Downregulation of the Retinoblastoma Gene Expression in the Progression of Malignant Melanoma

Korabiowska, M; Ruschenburg, I; Betke, Herbert; Stachura, Jerzy; Schlott, Thilo; Cardó, Carlos Cordón; Brinck, Ulrich

doi:10.1159/000064338

Cited by 21 publications

(13 citation statements)

References 24 publications

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“…Results show a greater impact on p16 than on ARF, thus obtaining by predictive modelling an interpretation supporting coincident alterations in p53, or deletions in exon 1b, to achieve dual inactivation of RB and p53 pathways. These data add to the recurrent inactivation patterns reported above.Further support of the Yang et al viewpoint comes from the functional disruption of the RB locus, reported to occur in melanoma cell lines (Bartkova et al, 1996), a finding in keeping with the lack of RB expression shown in melanoma specimens (Korabiowska et al, 2001).Our own analysis of RB protein expression in cell lines harboring wild-type p16 and CDK4 genes showed that in three of eight cases studied RB was not detectable by immunoblotting. Notably, of the four of 41 tested cell lines expressing the p16 protein, three lines obtained from different lesions of a single patient, all harboring a mutated p53 and wild-type CDKN2A genes and detectable p16 and ARF proteins, lack RB protein expression (M. Rodolfo, unpublished results).…”

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confidence: 76%

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A Merging Duo in Melanoma Formation

Rodolfo

Parmiani

2005

Journal of Investigative Dermatology

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It is well known that cutaneous melanoma is characterized by an early onset of metastatic spread as even very thin primary lesions are able to generate metastasis, and metastatic disease may occur in the absence of a detectable primary lesion. Deciphering the genetic alterations and the signalling pathways involved in the neoplastic transformation of melanocytes will provide the basis for identifying new drugs targeting the molecules involved and which could overcome melanoma cell resistance to cytotoxic compounds.Though many genes have been reported to be involved in human melanoma formation, their specific role and interaction and the underlying mechanisms of action in melanocyte transformation remain elusive. In most of the previous studies, the authors' attention was focussed on a single pathway whose alteration might result in neoplasia.For example, whereas the role of p16 inactivation in melanoma is well established, that of p53 pathway disruption is not. Because of the central role played by the p53 pathway in tumor pathogenesis through the control of genomic stability, cell cycle arrest, induction of apoptosis, and transcriptional activity on genes involved in tumor progression (Milyavsky et al, 2005), the potential contribution of p53 in melanoma needs clarification.In fact, the frequency of p53 mutations detected in melanoma has been generally reported to be lower than in other tumor types. The most common mechanism determining alterations in the p53 pathway in melanoma is represented by the homozygous deletion of the alternative reading frame (ARF) and p16 genes as the result of CDKN2A locus injury. Since ARF preserves the functional activity of p53, whereas p16 is more relevant for retinoblastoma (RB), deletions involving CDKN2A exons can theoretically disrupt both regulatory pathways.But if homozygous deletions of exons 1a and 1b (or 1a and 2) of CDKN2A affect both p16 and ARF, the effects of point mutations occurring in exon 2 are less clear, since few of them have been functionally characterized for their effect on ARF, thus leaving doubts on the real need of p53 pathway inactivation.Nonetheless, concomitant mutations in TP53 and p16 genes have been reported in some melanoma cell lines and, in a recent study, we found TP53 mutations either concomitant or alternative with respect to those of the CDKN2A locus, the latter always being associated with BRAF mutations. Of note, this mutational profile is preferentially found in poorly surviving patients (Daniotti et al, 2004).In this issue of the Journal, Yang et al (2005) have reassessed the potential effect of inactivating the two master regulatory pathways RB and p53 in human melanoma formation by analyzing data on gene alterations in a large collection of cell lines. The authors come to the conclusion that disruption of both pathways can be detected in the large majority (70%-80%) of the melanoma studied, thus indicating that concomitant injury of both pathways might represent the basis of human melanocyte transformation.The authors consider mutation...

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confidence: 76%

“…Further support of the Yang et al viewpoint comes from the functional disruption of the RB locus, reported to occur in melanoma cell lines (Bartkova et al, 1996), a finding in keeping with the lack of RB expression shown in melanoma specimens (Korabiowska et al, 2001).…”

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confidence: 64%

A Merging Duo in Melanoma Formation

Rodolfo

Parmiani

2005

Journal of Investigative Dermatology

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“…Participants provided background [17], mouse anti-pRb mAb NCL-Rb1 (Novocastra Laboratories, Newcastle-upon-Tyne, UK), mouse anti-p53 protein mAb NCL-p53-DO7 (Novocastra Laboratories), and mouse anti-p16 protein mAb (clone G175-405; BD PharMingen, San Diego, California, USA), respectively. Immunohistochemical analysis of melanomas using phospho-p44/42 MAPK, NCL-Rb1, NCL-p53-DO7, and G175-405 have previously been reported [6,7,[18][19][20]; however, immunohistochemical techniques were modified for optimal staining of our archival tissue. Staining with each antibody was performed separately, each in a single batch.…”

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confidence: 99%

Histologic and epidemiologic correlates of P-MAPK, Brn-2, pRb, p53, and p16 immunostaining in cutaneous melanomas

et al. 2008

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Histologic, molecular, and epidemiologic data suggest that cutaneous melanomas arise through diverse causal pathways, one of which appears mediated by chronic sunlight exposure, and another associated with a nevus-prone phenotype. To further explore etiologic heterogeneity, we compared expression of key melanoma-related proteins according to histologic characteristics of the tumors and epidemiologic risk factors among a sample of 129 patients newly diagnosed with melanoma. Tumor tissue was stained with antibodies to phospho-mitogen-activated protein kinase (P-MAPK), Brn-2, retinoblastoma protein (pRb), p53, and p16. Using logistic regression analysis, we estimated the odds ratio (OR) and 95% confidence interval (95% CI) of protein expression associated with factors of interest. Except for pRb, candidate protein expression was detected in fewer than half the melanomas examined (P-MAPK, 39%; Brn-2, 30%; p53, 24%; p16, 41%). Strong pRb expression was associated with the presence of >20 solar keratoses (OR 6.5, 95% CI: 1.7-25.1) and melanomas with marked to moderate solar elastosis. p53 expression was positively associated with skin that readily burned (OR 3.8, 95% CI: 0.8-19.0) and was inversely associated with >60 nevi (OR 0.3, 95% CI: 0.04-1.5). Melanomas expressing P-MAPK were more likely to have contiguous neval remnants (OR 2.7, 95% CI: 1.1-6.5). P-MAPK and Brn-2 immunopositive melanomas were >/=4-fold more likely to be of the superficial spreading subtype. Brn-2 and p16 immunopositive melanomas had a greater Breslow thickness than melanomas that did not express these proteins. Brn-2, pRb, and p16 proteins were consistently coexpressed. These findings support the hypothesis that molecular profiles of melanoma reflect their histologic and epidemiologic characteristics, offering further evidence of more than one melanoma causal pathway. Exactly how the expression of each protein relates to the causal pathways needs to be further explored.

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“…In small cell lung cancer (SCLC), for example, the prevalence of RB1 loss is more than 90% [12,13], while RB1 function in cervical cancer is suppressed by directly associating with HPV-E7 oncoprotein at a frequency of at least 90% [14,15]. A moderate frequency of RB1 dysfunction has been reported in several other types of cancers such as bladder, prostate cancers, and melanoma [16-18]. The RB1 loss is caused by several molecular events such as point mutations, deletion, or inactivation through associating viral proteins [19].…”

Section: Introductionmentioning

confidence: 99%

Expression ratio of CCND1 to CDKN2A mRNA predicts RB1 status of cultured cancer cell lines and clinical tumor samples

et al. 2011

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BackgroundThe retinoblastoma product (RB1) is frequently deregulated in various types of tumors by mutation, deletion, or inactivation through association with viral oncoproteins. The functional loss of RB1 is recognized to be one of the hallmarks that differentiate cancer cells from normal cells. Many researchers are attempting to develop anti-tumor agents that are preferentially effective against RB1-negative tumors. However, to identify patients with RB1-negative cancers, it is imperative to develop predictive biomarkers to classify RB1-positive and -negative tumors.ResultsExpression profiling of 30 cancer cell lines composed of 16 RB1-positive and 14 RB1-negative cancers was performed to find genes that are differentially expressed between the two groups, resulting in the identification of an RB1 signature with 194 genes. Among them, critical RB1 pathway components CDKN2A and CCND1 were included. We found that microarray data of the expression ratio of CCND1 and CDKN2A clearly distinguished the RB1 status of 30 cells lines. Measurement of the CCND1/CDKN2A mRNA expression ratio in additional cell lines by RT-PCR accurately predicted RB1 status (12/12 cells lines). The expression of CCND1/CDKN2A also correlated with RB1 status in xenograft tumors in vivo. Lastly, a CCND1/CDKN2A assay with clinical samples showed that uterine cervical and small cell lung cancers known to have a high prevalence of RB1-decifiency were predicted to be 100% RB1-negative, while uterine endometrial or gastric cancers were predicted to be 5-22% negative. All clinically normal tissues were 100% RB1-positive.ConclusionsWe report here that the CCND1/CDKN2A mRNA expression ratio predicts the RB1 status of cell lines in vitro and xenograft tumors and clinical tumor samples in vivo. Given the high predictive accuracy and quantitative nature of the CCND1/CDKN2A expression assay, the assay could be utilized to stratify patients for anti-tumor agents with preferential effects on either RB1-positive or -negative tumors.

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Downregulation of the Retinoblastoma Gene Expression in the Progression of Malignant Melanoma

Cited by 21 publications

References 24 publications

A Merging Duo in Melanoma Formation

A Merging Duo in Melanoma Formation

Histologic and epidemiologic correlates of P-MAPK, Brn-2, pRb, p53, and p16 immunostaining in cutaneous melanomas

Expression ratio of CCND1 to CDKN2A mRNA predicts RB1 status of cultured cancer cell lines and clinical tumor samples

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