Combinations of apoptosis and cell-cycle control biomarkers predict the outcome of human melanoma

Piras, Franca; Perra, Maria Teresa; Murtas, Daniela; Minerba, Luigi; Floris, C.; Maxia, Cristina; Demurtas, Paolo; Ugalde, Jorge; Ribatti, Doménico; Sirigu, P.

doi:10.3892/or_00000003

Cited by 15 publications

(15 citation statements)

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“…A novel addition to the eligible literature in recent years is research assessing MPDs (18,21,22). When ranked by P-value together with single-molecule predictors of outcome, these multimarker assays seem to do better as predictors of outcome compared with individual biomarkers.…”

Section: Discussionmentioning

confidence: 99%

“…In other cases [GRP78 (26), cyclin B1 (32), CDK1 (32), nm23 (33,34), and topoisomerase II (32)], the opposite was observed; gene transcript levels differ while no significant outcome-related effect was observed at the protein level. For the remaining 16 molecules [BCL2 (32,38), survivin (18,32) (28,44), and SPP1/osteopontin (29,45,46)], concordance could not be assessed due to between-study differences making a direct comparison untenable. In addition, there were 4 molecules for which disparate findings were observed between different measures of clinical outcome.…”

Section: Bioinformatic Analysismentioning

confidence: 99%

“…The largest study remains that conducted by Weinlich and colleagues in 2006 (28) involving more than 1,270 patients. For the first time, some studies (18,21,22) evaluated the combined effect of 3 or more markers in a multivariate setting [multimarker prognostic discriminators (MPD)]. It is notable that RGS1, b-catenin, p16INK4a, p21WAF1, p53, SPP1/osteopontin, and NCOA3 are the only eligible biomarker candidates to have been investigated by more than 1 research group, with respect to at least 2 outcomes, and as part of an MPD set.…”

Section: Included Studiesmentioning

confidence: 99%

“…In contrast, 6 molecules were assessed as having no significant relationship with outcome at the protein level but appeared on the Winnepenninckx and colleagues (30) differently expressed gene list [CDK1 (32), cyclin B (32), GRP78 (26), nm23 (33,34), survivin (18,32), and TOPII (32)]. …”

Section: Bioinformatic Analysismentioning

confidence: 99%

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Melanoma Prognosis: A REMARK-Based Systematic Review and Bioinformatic Analysis of Immunohistochemical and Gene Microarray Studies

Schramm

Mann

2011

Molecular Cancer Therapeutics

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Despite intensive research efforts, within-stage survival rates for melanoma vary widely. Pursuit of molecular biomarkers with improved prognostic significance over clinicohistological measures has produced extensive literature. Reviews have synthesized these data, but none have systematically partitioned highquality studies from the remainder across different molecular methods nor examined system properties of that output. Databases were searched for studies analyzing protein expression by immunohistochemistry (n ¼ 617, extending the only systematic review to date by 102 studies) or for gene expression microarray studies (n ¼ 45) in melanoma in relation to outcome. REMARK-derived criteria were applied to identify highquality studies. Biomarkers and pathways were functionally assessed by using gene ontology software. Most manuscripts did not meet REMARK-based criteria, an ongoing trend that can impede translational research. Across REMARK-compliant literature, 41 proteins were significantly associated with outcome. Multimarker tests consistently emerged among the most promising potential biomarkers, indicating a need to continue assessing candidates in that composite setting. Twenty-one canonical pathways were populated by outcomerelated proteins but not by those that failed to show such an association; we propose that this set of pathways warrants closer investigation to understand drivers of poor outcome in melanoma. Two-gene expression microarray studies met REMARK-based criteria reflecting a genuine paucity of literature in the area. The 254 outcome-related genes were examined for correspondences with the systematically identified protein signature. This analysis highlighted proliferating cell nuclear antigen and survivin as priorities for further examination as biomarkers in melanoma prognosis, and illustrated ongoing need to integrate alternative approaches to biomarker discovery in melanoma translational research.

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Section: Discussionmentioning

confidence: 99%

Section: Bioinformatic Analysismentioning

confidence: 99%

Section: Included Studiesmentioning

confidence: 99%

Section: Bioinformatic Analysismentioning

confidence: 99%

See 2 more Smart Citations

Melanoma Prognosis: A REMARK-Based Systematic Review and Bioinformatic Analysis of Immunohistochemical and Gene Microarray Studies

Schramm

Mann

2011

Molecular Cancer Therapeutics

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“…It is implicated in cell division, prevention of apoptosis, cellular stress response and checkpoint mechanisms of genomic integrity (16). It is overexpressed in many human malignancies, and such overexpression is associated with poor prognosis (17)(18)(19). Transcription of the survivin gene is inhibited by the p53 tumor suppressor (20), essential in the regulation of cellular response to DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor-κB expression is predictive of overall survival in patients with cutaneous melanoma

Murtas¹,

Piras²,

Minerba³

et al. 2010

Oncology Letters

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Abstract. Nuclear factor (NF)-κB is one of the most important transcription factors that plays a crucial role in the regulation of a wide spectrum of genes involved in modulating the cell cycle, apoptosis, cell growth, angiogenesis, inflammation and the tissue invasiveness of highly malignant cells. NF-κB activity has been found to be constitutively elevated in a number of human tumors from either a haematological or solid origin, such as melanomas. In several studies, NF-κB activation was shown to be an adverse prognostic factor, and in melanoma it was proposed as an event that promotes tumor progression. This study aimed to evaluate whether NF-κB activation in tumor tissues, assessed by the expression of the NF-κB p65 subunit, has an effect on the survival of melanoma patients. The expression of NF-κB was immunohistochemically investigated, and the correlation with survival was analyzed. Furthermore, the immunostaining for p53 and survivin was evaluated, and the relationship of these apoptotic and anti-apoptotic factors with NF-κB expression was analyzed. Kaplan-Meier analysis showed that patients with low levels of NF-κB in the nuclei of tumor cells had a significantly longer survival compared to those with high levels. Multivariate analysis confirmed the predictive value of nuclear NF-κB, showing that its expression maintains significance after the model was adjusted using clinicopathological factors. The results demonstrate the correlation of NF-κB p65 nuclear staining with the disease-specific 5-year survival of melanoma patients and suggest that nuclear NF-κB p65 may be promising as an early independent prognostic factor in patients with primary cutaneous melanoma. IntroductionNuclear factor (NF)-κB is one of the most important transcription factors that plays an essential role in the regulation of the expression and function of a wide spectrum of genes involved in the modulation of the cell cycle, apoptosis, cell growth, angiogenesis, inflammation and tissue invasiveness of highly malignant cells (1-3). NF-κB is a homodimeric or heterodimeric complex comprising proteins of the Rel-family: p65 (RelA), RelB, c-Rel, p50 (NF-κB1) and p52 (NF-κB2), all of which contain a Rel homology domain in the N-terminal region that mediates dimerization and DNA binding (4). The most commonly detected dimers are p65/p50, p65/p65 and p50/p50. Due to the presence of a strong transcriptional activation domain, p65 is responsible for the majority of NF-κB transcriptional activity (5). Moreover, the p65/p50 heterodimer comprises the major activated form of NF-κB in numerous cell types (4). NF-κB proteins are expressed in most cells, but are normally sequestered in the cytoplasm through binding with the inhibitors of NF-κBs (IκBs) (6). A number of pathways of cell stimulation, such as pro-inflammatory, mutagenic and pro-apoptotic stimuli, lead to the activation of the IκB kinase complex which phosphorylates the IκBs, targeting them for ubiquitination and degradation by the 26S proteosome according to the canonical NF-κB signal ...

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Construction and Analysis of Multiparameter Prognostic Models for Melanoma Outcome

Rothberg

Rimm

2013

Methods in Molecular Biology

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Summary The outcome of Stage II melanoma is uncertain. Despite that 10-year melanoma-specific survival can approach 50% following curative-intent wide local excision and negative sentinel lymph node biopsy, the adverse risk-benefit ratio of interferon-based adjuvant regimens precludes their use in most patients. The discovery and translation of protein-based prognostic biomarkers into the clinic offers the promise for residual risk stratification of Stage II melanoma patients beyond conventional clinicopathologic criteria to identify an additional subset of patients who, based upon tumor molecular profiles, might also derive benefit from adjuvant regimens. Despite incorporation of Ki-67 assays into clinical practice, systematic review of REMARK-compliant, immunostain-based prognostic biomarker assays in melanoma suggests that residual risk of recurrence might be best explained by a composite score derived from a small panel of proteins representing independent features of melanoma biology. Reflecting this trend, to date, 5 such multi-parameter melanoma prognostic models have been published. Here, we review these 5 models and provide detailed protocols for discovering and validating multi-parameter models including: appropriate cohort recruitment strategies, comprehensive laboratory protocols supporting fully quantitative chromogenic or fluorescent immunostaining platforms, statistical approaches to create composite prognostic indices recommended steps for model validation in independent cohorts.

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Combinations of apoptosis and cell-cycle control biomarkers predict the outcome of human melanoma

Cited by 15 publications

References 2 publications

Melanoma Prognosis: A REMARK-Based Systematic Review and Bioinformatic Analysis of Immunohistochemical and Gene Microarray Studies

Melanoma Prognosis: A REMARK-Based Systematic Review and Bioinformatic Analysis of Immunohistochemical and Gene Microarray Studies

Nuclear factor-κB expression is predictive of overall survival in patients with cutaneous melanoma

Construction and Analysis of Multiparameter Prognostic Models for Melanoma Outcome

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