Biomarkers: The Useful and the Not So Useful—An Assessment of Molecular Prognostic Markers for Cutaneous Melanoma

Rothberg, Bonnie E. Gould; Rimm, David L.

doi:10.1038/jid.2010.149

Cited by 50 publications

(38 citation statements)

References 228 publications

(184 reference statements)

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“…Several markers could be considered in more than one category based on their various biological functions. In such cases, the markers were categorized according to their most documented characteristics based on the available literature 91 . Only markers showing independent prognostic or predictive value in two or more separate studies are discussed (Fig.…”

Section: Resultsmentioning

confidence: 99%

Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer

Ansari

Rosendahl

Elebro

et al. 2011

British Journal of Surgery

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None of the molecular markers described can be recommended for routine clinical use as they were identified in small cohorts and there were inconsistencies between studies. Their prognostic and predictive values need to be validated further in prospective multicentre studies in larger patient populations. A panel of molecular markers may become useful in predicting individual patient outcome and directing novel types of intervention.

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Section: Resultsmentioning

confidence: 99%

Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer

Ansari

Rosendahl

Elebro

et al. 2011

British Journal of Surgery

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“…The candidate markers were chosen because of their described role in MM in the literature [10], [11], [14] or on the basis of previous studies by our group [12], [15].…”

Section: Methodsmentioning

confidence: 99%

A Seven-Marker Signature and Clinical Outcome in Malignant Melanoma: A Large-Scale Tissue-Microarray Study with Two Independent Patient Cohorts

et al. 2012

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BackgroundCurrent staging methods such as tumor thickness, ulceration and invasion of the sentinel node are known to be prognostic parameters in patients with malignant melanoma (MM). However, predictive molecular marker profiles for risk stratification and therapy optimization are not yet available for routine clinical assessment.Methods and FindingsUsing tissue microarrays, we retrospectively analyzed samples from 364 patients with primary MM. We investigated a panel of 70 immunohistochemical (IHC) antibodies for cell cycle, apoptosis, DNA mismatch repair, differentiation, proliferation, cell adhesion, signaling and metabolism. A marker selection procedure based on univariate Cox regression and multiple testing correction was employed to correlate the IHC expression data with the clinical follow-up (overall and recurrence-free survival). The model was thoroughly evaluated with two different cross validation experiments, a permutation test and a multivariate Cox regression analysis. In addition, the predictive power of the identified marker signature was validated on a second independent external test cohort (n = 225). A signature of seven biomarkers (Bax, Bcl-X, PTEN, COX-2, loss of β-Catenin, loss of MTAP, and presence of CD20 positive B-lymphocytes) was found to be an independent negative predictor for overall and recurrence-free survival in patients with MM. The seven-marker signature could also predict a high risk of disease recurrence in patients with localized primary MM stage pT1-2 (tumor thickness ≤2.00 mm). In particular, three of these markers (MTAP, COX-2, Bcl-X) were shown to offer direct therapeutic implications.ConclusionsThe seven-marker signature might serve as a prognostic tool enabling physicians to selectively triage, at the time of diagnosis, the subset of high recurrence risk stage I–II patients for adjuvant therapy. Selective treatment of those patients that are more likely to develop distant metastatic disease could potentially lower the burden of untreatable metastatic melanoma and revolutionize the therapeutic management of MM.

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“…For IHC-based literature, the review process uses the stringent REMARK-based method developed by Gould Rothberg and colleagues (5). Our update of their study expands their list of candidate biomarkers from 62 to 81 proteins and highlights promising candidates (e.g., survivin, PCNA, and MPDs) for further validation as biomarkers of prognosis, of the more than 700 protein species that have been assessed in any way in the literature (47). We have also adapted the REMARK criteria for application to assessment of all published peer-reviewed gene expression microarray-based research involving primary cutaneous melanoma and prognosis.…”

Section: Discussionmentioning

confidence: 99%

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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Biomarkers: The Useful and the Not So Useful—An Assessment of Molecular Prognostic Markers for Cutaneous Melanoma

Cited by 50 publications

References 228 publications

Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer

Systematic review of immunohistochemical biomarkers to identify prognostic subgroups of patients with pancreatic cancer

A Seven-Marker Signature and Clinical Outcome in Malignant Melanoma: A Large-Scale Tissue-Microarray Study with Two Independent Patient Cohorts

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

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