A comparison of morphine, pethidine and fentanyl in the postsurgical patient-controlled analgesia environment

Oncogene and tumor suppressor gene mutations are candidate biomarkers for cancer risk assessment and lesion detection. The K-ras oncogene has previously been associated with non-small cell lung cancer (NSCLC), particularly adenocarcinomas in which reported rates of mutation have approached 30-40%. We have analyzed non-malignant lung tissue from patients with lung cancer and primary lung cancers for K-ras gene mutations. Mutations were detected in 32% cancers and 29% non-malignant lung tissue from patients with cancer. The majority of tumors testing positive were adenocarcinoma of the lung. Normal DNA controls, including peripheral blood lymphocytes and normal lung from non-smokers, were negative. The ability to detect genetic alterations in non-malignant lung tissues is consistent with the concept that genetic alterations are involved in field cancerization of the aerodigestive tract.     

Fluorescent brighteners: novel stains for the flow cytometric analysis of microorganisms

Genetic damages are frequently found in both tumor and normal cells at carcinogen exposed areas in the patients with upper aerodigestive tract cancer. These phenomena are explained by the multistage process and/or field cancerization theories. The c-erbB-2 proto-oncogene has been amplified in many human tumors including breast, stomach, kidney and lung cancers. To study the possible evidence of multistage process and/or field cancerization in the development of gastric adenocarcinoma, the amplification statuses of c-erbB-2 proto-oncogene using the Southern hybridization technique were evaluated at the 45 gastric adenocarcinoma specimen sets consisting of tumor tissue, adjacent normal tissue (within 2 cm of the primary tumor), metastatic tissue and normal stomach tissue (at least 5 cm away from primary tumor). As a result, c-erbB-2 proto-oncogene at 2 specimen sets (4.4%) was amplified 2- to 4-fold to normal control status. In these 2 cases, c-erbB-2 proto-oncogene at histologically normal tissue adjacent to tumor tissue was amplified. And, the metastatic tissue of 1 case also exhibited c-erbB-2 proto-oncogene amplification of which the degree was less than that of tumor tissue. From these results, we were able to suspect that c-erbB-2 proto-oncogene amplification in the normal tissue adjacent to tumor tissue could be a biomarker of premalignant changes in a small proportion of gastric adenocarcinoma patients. And, this result might suggest the possible role of multistage process and/or field cancerization in the development of gastric adenocarcinoma.     

Potential early markers of carcinogenesis in the mucosa of the head and neck using exfoliative cytology

Patients with head and neck squamous cell carcinoma (HNSCC) who are thought to be cured are at high risk of development of a secondary primary tumour in the mucosa of the upper aerodigestive tract and the lungs. This phenomenon is in agreement with the concept of 'field cancerization', which implies that the whole mucosa is potentially condemned to the development of neoplasia. The hypothesis advanced in this study was that early markers of carcinogenesis should therefore be present in all cells of the mucosa of patients with HNSCC. The expression of cytokeratin 16, cytokeratin 19, and histo-blood group antigen H (ABH), type 2 chain was analysed by means of immunocytochemistry on exfoliated cells taken from six sites of the upper aerodigestive tract of the 'healthy' mucosa of previously untreated HNSCC patients (n = 25) and controls (n = 10). Statistically significant differences were found in the mucosal expression of these markers between patients and controls. Since no overlap in ABH type 2 chain expression existed between patients and controls and the expression between sites in a given individual was highly correlated, this marker was considered the most promising of those tested. These data suggest that cytokeratin 16, cytokeratin 19, and ABH type 2 chain are markers of field cancerization in easily available exfoliated cells, which may be applied to monitor and/or predict the occurrence of second primary tumours.     

Laboratory probing of oncogenes from human liquid and solid specimens as markers of exposure to toxicants

Recent discoveries regarding the mechanistic role of oncogenes and tumor suppressor genes in cancer development have opened a new era of molecular diagnosis. It has been observed repeatedly that genetic lesions serve as tumor markers in a broad variety of human cancers. The ras gene family, consisting of three related genes, H-ras, K-ras, and N-ras, acquires transforming activity through amplification or mutation in many tissues. If not all, then most types of human malignancies have been found to contain an altered ras gene. Because the ras oncogenes actively participate in both early and intermediate stages of cancer, several highly specific and sensitive approaches have been introduced to detect these genetic alterations as biomarkers of exposure to carcinogens. There is also mounting evidence that implicate chemical-specific alterations of the p53 tumor suppressor gene detected in most human tumors. Therefore, it seems a reliable laboratory approach to identify both altered p53 and ras genes as biomarkers of human chronic or intermittent exposure to toxicants in a variety of occupational settings.     

Clonal and chronological genetic analysis of multifocal cancers of the bladder and upper urinary tract

Recent molecular genetic studies have suggested that multifocal urothelial cancers are derived from an identical progenitor cell. However, the clonal origin of multifocal urothelial cancers of a low-grade superficial type has not been fully defined. Using microsatellite markers, we examined genetic alterations at 20 loci on eight chromosomal arms (2q, 4p, 4q, 8p, 9p, 9q, 11p, and 17p) in 87 metachronous and/or synchronous multifocal urothelial cancers, which included 84 low-grade superficial papillary tumors from 29 patients. Judging from the patterns of loss of heterozygosity, microsatellite shifts, and the subchromosomal partial deletion, multifocal tumors in at least 20 (80%) of the 25 evaluable patients were considered to be derived from a single progenitor cell, although the possibility remained that multifocal tumors in a small subset of patients might develop from distinct progenitor cells due to field cancerization. In 13 of the 20 patients, a chronological genetic analysis was available: genetic heterogeneity was detected in 3 (23%) patients, and an apparent accumulated pattern of genetic alterations was detected in only 1 (8%) patient. In the 20 patients with multifocal tumors of an identical clonal origin, discordant microsatellite alterations were observed, with significantly lower frequencies on chromosome 9 compared to those on the other chromosomes tested. The results indicate that most multifocal low-grade superficial urothelial cancers are genetically stable despite their incidence of frequent recurrence, and genetic divergence occurs in a subset of patients. This heterotopic spread and genetic divergence may occur long before the clinical manifestation of multiplicity from a single transformed cell. These data support the previous view that heterotopic spread of transformed progenitor cells and genetic divergence occur after chromosome 9 alterations in most of low-grade superficial urothelial cancers.     

Clonal heterogeneity in human esophageal squamous cell carcinomas on DNA analysis

Cancers are thought to arise through multistep accumulation of somatic mutations in the progeny of a single cell. Multiple mutations may induce molecular intratumor heterogeneity. Therefore, we examined molecular clonal heterogeneity in esophageal squamous cell carcinomas. Twenty-four esophageal squamous cell carcinomas and associated lymph node metastases were examined for microsatellite alterations, and abnormalities of the p53 and transforming growth factor-beta type II receptor (TGF-beta RII) genes. There were eight cases (33%) showing different patterns of loss of heterozygosity in primary tumors and metastatic lymph nodes with microsatellite markers. On the other hand, the abnormalities of p53 were identical in all these cases. No mutation was detected in the simple repeated sequences of the TGF-beta RII gene. These results indicate that molecular clonal heterogeneity exists in esophageal squamous cell carcinomas. Therefore, care is necessary in preoperative genetic diagnosis using biopsy samples.     

Multistep carcinogenesis of breast cancer and tumour heterogeneity

Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.     

Allelic loss at chromosomes 3p, 8p, 13q, and 17p associated with poor prognosis in head and neck cancer

BACKGROUND: Little is known about the molecular genetic events that contribute to the pathogenesis of squamous cell carcinoma of the upper aerodigestive tract. Previous molecular genetic studies have been limited to the identification of mutations of the p53 (also known as TP53) tumor suppressor gene, activation of a limited set of oncogenes, allelic loss at 3p and other locations, and occasional association with human papillomavirus infection. PURPOSE: Our purpose was to screen tumor tissue and blood from patients with squamous cell carcinoma of the upper aerodigestive tract for loss of heterozygosity at polymorphic loci corresponding to each of the autosomal chromosomes and to identify the locations of additional putative tumor suppressor genes, other than RB (also known as RB1) and p53, that may contribute to the pathogenesis of this disease. METHODS: Tumor tissue and blood were obtained from 68 consecutive patients with squamous cell carcinoma of the upper aerodigestive tract. In all cases, tumor tissue was obtained from the center of the surgical specimen. The relative absence of non-neoplastic tissue was confirmed by frozen-section histologic examination of immediately adjacent tissue. Initially, 30 paired tissue and blood samples were tested for loss of heterozygosity by polymerase chain reaction (PCR) to amplify 43 different highly polymorphic sequences containing small oligonucleotide repeats. After PCR amplification, with unique oligonucleotides flanking the repeat, visualization and sizing of the alleles on DNA sequencing gels were performed. Specific loss of heterozygosity was distinguished from random genetic loss due to generalized chromosomal instability if it occurred in more than 20% of specimens tested for a particular marker. RESULTS: Significant loss of heterozygosity (> 20%) occurred at alleles at chromosome bands 3p21 (32%), 3p25-26 (56%), 8pter-21.1 (31%), 13q14 (27%), and 17p12 (45%). Loss of heterozygosity at more than two loci was significant with a poor prognosis (P = .039). CONCLUSIONS: These findings demonstrate that squamous cell carcinoma of the upper aerodigestive tract exhibits genetic alterations at multiple loci and that allelic loss at more than two locations is indicative of a poor prognosis (the likelihood of the patient dying of disease). IMPLICATIONS: While tumor suppressor genes at 3p (VHL), 13q (RB), and 17p (p53) have been identified, altered genes at other loci on 3p and on 8p have not yet been characterized. Furthermore, the genotype at these loci for squamous cell carcinoma of the upper aerodigestive tract has prognostic importance and may identify the patients who should receive the most aggressive treatment.     

Histopathologic and molecular alterations in bronchial epithelium in habitual smokers of marijuana, cocaine, and/or tobacco

BACKGROUND: Tobacco smoking has been observed to cause molecular alterations in bronchial epithelium that antedate the development of lung carcinoma. The rising prevalence of marijuana and cocaine use among young adults in the United States prompted us to investigate whether similar molecular and histopathologic alterations occur in habitual smokers of marijuana and/or cocaine who may or may not also smoke tobacco. METHODS: Bronchoscopy was performed in 104 healthy volunteer subjects, including 28 nonsmokers and 76 smokers of one or more of the following substances: marijuana, tobacco, and/or cocaine. Bronchial mucosa biopsy specimens and brushings were analyzed for histopathologic changes, for immunohistopathologic expression of intermediate or surrogate end-point markers that are linked to an increased risk of cancer (Ki-67 [a marker of cell proliferation], epidermal growth factor receptor, p53, Her-2/neu [also known as erbB-2 and ERBB2], globular actin, and abnormal DNA ploidy). Reported P values are two-sided. RESULTS: Smokers of any one substance or of two or more substances exhibited more alterations than nonsmokers in five to nine of the 10 histopathologic parameters investigated (all P < .05), and they exhibited more molecular abnormalities than nonsmokers. Differences between smokers and nonsmokers were statistically significant (all P < or = .01) for Ki-67, epidermal growth factor receptor, globular actin, and DNA ploidy. There was general agreement between the presence of molecular abnormalities and histopathologic alterations; however, when disagreement occurred, the molecular abnormalities (e.g., Ki-67 and epidermal growth factor receptor) were more frequently altered (all P < or = .01). CONCLUSIONS: These findings suggest that smoking marijuana and/or cocaine, like tobacco smoking, exerts field cancerization effects on bronchial epithelium, which may place smokers of these substances at increased risk for the subsequent development of lung cancer.     

Detection of loss of heterozygosityat microsatellite loci in esophageal squamous-cell carcinoma

Microsatellite alterations at 3 genetic loci (chromosomes 2p, 3p and 17p) were analyzed in 25 tumors (20 primary tumors and 5 metastatic lymph nodes) from 20 patients after surgical treatment for esophageal cancer. DNA samples from tumors were compared with control DNA from lymphocytes obtained from the peripheral blood of the individual patients. Microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] were detected in 15% of 20 primary tumors with marker D2S123 (chromosome 2p), 55% with marker D3S1067 (chromosome 3p) and 50% with marker TP53 (chromosome 17p). The 3-year disease-free survival rate of the 10 patients who had tumors without alterations or with an alteration at only 1 of 3 microsatellite loci was 75% and it was better than that of the 10 patients who had tumors with alterations at 2 or 3 microsatellite loci (48%, p = 0.049). This finding suggests that esophageal cancer with alterations at multiple microsatellite loci might have strong malignant potential. However, MSI was only detected in one of 20 patients, which suggests that MSI might not play an important role in the development of this cancer. Three of 5 metastatic lymph nodes showed no LOH even though primary tumors of these patients exhibited LOH with 1 or 2 markers, and 1 metastatic lymph node had LOH that was detected with D3S1067 even though the primary tumor of this patient had no LOH with all markers. Thus, clonal heterogeneity might exist in esophageal squamous-cell carcinomas.     

3 different malignancies of the aerodigestive tract after chronic abuse of cannabis products

The occurrence of multilocular malignant tumors in the upper aerodigestive tract in young patients with known marijuana abuse has been described by other authors. A case of a 28-year-old man who was known to abuse alcohol, nicotine and cannabis for some years is presented. He suffered simultaneously from a squamous cell carcinoma of the hypopharynx with bilateral cervical metastases, an adenocarcinoma of the transverse colon and a primary hepatocellular carcinoma. This case is the first reported that shows the occurrence of three separate malignant tumors with different histologies in the aerodigestive tract which could be related to a chronic abuse of cannabis.     

Field cancerization: why late "recurrent" ovarian cancer is not recurrent

OBJECTIVE: Late "recurrence" of ovarian cancer may result from either regrowth of dormant tumor cells or from development of a new cancer caused by the phenomenon of field cancerization. Clinically, some recurrent ovarian cancers show the same therapeutic sensitivities to chemotherapy and surgery as did the primary disease, whereas others are refractory to all therapy. We hypothesize that recurrent ovarian cancers are distinguishable on the basis of a molecular genetic fingerprint and that some are actually new primary cancers of the peritoneum rather than recurrent ovarian cancer. STUDY DESIGN: We constructed molecular genetic fingerprints of 13 paired primary and late recurrent ovarian cancers to study their clonal relationships. The tumor pairs were analyzed for p53 mutations and allelotypes, patterns of X-chromosome inactivation, loss of heterozygosity, and microsatellite instability at 12 different loci on 6 different chromosomes. Techniques used included single-strand conformational polymorphism mutation screening and polymerase chain reaction-based sequence analysis of the p53 locus, restriction digestion of the androgen receptor locus to determine X-chromosome inactivation, and polyacrylamide gel electrophoresis of highly polymorphic dinucleotide, trinucleotide, and tetranucleotide repeats. RESULTS: The average age at initial diagnosis for this cohort was 54.7 years (range 45.3 to 65.5). Mean interval to recurrence was 42.7 months (range 28 to 62). Molecular fingerprints were characterized for 4 to 8 informative loci per tumor pair. The fingerprints of 10 (77%) differed significantly, strongly suggesting that a second primary cancer had developed. The remaining 3 tumor pairs demonstrated identical allelotypes consistent with regrowth of dormant tumor cells. CONCLUSION: Our results are consistent with the "field cancerization" hypothesis of ovarian carcinogenesis but could also be explained by a polyclonal tumor origin, which contrasts with the currently accepted monoclonal theory of ovarian carcinogenesis. Late development of a new primary cancer may herald the proband as a member of a familial cancer phenotype. These studies provide a molecular genetic rationale that both explains and prognosticates the clinical course of recurrent ovarian cancer.     

Retinoid chemoprevention of aerodigestive cancer: from basic research to the clinic

Epithelial cancers in the lung and head and neck are a devastating group of diseases which account for approximately 35% of cancer deaths in the United States. Chemoprevention is a new strategy to block or reverse the carcinogenic process. Biological concepts including field carcinogenesis and multistep carcinogenesis strongly support the rationale for using chemopreventive approaches. Our group has focused on applications of translational retinoid studies to increase our knowledge of the molecular events in biology and chemoprevention. In this review, we will focus on four issues, biology, retinoids, retinoid clinical trials, and translational research, in the chemoprevention of aerodigestive cancers.     

The clinical role of molecular genetics in soft tissue tumor pathology

Cytogenetic and molecular analysis of soft tissue tumors has yielded a wealth of information over the past decade. Some of the genetic aberrations that have been identified appear to be fairly specific for individual tumor types. It is because of this specificity that these findings harbor the promise to become useful as diagnostic and/or prognostic markers. Technical advances that allow the application of cytogenetic and molecular techniques to archival material have been crucial in this respect. Molecular genetics has already become an integral part of the work-up of some tumors, e.g., small cell sarcomas of childhood, which demonstrate fairly characteristic translocations, often involving the Ewing's sarcoma gene. Some genetic abnormalities have become established as prognostic markers, such as the deletion of the short arm of chromosome 1 for neuroblastomas. Soft tissue tumor pathology has also benefitted from major advances in identifying genes that are critical in mesenchymal differentiation or cell cycle control. MyoD is a good example of a such a gene, that has become useful as a diagnostic tool in rhabdomyosarcomas. Beyond potential practical applications of cytogenetic and molecular analyses in the diagnosis of these tumors, we also review their impact on several philosophical concepts concerning soft tissue neoplasia.     

Allelotype analysis of mouse skin tumors using polymorphic microsatellites: sequential genetic alterations on chromosomes 6, 7, and 11

Allelotype analysis of human tumors has been instrumental in the effort to discover and clone novel tumor suppressor genes. However, this approach has not been systematically applied to animal models of carcinogenesis. We describe here the first attempt to allelotype a nonhuman tumor, i.e., chemically induced mouse skin tumors, using a panel of polymorphic microsatellite markers. The results indicated that markers on chromosomes 6 and 7 were imbalanced, consistent with trisomy in both benign and malignant skin tumors. A proportion of carcinomas also showed loss of heterozygosity on chromosome 11, where the p53 gene is located, and more rarely, on chromosomes 4, 6, and 15. The significance of these alterations is highlighted by the observations of no allelic imbalance for markers on 12 other chromosomes.     

Uncertainty analysis methods for comparing predictive models and biomarkers: A case study of dietary methyl mercury exposure

Biologically based markers (biomarkers) are currently used to provide information on exposure, health effects, and individual susceptibility to chemical and radiological wastes. However, the development and validation of biomarkers are expensive and time consuming. To determine whether biomarker development and use offer potential improvements to risk models based on predictive relationships or assumed values, we explore the use of uncertainty analysis applied to exposure models for dietary methyl mercury intake. We compare exposure estimates based on self-reported fish intake and measured fish mercury concentrations with biomarker-based exposure estimates (i.e., hair or blood mercury concentrations) using a published data set covering 1 month of exposure. Such a comparison of exposure model predictions allowed estimation of bias and random error associated with each exposure model. From these analyses, both bias and random error were found to be important components of uncertainty regarding biomarker-based exposure estimates, while the diary-based exposure estimate was susceptible to bias. Application of the proposed methods to a simple case study demonstrates their utility in estimating the contribution of population variability and measurement error in specific applications of biomarkers to environmental exposure and risk assessment. Such analyses can guide risk analysts and managers in the appropriate validation, use, and interpretation of exposure biomarker information.     

Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.     

Reaction of alpha-tocopherol with alkyl and alkylperoxyl radicals of methyl linoleate

The common cytogenetic finding characteristic of human malignant testicular germ-cell tumors is the presence of an isochromosome of the short arm of chromosome 12, i(12p), suggesting alterations in the proto-oncogenes (e.g., c-Ki-ras2) or putative tumor suppressor genes (TSG) that are localized here. However, to date there is no proof for such alterations. Conversely, alterations in expression of the retinoblastoma gene, a classical TSG, have been reported for the majority of testicular tumors. Other molecular genetic alterations have been described, affecting genes that are involved in the normal regulation of spermiogenesis, such as the c-kit gene product and its ligand SCF, as well as hst1, which is normally expressed in embryonal tissues only. The well-documented sensitivity of testicular tumors to chemotherapeutic agents may be caused by decreased activity of the glutathione S-transferase detoxification enzymes, as well as alterations of the expression of this gene family.     

Solvent polarity and pH effects on the spectroscopic properties of neutral red: application to lysosomal microenvironment probing in living cells

To investigate the molecular mechanism of gastric carcinogenesis, we analyzed genetic instability and p53 gene mutations in 40 primary gastric carcinomas. Tumor samples were from untreated patients with no family history suggestive of genetic predisposition to cancer. We screened six microsatellite loci by the polymerase chain reaction (PCR) method, and exons 5-8 of the p53 gene by the PCR-based denaturing gradient gel electrophoresis and sequencing techniques. Microsatellite instability was detected in 32.5% (13/40), and gene mutations in 40% (16/40), of the tumors analyzed. No statistically significant associations were found between genetic alterations and clinico-pathological variables (with the exception of diffusion of lymph node metastases, which was inversely associated with the presence of microsatellite alterations; P < 0.01). Interestingly, a negative association was found between genetic instability and p53 gene mutations: 11 out of 13 tumors showing instability proved to carry a nonmutated p53 gene versus 2/13 carrying a mutated gene (P = 0.03). These observations suggest that genetic instability and p53 gene mutations play a crucial role in the gastric carcinogenic process, but likely act through distinct pathways during cancer development. However, genetic instability is not in and of itself neoplastic. Therefore, we investigated whether insertion/deletion mutations of the polyadenine tract within the transforming growth factor-beta type II receptor gene (TGF-beta RII) were frequently present in gastric tumors with an RER+ (replication error) phenotype. We found RII mutations in 8/40 (20%) samples: mutations were present in 7/13 (54%) RER+ tumors versus 1/27 (4%) RER- cases (P < 0.001).     

Absence of Fhit protein in primary lung tumors and cell lines with FHIT gene abnormalities

Genomic alterations and abnormal expression of the FHIT gene at 3p14.2 have been observed in cell lines and primary tumors of the lung. To correlate FHIT locus DNA and RNA lesions with effects on Fhit protein expression, we have analyzed 11 lung cancer cell lines, 15 small cell lung carcinomas, and 38 pairs of non-small cell primary tumors and bronchial mucosa specimens by molecular genetic and immunocytochemical methods. Using specific antibodies against the Fhit protein, we observed concordance between RNA abnormalities and lack of Fhit protein expression in lung tumors and cell lines. In addition, absence of Fhit protein in some precancerous dysplastic lesions suggested that FHIT inactivation may occur at an early phase of lung carcinogenesis.