Biomedical subjects

W F Benedict

Publications and source records attributed to W F Benedict.

At least 19 recordsLinked to original sources

PubMed1995

Genetic disparity between morphologically benign cysts contiguous to ovarian carcinomas and solitary cystadenomas.

BACKGROUND: Ovarian carcinomas occasionally contain large, histologically benign cysts contiguous to the clearly malignant areas (cystadenocarcinomas). The question of whether such cysts are remnants of pre-existing benign tumors (cystadenomas) or constitute integral components of the carcinomas is important in clarifying the role of cystadenomas in ovarian carcinogenesis. It is also important for our general understanding of tumor heterogeneity, a phenomenon thought to result from the gradual accumulation of genetic abnormalities in initially homogeneous tumors. This question is also pertinent to the clinical management of ovarian cystadenomas, which are frequent in women of childbearing age and are usually treated surgically based on the possibility that they may give rise to carcinomas. PURPOSE: Reasoning that molecular markers of ovarian malignancy would be confined to the histologically malignant portions of cystadenocarcinomas if the morphologically benign portions are in fact pre-existing typical cystadenomas, we sought to verify that mutations in the p53 tumor suppressor gene are markers of malignancy in ovarian tumors and to determine the distribution of such mutations in cystadenocarcinomas. METHODS: We used immunohistochemical and DNA-sequencing techniques to analyze 46 ovarian carcinomas, 21 ovarian tumors of low malignant potential, and 16 solitary cystadenomas for the presence of p53 mutations. We then used similar techniques to examine the distribution of such mutations in different portions of cystadenocarcinomas. The observed differences in mutation frequencies were analyzed by the two-tailed Fisher's exact test. RESULTS: Mutations in the p53 gene were present in 24 (52%) of the 46 carcinomas, but they were absent in the 21 tumors of low malignant potential (P < .0001) and the 16 solitary cystadenomas (P = .0002). Six of six cystadenocarcinomas with p53 mutations showed the presence of the same mutations in the adjacent, histologically benign cysts. The mutations were seen not only in cells immediately adjacent to the carcinomas, but also throughout the morphologically benign cysts. Twenty (83%) of the 24 cases showing mutation of one p53 allele also showed loss of genetic heterozygosity, suggesting that the other p53 allele was deleted. Such allelic loss, if present in morphologically malignant portions of cystadenocarcinomas, was also observed in the contiguous cysts. CONCLUSIONS: Ovarian carcinomas can be distinguished from ovarian cystadenomas and tumors of low malignant potential by p53 mutations. The fact that the mutations were present in histologically benign cysts contiguous to ovarian carcinomas suggests that such cysts are not typical cystadenomas and may carry a genetic predisposition to carcinogenesis that is not present in ordinary cystadenomas.

Carcinoma↗

PubMed1995

Frequent loss of heterozygosity at the retinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors: evidence for a chromosome 13 tumor suppressor gene other than RB.

Mice bearing retinoblastoma susceptibility gene (RB) germ-line mutations almost invariably develop pituitary neoplasms. We therefore tested 17 patients with pituitary tumors for loss of heterozygosity (LOH) using an RB sequence polymorphism and 5 polymorphic microsatellite markers surrounding the RB gene on the long arm of chromosome 13. In all of the 13 malignant or highly invasive pituitary tumor cases, and in 4 of their respective metastases, a RB allele was lost. In contrast, no LOH at the RB locus was detected in 4 benign pituitary adenoma cases. Three invasive tumors also lost a portion of 13q, which included D13s137, D13s133, and D13s118 telomeric and centromeric to RB, respectively. Immunohistochemical analysis, however, revealed the presence of RB protein in tumors with LOH and the RB locus. Therefore, although inactivation of RB may play a role in the development of invasive pituitary adenomas and carcinomas in mice, another tumor suppressor gene on 13q is likely involved in human pituitary tumor progression. LOH of 13q markers may also be of predictive value in determining the biological behavior of pituitary macroadenomas and their progression to invasiveness and frank malignancy.

Alleles↗

PubMed1995

Retinoblastoma-like phenotype expressed in medulloblastomas.

The previous demonstration of rod-opsin and S-antigen (S-Ag), a protein which arrests visual phototransduction, in retinoblastomas and in a subgroup of medulloblastomas has suggested a relationship between these tumors. We examined 17 medulloblastomas for the presence of a retinoblastoma-like phenotype. Overall 41% of the tumors were immunoreactive for S-Ag. Two tumors with well-differentiated Flexner-Wintersteiner rosettes were also immunoreactive for S-Ag, but not for epithelial membrane antigen (EMA). In contrast, most ependymal rosettes in two ependymomas stained positive for EMA along the luminal surface, consistent with a previous study, and were negative for S-Ag. Because calcification in areas of necrosis is a near constant finding in retinoblastomas, the medulloblastomas were evaluated for the presence of calcification, using Von Kossa staining. Forty-one percent showed calcification in areas of necrosis and 29% were positive for both calcification and S-Ag immunoreactivity. There was a statistically significant concordance between calcification and S-Ag immunoreactivity in the medulloblastomas (p < 0.05). Despite similar phenotypic features, a shared mechanism of tumori-genesis for retinoblastomas and the subgroup of medulloblastomas with photoreceptor differentiation could not be identified since all 17 medulloblastomas were found to express functional Rb protein, as indicated by positive nuclear immunoreactivity.

Adolescent↗

PubMed1995

The loss of retinoblastoma gene in association with c-myc and transforming growth factor-beta 1 gene expression in human bladder cancer.

PURPOSE: We investigate the roles and possible interactions of the retinoblastoma, transforming growth factor-beta 1 and c-myc genes in bladder cancer. MATERIALS AND METHODS: The expression of these 3 genes was examined in 38 biopsy specimens of human bladder cancer by immunohistochemical analysis or Northern blotting. RESULTS: Loss of the retinoblastoma protein expression was most significantly correlated with high grade cancer. Over expression of c-myc or expression of transforming growth factor-beta 1 was less associated with tumor grade or stage, although c-myc over expression defined stage Ta against other stage tumors, since no stage Ta lesions had increased c-myc expression. Finally, loss of retinoblastoma gene function did not correlate with either c-myc or transforming growth factor-beta 1 expression. CONCLUSIONS: These results further support that retinoblastoma gene inactivation is an important factor in the progression of bladder cancer, and suggest that transforming growth factor-beta 1 and c-myc are not regulators or are not regulated by retinoblastoma gene expression.

Gene Expression Regulation, Neoplastic↗

PubMed1995

Growth-factor stimulation reveals two mechanisms of retinoblastoma gene inactivation in human myelogenous leukemia cells.

Mutation or deletion of the retinoblastoma tumor suppressor gene (Rb) or abnormal Rb protein expression is found in many types of human solid tumors. Low or absent levels of Rb protein are usually found in the leukemic cells of patients with acute myelogenous leukemia (AML) who have an extremely poor prognosis. The absence of Rb protein in these AML cells could result from defects in the Rb gene or from abnormal cell cycle regulation that affects Rb expression. To test these possibilities and to examine whether a low level of Rb protein in AML cells could be up-regulated, we studied the effect that growth factors interleukin 3 (IL3) and granulocyte-macrophage colony stimulating factor (GM-CSF) had on the levels of Rb protein and Rb phosphorylation in AML cells from patients with low Rb or no Rb protein expression. We observed three responses to growth factor-stimulation in leukemic cells taken from patients with AML: (1) some AML cell samples entered a proliferative phase, and Rb protein levels increased with the appearance of normally phosphorylated forms of Rb protein and positive nuclear staining for Rb protein; (2) some AML cell samples became more proliferative, but the levels of Rb protein remained low or absent; and (3) some AML cell samples showed no response. These results indicate that at least two different mechanisms may be responsible for the lack of Rb protein in the leukemic cells of some patients with AML.

Gene Expression Regulation, Leukemic↗

PubMed1994

Enhanced tumor cell growth suppression by an N-terminal truncated retinoblastoma protein.

The retinoblastoma (RB) gene encodes a nuclear phosphoprotein of 928 amino acids (pRB). Thus far, much effort in RB research has been focused on both the viral oncoprotein-binding domains and the C-terminal domain, whereas little is known about the N-terminal moiety of the protein. We report here that an N-terminal truncated RB protein of approximately 94 kDa (pRB94) exerts more potent cell growth suppression as compared to the full-length pRB protein in a diversity of tumor cell lines examined, including those having a normal endogenous RB gene. Tumor cells transfected with the pRB94-expressing plasmids displayed multiple morphological changes frequently associated with cellular senescence and/or apoptosis. They failed to enter S phase and rapidly died. The pRB94 expressed in recipient tumor cells had a longer half-life than the full-length pRB protein and tended to remain in an active un- or hypophosphorylated form. Since it has also been found that N-terminal truncated RB proteins often accumulated in growth-arrested and/or differentiated tumor cells, we suggest that N-terminal truncation of pRB may be one of the cellular mechanisms modulating the RB protein function in cell-cycle control.

Animals↗

PubMed1994

Infrequent inactivation of the retinoblastoma gene despite frequent loss of chromosome 13q in head and neck squamous cell carcinoma.

Our recent allelic analysis of head and neck squamous cell carcinomas identified a high incidence of chromosomal loss on 13q. To further define an area of minimal loss, we tested 60 primary head and neck squamous cell carcinomas in 59 patients for loss of heterozygosity (LOH) by using 10 polymorphic microsatellite markers spanning the long arm of chromosome 13. We examined the same primary tumors for inactivation of the retinoblastoma (Rb) gene by immunohistochemical analysis of paraffin-embedded specimens. Thirty-one of 60 (52%) tumors demonstrated LOH in at least one 13q marker. Twenty-nine of 31 (94%) lost a portion of 13q that included D13s133, which lies just telomeric to the Rb gene at 13q14.3. However, immunohistochemical staining revealed absence of Rb protein in only 6 of these 31 tumors (19.4%) with LOH. All but one tumor without LOH on 13q displayed normal Rb protein staining. Although Rb may be inactivated by an unusual mechanism in some head and neck squamous cell carcinomas, our data suggest that another tumor suppressor gene locus at 13q14 is likely to be involved in head and neck tumor progression.

Adult↗

PubMed1994

Deletions of chromosome 13q, mutations in Retinoblastoma 1, and retinoblastoma protein state in human hepatocellular carcinoma.

Twenty-one tumors from 18 patients (two independent tumors were obtained from each of three patients) with hepatocellular carcinomas were examined for loss of heterozygosity (LOH) at loci on chromosome 13q, using 15 polymorphic nucleotide sequences of microsatellites as genetic markers. The results revealed LOH in a common region between the centromeric D13S127 locus (13q12.2-q14.1) and the telomeric D13S137 (13q14.3) locus, including the RB1 locus, in nine of 21 tumors. Immunohistochemical staining of paraffin-embedded tumor sections indicated loss of retinoblastoma (RB) protein expression in all tumors showing LOH except one. Absence of RB protein expression was also observed in three of 12 tumors without LOH. Single-strand conformation polymorphism analysis of polymerase chain reaction products using primers flanking all 27 exons of the RB1 gene, as well as nucleotide sequencing, revealed tumor-specific small deletions of the RB1 coding region in the remaining RB1 allele of two tumors having LOH at the RB1 locus with concomitant loss of RB protein expression. Our results indicate that the loss of a region of chromosome 13q including the RB1 locus significantly (P < 0.006) correlates with loss of RB protein in hepatocellular carcinomas. However, tumor-specific mutations of the RB1 gene were detected in only two of 13 tumors with LOH and/or lack of RB protein expression, indicating that analysis of the RB1 status at the protein level in these tumors may be more sensitive than the actual mutational analysis.

Base Sequence↗

PubMed1994

Aberrant RB gene expression in routinely processed, archival tumor tissues determined by three different anti-RB antibodies.

The retinoblastoma (RB) susceptibility gene encodes a nuclear phosphoprotein which is likely involved in cell cycle control and cell differentiation. The RB protein is mutated or absent in a variety of human malignancies. Its role as a molecular marker for clinical tumor behavior is under extensive investigation. However, studies on the status of the RB protein in primary or metastatic tumors and their precursor lesions have been slowed by the lack of availability of a sensitive, reliable assay which allows examination of RB expression in selected cell populations within archival tissues. Thus far, meaningful immunohistochemical analysis of RB protein in formalin-fixed, paraffin-embedded specimens has been achieved only with the polyclonal antibody RB-WL-I. We now describe a method which produced excellent staining results in formalin-fixed, routinely processed tissues, using commercially available monoclonal antibodies (MAbs) in conjunction with an antigen-retrieval step. The resulting stains were superior to those on frozen sections and comparable to those obtained with RB-WL-I. Twelve of 51 random invasive bladder cancers (24%) had abnormal expression of the RB gene, as determined by immunohistochemistry. Smaller cohorts of breast, prostate and lung carcinomas had incidences of aberrant RB gene expression ranging from 9% to 24%. Since the staining method was widely applicable to essentially all formalin-fixed, archival tissues, it may expedite studies on the biological and clinical significance of altered RB expression in human neoplasia.

Antibodies, Monoclonal↗

PubMed1994

Levels of retinoblastoma protein expression in newly diagnosed acute myelogenous leukemia.

The relationship between the level of retinoblastoma protein (RB) expression and the survival of 113 newly diagnosed acute myelogenous leukemia (AML) patients was studied. Western blotting was used to determine the level of RB protein present in peripheral blood leukemia cells and results were confirmed in 26 patients by immunohistochemistry. The leukemic cells from 22/113 AML patients (19%) contained RB protein at levels that were equal to or less than the level of RB observed in the mononuclear cell fraction of peripheral blood from normal individuals (Low RB). Levels of RB greater than that of normal blood (Elevated RB) were seen in 91 patients (81%). The median survival of patients with low RB was significantly shorter than that seen in patients with elevated RB, 12 weeks versus 40 weeks (P = .02). Remission induction frequency was 36% in low RB patients compared with 68% in AML patients with elevated RB (P = .01). Multivariate analysis showed that low RB protein level was an independent prognostic factor predictive or poor survival after allowing for other known prognostic factors. These data suggest that a low level of the RB protein at the time of diagnosis is associated with shortened survival in AML patients because of inferior response to conventional therapy. Monitoring of the RB level could identify a subgroup of AML patients with an extremely poor prognosis when treated with chemotherapy alone, who would be eligible for alternative therapeutic strategies.

Adolescent↗

PubMed1994

Further characterization of retinoblastoma gene-mediated cell growth and tumor suppression in human cancer cells.

We have transfected the osteosarcoma cell line Saos2 and the bladder carcinoma cell line 5637 with additional retinoblastoma (RB) expression plasmids. The RB-reconstituted Saos2 and 5637 cells showed only slightly lower ratios of cells undergoing DNA synthesis compared to their parental RB- tumor cells, and there were no noticeable changes in cell morphology. Furthermore, we have isolated long-term RB+ clones from Saos2, 5637, and the retinoblastoma cell line WERI-Rb27 after transfection/transduction with a RB expression plasmid or retrovirus. These clones were similar to their parental cell lines in terms of morphology and growth rates, and they all expressed functional RB protein (p110RB) as evidenced by its potential of phosphorylation, simian virus 40 large tumor antigen binding, and nuclear tethering. No mutation or deletion of the exogenous RB gene was detectable by PCR and single-strand conformation polymorphism analysis. In addition, either the individual or pooled RB+ clones did form malignant tumors in nude mice but usually with a longer latency period and lower frequency. Such tumors also retained normal RB expression, suggesting that at least a portion of the RB-reconstituted tumor cells were still tumorigenic. This phenomenon is referred to by us as tumor suppressor resistance (TSR).

Animals↗

PubMed1994

Altered retinoblastoma protein expression and prognosis in early-stage non-small-cell lung carcinoma.

BACKGROUND: Altered retinoblastoma (RB [also known as RB1]) gene expression was initially found in a small cohort study to occur in five (22%) of 23 patients with primary stage I and II non-small-cell lung carcinomas (NSCLCs). Putative mutation of the p53 gene (also known as TP53) has also been found to occur frequently in stage I and II NSCLCs and to be associated with more aggressive disease and a poorer prognosis. PURPOSE: Our purpose was to determine the Rb protein status in the same cohort that had been previously studied for their p53 protein status and to document whether loss of Rb protein expression was also an important factor in overall survival. METHODS: One hundred one stage I or II NSCLC specimens were analyzed by immunohistochemical staining. These paraffin-embedded tumor sections were obtained from individual paraffin blocks prepared for each patient in the previous study. Patient survival status was obtained from hospital and tumor registry records. RESULTS: Altered Rb protein expression was found in 24 of 101 stage I and II NSCLCs. The median survival was 32 months for patients with Rb-positive (Rb+) tumors and 18 months for individuals in whom expression of Rb protein was absent or altered (Rb-) in tumor cells. Log-rank analysis of the differences in overall survival was statistically significant (P = .007). When these results were combined with the p53 status in the same tumor, the median survival was 12 months for those individuals who had theoretically the worst pattern (Rb-/p53+) and 46 months for those patients with theoretically the best pattern (Rb+/p53-) (P < .001). The Rb+ and Rb- groups in this cohort were well balanced with respect to the distribution of age, disease stage, histologic types, p53 status, and sex. Using a multivariate proportional hazards regression model, both altered Rb and p53 status were found to be significantly associated with poor prognosis (P = .005 and .012, respectively) in the overall cohort. CONCLUSION: Altered Rb protein expression is an independent prognostic marker for overall decreased survival in early-stage NSCLC as detected by absence of nuclear Rb protein staining. There appears to be a poorer prognosis when loss of Rb protein function and mutated p53 protein occur in the same tumor. IMPLICATIONS: If these findings can be confirmed in larger prospective studies, the results would suggest that both the Rb and p53 status should be utilized as independent prognostic factors in early-stage NSCLC.

Adenocarcinoma↗

PubMed1994

Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma.

BACKGROUND: The origin and molecular pathogenesis of parathyroid carcinoma are unknown. This life-threatening cause of primary hyperparathyroidism cannot be reliably distinguished from its benign counterpart on the basis of histopathological features alone. Because the PRAD1, or cyclin D1, gene, a cell-cycle regulator, has been implicated in a subgroup of benign parathyroid tumors, we examined the possibility that another cell-cycle regulator with possible functional links to PRAD1, the retinoblastoma tumor-suppressor gene (RB), might be involved in the molecular pathogenesis of parathyroid carcinoma. METHODS: Parathyroid carcinomas from 9 patients and adenomas from 21 were studied for evidence of tumor-specific loss of RB gene DNA (allelic loss) by analysis of four DNA polymorphisms and for evidence of altered expression oF RB protein by immunohistochemical staining. RESULTS: All of 11 specimens from 5 patients with parathyroid carcinoma and informative DNA patterns and 1 of 19 specimens from 19 patients with parathyroid adenoma and informative DNA patterns lacked an RB allele. Fourteen of 16 specimens (88 percent) from the nine patients with carcinoma had abnormal expression of RB protein (a complete or predominant absence of nuclear staining for the protein). None of the 19 adenomas, including the tumor with loss of an RB allele, had unequivocally abnormal staining for RB protein. CONCLUSIONS: Inactivation of the RB gene is common in parathyroid carcinoma and is likely to be an important contributor to its molecular pathogenesis. The presence of such inactivation may help to distinguish benign from malignant parathyroid disease and may have useful diagnostic, prognostic, and therapeutic implications.

Adenoma↗

PubMed1994

The retinoblastoma gene is involved in malignant progression of astrocytomas.

Loss of chromosome 13q occurs in up to 50% of human astrocytomas, suggesting the presence of an astrocytoma tumor suppressor gene on that chromosome. To determine whether the retinoblastoma susceptibility gene (Rb) on 13q14 contributes to the formation of astrocytomas, we examined 85 tumors for loss of heterozygosity (LOH) at the intragenic Rb 1.20 locus. LOH was detected in 16 of 54 informative high-grade astrocytomas (30%), but was not detected in 12 low-grade gliomas. Deletion mapping with flanking markers on 13q revealed that the Rb 1.20 region was preferentially targeted by the deletions. Tumors with LOH at Rb 1.20 were examined for mutations in the remaining Rb allele using single-strand conformational polymorphism (SSCP) analysis and direct DNA sequencing. Mutations were detected in exon 8 (1 tumor), exon 24 (2 tumors), and intron 24 (1 tumor). Rb protein expression, as assessed by immunohistochemistry, was altered in 3 of 9 cases with LOH and in 1 tumor without LOH. Our results demonstrate that Rb inactivation contributes to the formation of high-grade astrocytomas, and therefore implicate a second, known tumor suppressor gene in astrocytoma tumorigenesis.

Astrocytoma↗

PubMed1994

Chromosome 13 transfer provides evidence for regulation of RB1 protein expression.

The human retinoblastoma susceptibility gene (RB1) located on chromosome 13 has been shown to function as a growth/tumor suppressor gene in a large number of human cancers. Although constitutive expression has been observed in most cultured cells and normal tissues, overexpression of RB1 protein has not been well documented. Perhaps regulating the level of normal RB1 protein expression is one of several ways of controlling its function. To test this hypothesis, we transferred normal copies of chromosome 13 via microcell fusion into the human fibrosarcoma cell line HT1080. Microcell hybrids were generated that contained one, two, or three extra copies of the transferred fibroblast chromosome 13. Compared to the parental cell line, the hybrids were completely unaltered with respect to several properties in vitro and in vivo, including morphology, growth rate, and tumor formation. Northern blot analysis revealed a stepwise increase in RB1 mRNA expression which increased in proportion to the number of alleles present in each cell line. Although RB1 protein exhibited correct nuclear localization and was phosphorylated in a normal cell cycle-dependent manner in the hybrids, the increased level of protein expression in each hybrid was nearly identical and did not increase beyond a threshold amount, although mRNA expression continued to increase. These results demonstrate that HT 1080 cells can tolerate an increase level of RB1 protein, but that expression beyond a certain level may be down-regulated. These transfer studies provide evidence for regulation of RB1 protein expression and may suggest an alternative form of monitoring and controlling normal RB1 functioning.

Animals↗

PubMed1992

Changes in growth and tumorigenicity following reconstitution of retinoblastoma gene function in various human cancer cell types by microcell transfer of chromosome 13.

Functional loss of the retinoblastoma (RB) gene has been implicated in the initiation or progression of several human tumor types including cancer of the eye, bone, bladder, and prostate. To examine the consequence of adding one RB allele containing its normal regulatory elements back into representative examples of each of these cancer types, as well as to compare the results to those previously reported using various RB complementary DNA constructs, a neomycin resistant marked 13 chromosome was transferred by microcell fusion. Several attempts to obtain RB positive osteosarcoma cells failed. In addition, only one RB positive retinoblastoma clone was isolated. This clone contained many large cells, could not be maintained in long-term culture, and produced only RB negative tumors. Three RB positive bladder cancer cell clones were obtained, all of which grew slower in culture than their RB negative parental counterpart and did not form colonies in soft agar. Tumorigenicity was markedly suppressed in these clones. One clone yielded no tumors, and the other 2 clones produced only one small tumor each, both of which were RB negative. In contrast, the 2 RB positive prostate cancer cell clones isolated had no differences in their cell culture growth properties, including growth in soft agar compared to the parental cells. One of the clones was nontumorigenic, while the other clone produced 4 small tumors, all of which were RB positive. These results indicate that the transfer of one RB allele by microcell transfer produces different levels of growth inhibition as well as tumor suppression, depending on the cell type examined. In the case of prostate cancer, the function of the RB gene in tumor suppression appears to be independent from its growth regulatory function, since no growth inhibition in cell culture was noted in these cells, although tumor suppression was significant.

Alleles↗

PubMed1992

Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer.

BACKGROUND: The clinical behavior of the tumor in patients with locally advanced bladder carcinoma is unpredictable. Current predictors of clinical behavior include depth of muscle invasion, presence of vascular invasion, proliferation rate, and loss of blood group antigens. Treatment selection would be facilitated by the development of a reliable marker of tumor progression. Functional retinoblastoma (RB) gene loss has been reported to occur in bladder carcinoma, but the significance of this loss is unknown. PURPOSE: We have evaluated the frequency of functional loss of the RB gene in locally advanced bladder carcinoma and have compared the results to known prognostic factors in the same cohort. METHODS: Forty-three study patients with pathologically well-characterized, locally advanced bladder carcinoma, who were placed in a protocol incorporating surgery and chemotherapy, were studied for known clinical and pathological prognostic indicators as well as for their Rb status. Formalin-fixed and paraffin-embedded archival primary tumor tissues were used for histological and immunohistochemical analyses. RESULTS: Altered Rb protein expression was documented in 37% of the tumor specimens. The high rate of altered Rb expression found in this cohort with advanced urothelial tumors strongly suggests that RB functional loss may be associated with tumor progression in this malignancy. Altered Rb protein expression was found to be independent of other known prognostic variables. A significantly poorer tumor-free survival rate also was noted for those patients who had a tumor with an altered Rb protein with or without vascular invasion. CONCLUSION: The high frequency of Rb alteration in locally advanced bladder carcinomas, plus the fact that a significant correlation could not be found between the Rb status and other known prognostic markers in this preliminary study, suggests that altered RB expression may be an independent prognostic marker of tumor progression in bladder cancer.

Gene Expression Regulation, Neoplastic↗

PubMed1992

Altered RB expression is a prognostic clinical marker involved in human bladder tumorigenesis.

We are now beginning to understand the development of bladder cancer at the molecular level. Tumor evolution involves the interaction of both oncogenes and tumor suppressor genes. One of the key tumor suppressor genes in this process is the retinoblastoma (RB) gene. Much has been learned recently about the role of this gene in the tumor progression and prognosis of bladder cancer, although several questions are still unanswered. The progress made on this subject in our laboratory as well as others will be the focus of this report.

Biomarkers, Tumor↗