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Biomedical subjects

M P Rosin

Publications and source records attributed to M P Rosin.

At least 19 recordsLinked to original sources
PubMed2002

Comparison of HPV infection, p53 mutation and allelic losses in post-transplant and non-posttransplant oral squamous cell carcinomas.

BACKGROUND: Oral squamous cell carcinoma (SCC) is increasingly found in transplant recipients, although little is known of the natural history of the disease or the mechanism underlying this increase. METHODS: In this article we describe the history of development of 5 oral post-transplant SCCs (PSCCs) and compare their genetic profiles to 34 non-posttransplant SCCs (NPSCCs). RESULTS: Of the five patients with PSCCs, 3 had bone marrow transplants and two, kidney. All three PSCCs from bone marrow recipients were preceded locally by graft-vs.-host disease (GVHD). Two of the GVHD were biopsied and demonstrated dysplasia. Similar frequencies of loss of heterozygosity (LOH) occurred in PSCCs and NPSCCs at 3p, 9p, 17p and 8p, with lower frequencies in PSCCs at 4q (39% vs. 0%), 11q (53% vs. 20%) and 13q (45% vs. 20%), although the latter were not significantly different. Only 1 PSCC had a p53 mutation, compared to historical values of 40-60% for NPSCC. Interestingly, human papillomavirus (HPV) DNA was detected in 3 (60%) PSCCs, in comparison to only 4 (12%) of the 34 NPSCCs (P = 0.0346). CONCLUSIONS: Dysplasia in oral GVHD may be a strong indicator of cancer risk and should not be regarded as reactive changes to lichenoid mucosites. The low level of p53 mutation and increased HPV infection support the involvement of HPV in the development of PSCC, while the similarity in LOH patterns suggests that other aspects of carcinogenesis may be comparable in these two types of SCCs.

Adult↗
PubMed2001

Increased genetic damage in oral leukoplakia from high risk sites: potential impact on staging and clinical management.

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. METHODS: Recent studies have shown that loss of heterozygosity (LOH) in oral premalignancies is associated with risk of progression. The authors analyzed 127 oral dysplasias for LOH on 3 chromosome arms (3p, 9p, and 17p). The lesions included 71 from the floor of mouth, ventrolateral tongue, and soft palate complex (designated high risk [HR] sites) and 56 from the rest of the oral cavity (low risk [LR] sites). RESULTS: Dysplasias from HR sites contained significantly higher LOH frequencies than LR sites (percentage with any loss, P = 0.0004; percentage with multiple losses, P = 0.0001; percentage loss on each of the arms, P < 0.05). Loss on 3p and/or 9p, a pattern associated with a 24-fold increased risk of progression (Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357-62) was more frequent among HR lesions (P = 0.0005). Loss of heterozygosity frequencies were elevated at HR sites among both genders and among smokers and nonsmokers. For different histologic groups, LOH frequencies were elevated for HR sites in mild dysplasias (P < 0.05) and moderate dysplasias (marginal significance, P = 0.06), but not in severe dysplasias/carcinoma in situ. CONCLUSIONS: Anatomic location of mild and moderate oral dysplasias in Western populations may be an important diagnostic indicator because lesions at HR sites have a greater tendency to include genetic alterations associated with elevated risk of progression.

Adult↗
PubMed2001

Impact of localized treatment in reducing risk of progression of low-grade oral dysplasia: molecular evidence of incomplete resection.

Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This is mainly due to the difficulty 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 affected outcome, and to evaluate the effect of treatment on lesions with different genetic profiles, which are defined 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 significance. 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 significantly reduced the risk of progression for cases with intermediate (P=0.043) and high risk (P=0.001) genetic profiles, but not cases with low-risk profiles. A 9.1-fold decrease in progression risk was observed for those with high-risk profile. Altogether, these data suggest the use of molecular profiles 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.

Adult↗
PubMed2001

Loss of heterozygosity: a potential tool in management of oral premalignant lesions?

Oral leukoplakia, a heterogeneous group of lesions, demonstrates a varying degree of risk for cancer progression. Histology (presence and degree of dysplasia), the current gold standard for assessing this risk, is reasonably effective in judging the malignant risk of high-grade pre-invasive lesions. It is, however, a poor predictor for lesions without dysplasia, or with minimal dysplasia, as only a few of these lesions will progress to cancer. This poses an enormous dilemma for clinicians as to whether these lesions should be aggressively treated or not. Recent studies show that loss of specific chromosomal regions (loss of heterozygosity, LOH) that contain known or presumptive tumor suppressor genes is an early predictor of subsequent progression of oral premalignant lesions. Incorporation of LOH findings into staging of oral premalignancy could improve our ability to identify and manage high-risk premalignant lesions, particularly those with relatively benign histology but high-risk genetic changes (high-risk LOH pattern).

Carcinoma, Squamous Cell↗
PubMed2001

A high frequency of allelic loss in oral verrucous lesions may explain malignant risk.

Verrucous carcinoma (VC), a variant of squamous cell carcinoma (SCC), is distinct from SCC in morphology and behavior. The underlying genetic changes involved in the development of VC and its precursor verrucous hyperplasia (VH) are unknown. This study determined whether chromosomal regions frequently lost during the development of SCC are also lost in the VH/VC variant. Twenty-five VH and 17 VC were analyzed for loss of heterozygosity (LOH) at 19 loci on 7 chromosome arms using microsatellite analysis. These data were compared with those from 47 reactive hyperplasias, 92 dysplasias (54 low- and 38 high-grade), and 41 SCCS: The results showed that VC/VH shared many of the losses present in dysplasia/SCC but differed in two aspects. First, VC/VH showed early acquisition of loss, compared with a gradual accumulation of losses from dysplasias to SCC. The LOH pattern of VH was similar to that of high-grade dysplasia and sharply different from reactive hyperplasia. The loss in VH often involved multiple arms (in 60% of VH vs 0% of reactive lesions). Only a marginal elevation of loss was observed at 9p (p = 0.06) and 4q (p = 0.05) from VH to VC because of the high degree of loss already present in VH. Second, a strikingly lower frequency of loss at 17p was noted in VH/VC compared with dysplasia/SCC and may indicate human papillomavirus (HPV) involvement. The finding of high-risk LOH profiles in VH may partly account for the high-progression risk seen for VH and also has potentially important clinical implications. The difficult pathological diagnosis of VH/VC from reactive hyperplasia frequently requires repeated biopsies and results in delay in diagnosis and significantly increased mortality/morbidity. Microsatellite analysis might facilitate this differential diagnosis.

Aged↗
PubMed2000

High frequency of allelic loss in dysplastic lichenoid lesions.

Oral lichen planus (OLP) is a common mucosal condition that is considered premalignant by some, whereas others argue that only lichenoid lesions with epithelial dysplasia are at risk of progressing into oral carcinoma. A recent study from this laboratory used microsatellite analysis to evaluate OLP for loss of heterozygosity (LOH) at loci on three chromosomal arms (3p, 9p, and 17p) (Am J Path 1997;Vol151:Page323-Page327). Loss on these arms is a common event in oral epithelial dysplasia and has been associated with risk of progression of oral leukoplakia to cancer. The data showed that, although dysplastic epithelium demonstrated a high frequency of LOH (40% for mild dysplasia), a significantly lower frequency of LOH was noted in OLP (6%), which is even lower than that in hyperplasia (14%). Such results do not support OLP as a lesion at risk for malignant transformation. As a second step of the research, we determined LOH frequencies in 61 dysplastic lichenoid lesions (mild 35; moderate 19; severe 7) using the same microsatellite markers and compared these results with data obtained from the first study and from 13 normal mucosal specimens. Dysplastic lichenoid lesions showed a high frequency of loss (54% for lichenoid lesions with mild dysplasia), but values did not differ significantly from those observed in dysplasia of similar degree without lichenoid appearance. None of the normal mucosa demonstrated LOH. Epithelial dysplasia is a sign of malignant risk, independent of lichenoid changes. Such results suggest that pathologists should search for dysplasia carefully in lesions that otherwise qualify as OLP and that caution should be used when discounting dysplasia as being merely a reactive condition in lichenoid lesions.

Adult↗
PubMed2000

Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia.

One of the best approaches to identifying genetic changes critical to oral cancer progression is to compare progressing and nonprogressing oral premalignant lesions. However, such samples are rare, and they require long-term follow-up. The current study used the large archive network and clinical database in British Columbia to study loss of heterozygosity (LOH) in cases of early oral premalignancies, comparing those with a history of progression to carcinoma in situ or invasive cancer and those without a history of progression (referred to as nonprogressing cases). Each of 116 cases was analyzed for LOH at 19 microsatellite loci on seven chromosome arms (3p, 4q, 8p, 9p, 11q, 13q, and 17p). The progressing and nonprogressing cases showed dramatically different LOH patterns of multiple allelic losses. An essential step for progression seems to involve LOH at 3p and/or 9p because virtually all progressing cases showed such loss. However, LOH at 3p and/or 9p also occurred in nonprogressing cases. Individuals with LOH at 3p and/or 9p but at no other arms exhibit only a slight increase of 3.8-fold in relative risk for developing cancer. In contrast, individuals with additional losses (on 4q, 8p, 11q, or 17p), which appeared uncommon in nonprogressing cases, showed 33-fold increases in relative cancer risk. In conclusion, analysis of LOH at 3p and 9p could serve as an initial screening for cancer risk of early premalignancies. Follow-up investigation for additional losses would be essential for predicting cancer progression.

Chromosome Mapping↗
PubMed1999

Local tumor recurrence or emergence of a new primary lesion? A molecular analysis.

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.

Adult↗
PubMed1997

The use of exfoliative cell samples to map clonal genetic alterations in the oral epithelium of high-risk patients.

Although it is widely accepted that clonal genetic alterations are an essential component of tumor progression, little is known of the distribution of such changes in high-risk lesions or how such clones are altered over time. We explored the feasibility of using exfoliative cells collected by scraping the mucosal surface to detect allelic loss in oral lesions of 22 patients (14 squamous cell carcinomas, 2 carcinomas in situ, and 6 dysplasias). The data show that the patterns of allelic loss observed in these samples closely represent those observed in biopsies of the same region. Furthermore, early indications are that this approach can be used to detect recurrent outgrowth of clones of altered cells in patients after therapy.

Adult↗
PubMed1997

Rejoining of DNA double-strand breaks after the introduction of chromosome 11 into a radiosensitive bladder carcinoma cell line.

Insertion of a normal chromosome 11 into tumour cell lines can protect against a sensitivity to irradiation and oxidative stress. A possible mechanism underlying this effect is that there is a correction of a defect in the rejoining of double-strand breaks (dsb) by the chromosome insertion. In order to explore this hypothesis, three cell lines were evaluated for their ability to rejoin dsb: (1) a bladder carcinoma cell line ('parent') previously shown to be sensitive to irradiation and radical generating species; (2) a derivative of this cell line into which a normal chromosome 11 had been inserted by microcell fusion ('hybrid') showing corrected radiosensitivity; and (3) a 'revertant' cell line that had spontaneously lost the insert and reverted to the radiosensitive phenotype. Nuclear extracts from the 3 lines were isolated and evaluated for their capacity to rejoin plasmid (pUC18) DNA broken at defined restriction sites (SalI, EcoRI, KpnI, SmaI) in the lacZ gene. The extent of rejoining was determined by gel electrophoresis and the fidelity of rejoining determined by expression of the lacZ gene in E. coli DH5 alpha bacteria. Results suggest there is no difference between the 'parent', 'hybrid' and 'revertant' nuclear extracts in the fidelity and the total extent of rejoining, regardless of the type of break. However, there is an alteration in the distribution of rejoined products. Nuclear extracts from 'hybrid' cells tend to rejoin linear DNA into circular monomers with a greater efficiency than extracts from both 'parent' and 'revertant' cells. This alteration in distribution is observed when 3'- or 5'-protruding ends are rejoined but not in the rejoining of blunt ends. The results suggest that loci on chromosome 11 are involved in the rejoining of dsb, affecting the relative amount of the different rejoined products. Whether this alteration plays a role in the 'parent' cell's radiosensitivity is yet to be determined.

Cell Fusion↗
PubMed1997

Molecular analysis of oral lichen planus. A premalignant lesion?

Oral 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 reactive lesions, 40% 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 transformation through genetic pathways different from those of oral dysplasia.

Adolescent↗
PubMed1996

Micronucleus frequencies in urothelial cells of catheterized patients with chronic bladder inflammation.

Epidemiological studies suggest an association between chronic inflammation and increased risk for cancer, although the mechanism underlying this relationship is unresolved. In the present study, we test the hypothesis that DNA damage is induced in the epithelium of tissues during such inflammation by products of activated inflammatory cells. Individuals on long-term indwelling urinary catheterization were used as a study population. These individuals have chronic bladder inflammation and, as a population, an increased risk for bladder cancer. Urine of 29 patients and 26 age-matched non-catheterized controls was collected and micronucleus (MN) frequencies were determined in exfoliated urothelial cells in the urinary sediments. The urine from the catheterized group had large numbers of white blood cells (mean count, 26.6 +/- 3.6 cells per high-power field), indicating the presence of a chronic bladder infection and an inflammatory reaction. In contrast, white blood cells were not present in urine from individuals in the control group. There was no significant difference in MN frequencies in the 2 groups (mean frequencies, controls: 0.098 +/- 0.030%; catheterized: 0.140 +/- 0.025%, p = 0.13). These data imply that chromosomal damage does not always occur during chronic inflammation. Although the reasons for this observation are yet to be determined, possible explanations include the pathophysiology of the inflammatory reaction and the influence of vitamins, non-steroidal anti-inflammatory drugs and the catheter itself in protection against inflammatory cell-mediated DNA damage.

Adult↗
PubMed1996

Elevation of interferon beta-inducible proteins in ataxia telangiectasia cells.

The recently cloned ATM gene has been shown to bear considerable homology to phosphatidylinositol 3 kinases and, therefore, its product may function in signal transduction. In this study, we report constitutively elevated levels of two IFN-beta-inducible proteins, ubiquitin cross-reactive protein (UCRP), and low molecular weight protein (LMP2), in human fibroblasts with the inherited disease ataxia telangiectasia (AT). Using immunoblotting, it was found that a M(r) 15,000 band representing free UCRP was hardly detectable in normal cells, while it was the predominant band in AT cells. Similarly, the expression of a M(r) 23,000 protein, LMP2 was found to be higher in AT cells than in normal cells. Culturing three successive passages of the AT cell line in the presence of different concentrations of neutralizing antibodies against IFN-beta caused partial and complete reduction, respectively, of the free UCRP and LMP2 signals to normal levels. These results indicate that UCRP and LMP2 pools may be basally elevated in AT cells due to constitutive activation of the IFN-beta induction pathway and are in keeping with the recently reported constitutive activation of the NF-kappaB transcriptional activator in AT cells.

Antibodies↗
PubMed1995

Partial allelotype of carcinoma in situ of the human bladder.

Carcinoma in situ (CIS) of the urinary bladder is an aggressive lesion that frequently progresses to an invasive tumor, yet the underlying molecular changes in this lesion are largely unknown. In this study, we microdissected 31 cases of CIS and examined them for loss of heterozygosity (LOH) on 13 chromosomal arms. Twenty-nine microsatellite markers were chosen for this analysis based on their location in regions previously shown to be frequently lost in primary transitional cell carcinoma of the bladder. LOH of chromosome 9 was a frequent event in these samples, occurring in 77% of these lesions, with 19 of 31 cases showing deletion on the 9p arm (61%) and 17 of 28 cases displaying LOH on 9q (61%). Fine mapping at 9p21 demonstrated that CIS also displayed a high frequency of homozygous deletion surrounding the p16INK4A locus, like superficial papillary tumors, the other form of noninvasive lesion found in the bladder. However, loss of 14q (70%) was frequent in CIS yet extremely rare in papillary lesions (9%). Other chromosomal arms showing frequent LOH included 8p (65%), 17p (60%), 13q (56%), 11p (54%), and 4q (52%), whereas slightly lower frequencies of loss were observed for 11q (36%), 4p (32%), 3p (31%), 18q (29%), and 5q (20%). CIS lesions already possess many of the genetic alterations displayed by invasive transitional cell carcinomas, potentially accounting for the aggressive nature of these lesions.

Alleles↗
PubMed1995

High prevalence of expression of p53 oncoprotein in oral carcinomas from India associated with betel and tobacco chewing.

A recent study reported a low prevalence of p53 expression (11%) in oral squamous cell carcinomas (SCCs) from South Asia, in contrast to a high prevalence (averaging 52%) in other studies. It was proposed that the different aetiologies for oral SCCs in the South Asia population, i.e. betel and tobacco chewing in combination with smoking and alcohol consumption as compared to smoking and alcohol consumption alone in other populations, may account for the low prevalence of p53 expression. To confirm this hypothesis, we examined p53 expression immunohistochemically in 23 cases of oral SCC from patients in Southern India. Thirteen of the 23 SCCs (56.5%) demonstrated nuclear p53 staining. The expression of p53 was strongly correlated with the number of tobacco-containing quids chewed per day (r = 0.8). These data support the hypothesis that carcinogens derived from tobacco and betel chewing may induce p53 mutations, which in turn are involved in the development of oral cancer.

Adult↗
PubMed1994

Localized induction of micronuclei in the oral mucosa of xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) patients are predisposed not only to skin cancers but also to tumors on the tip of the tongue. Although this enhanced risk has been attributed to a defect in the repair of DNA damage induced by ultraviolet rays from sunlight there is a lack of data showing that DNA damage is occurring in vivo at these sites. In order to determine whether a relationship exists between exposure to ultraviolet light and the level of chromosomal breakage occurring in epithelial tissue in XP patients, the exfoliated cell micronucleus test was applied to different sites in the oral cavities of four XP patients: the right and left buccal mucosa, the dorsal tip of the tongue and the palate. Six Egyptian controls were sampled concurrently. Micronucleus (MN) frequencies were higher in XP patients than in controls for all sites except the palate, where technical difficulties were encountered. In addition, an unequal distribution of the frequency of micronucleated cells was found in the different sample sites of the oral cavity in the XP patients, with the greatest elevation in frequencies among cells collected from the dorsal tip of the tongue. In contrast, the frequency of micronucleated cells did not vary significantly in samples from different sites obtained from the controls. These data suggest that the complex interplay of host and environmental factors can affect MN frequencies when this endpoint is used to quantify in vivo genotoxic damage in a tissue.

Adult↗
PubMed1994

Inflammation, chromosomal instability, and cancer: the schistosomiasis model.

Evidence is accumulating in support of a role for reactive oxygen species in the etiology of cancer. Inflammatory cells, such as neutrophils, macrophages, and eosinophils, are an important endogenous source of oxygen radicals. Stimulation of these cells by tumor promoters or by foreign bodies (parasites, bacteria, etc.) causes the release of reactive oxygen species. Laboratory studies have shown that genetic damage and neoplastic transformation are induced in vitro in cells cocultured with activated inflammatory cells. We have recently begun to study the role of inflammatory reactions in inducing genetic damage in a human population. This paper describes our initial studies of Egyptian patients infected with Schistosoma haematobium. This infection induces chronic inflammation and irritation in the urinary bladder and is associated with increased cancer at this site. We describe a recently completed population study that shows that infected individuals have elevated levels of genetic damage in their bladders, as measured by the exfoliated cell micronucleus test. Treatment that kills the parasite also reduces the micronucleus frequencies. We also explore the hypothesis that altered sensitivity of clones of cells in these patients to reactive oxygen species could be a force that drives the development of neoplasia by facilitating clonal expansion. Evidence is presented for the possible involvement of loci on chromosome 11 in controlling the level of chromosomal breakage caused by oxidative damage. We have shown that bladder carcinoma cells are sensitive to micronucleus induction by promoter-activated neutrophils and that they can be protected from this damage by insertion of a normal chromosome 11. Further work is in progress to define the source of chromosomal breakage in schistosomiasis patients and to begin to develop an understanding of the host factors protecting bladder cells in these individuals from genetic damage.

Chromosome Aberrations↗