in many cancers. Howeve... more Loss of 3p has been associated with oral cancer progression and is common in many cancers. However, regions of alteration on 3p are poorly defined. We have constructed a high-resolution chromosomal array using a tiling set of 535 human bacterial artificial chromosomes that provides near complete coverage of 3p. Array comparative genomic hybridization analysis of 20 microdissected oral squamous cell carcinomas showed multiple and recurrent segments of copy number changes. These include a deletion containing the FHIT gene; novel segments of copy decrease at 3p22, 3p24, and 3p26; and an unexpected ϳ0.7 Mbp segmental increase at 3p21. These data strongly support the value of using chromosomal array comparative genomic hybridization for detailed profiling of oral squamous cell carcinomas.
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