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A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.

Meyer S, Fuchs TJ, Bosserhoff AK, Hofstädter F, Pauer A, Roth V, Buhmann JM, Moll I, Anagnostou N, Brandner JM, Ikenberg K, Moch H, Landthaler M, Vogt T, Wild PJ - PLoS ONE (2012)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital of Regensburg, Regensburg, Germany.

ABSTRACT

Background: Current 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 findings: Using 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.

Conclusions: The 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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Hazard Ratios of the Nine-Marker Signature learned by the FDR selection procedure.Markers with a hazard ratio smaller than 1.00 represent “protective markers” (MTAP, β-Catenin). Those with hazard ratios larger than 1.00 represent “risk markers” (Bax, Bcl-X, infiltration with CD20 positive B-lymphocytes, CD49d, COX-2, MLH1 and PTEN).
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pone-0038222-g001: Hazard Ratios of the Nine-Marker Signature learned by the FDR selection procedure.Markers with a hazard ratio smaller than 1.00 represent “protective markers” (MTAP, β-Catenin). Those with hazard ratios larger than 1.00 represent “risk markers” (Bax, Bcl-X, infiltration with CD20 positive B-lymphocytes, CD49d, COX-2, MLH1 and PTEN).

Mentions: Prognostic power of the 70 markers was assessed by calculating univariate proportional hazard models [19], yielding eleven markers significantly associated with overall survival (Table 1). To correct for multiple testing, the false discovery rate (FDR) procedure [20] was applied with a FDR of 0.15 reducing the set of significantly associated markers to nine (Figure 1) which were correlated with death from any cause: MTAP and β-Catenin were so called “protective markers”, where loss of expression was associated with worse outcome. The remaining other seven markers were assigned “risk markers”.


A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.

Meyer S, Fuchs TJ, Bosserhoff AK, Hofstädter F, Pauer A, Roth V, Buhmann JM, Moll I, Anagnostou N, Brandner JM, Ikenberg K, Moch H, Landthaler M, Vogt T, Wild PJ - PLoS ONE (2012)

Hazard Ratios of the Nine-Marker Signature learned by the FDR selection procedure.Markers with a hazard ratio smaller than 1.00 represent “protective markers” (MTAP, β-Catenin). Those with hazard ratios larger than 1.00 represent “risk markers” (Bax, Bcl-X, infiltration with CD20 positive B-lymphocytes, CD49d, COX-2, MLH1 and PTEN).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369875&req=5

pone-0038222-g001: Hazard Ratios of the Nine-Marker Signature learned by the FDR selection procedure.Markers with a hazard ratio smaller than 1.00 represent “protective markers” (MTAP, β-Catenin). Those with hazard ratios larger than 1.00 represent “risk markers” (Bax, Bcl-X, infiltration with CD20 positive B-lymphocytes, CD49d, COX-2, MLH1 and PTEN).
Mentions: Prognostic power of the 70 markers was assessed by calculating univariate proportional hazard models [19], yielding eleven markers significantly associated with overall survival (Table 1). To correct for multiple testing, the false discovery rate (FDR) procedure [20] was applied with a FDR of 0.15 reducing the set of significantly associated markers to nine (Figure 1) which were correlated with death from any cause: MTAP and β-Catenin were so called “protective markers”, where loss of expression was associated with worse outcome. The remaining other seven markers were assigned “risk markers”.

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University Hospital of Regensburg, Regensburg, Germany.

ABSTRACT

Background: Current 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 findings: Using 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.

Conclusions: The 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.

Show MeSH
Related in: MedlinePlus