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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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The Six-Marker Signature (without CD20) and Survival of Patients with Malignant Melanoma.Kaplan-Meier estimates show a significantly lower overall (p<0.00001, Panel A) and recurrence-free survival (p<0.01, Panel B) for melanoma patients with high-risk score.
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pone-0038222-g009: The Six-Marker Signature (without CD20) and Survival of Patients with Malignant Melanoma.Kaplan-Meier estimates show a significantly lower overall (p<0.00001, Panel A) and recurrence-free survival (p<0.01, Panel B) for melanoma patients with high-risk score.

Mentions: Presence of CD20-positive B-lymphocytes within or adjacent to MM tissue (Figures 8A–D ) was among the top seven biomarkers. However, the role of B-lymphocyte infiltration in MM is unknown and needs further investigation. The CD20-antigen is known to be an effective therapeutic target in the treatment of patients with CD20-positive B-Cell-Non-Hodgkin-Lymphomas. The monoclonal chimeric antibody Rituximab is indicated for alternative immunotherapy [32]. In MM, several subpopulations - some with stem cell-like characteristics - have been described including one with expression of CD20 (reviewed in [33]). In our study, only very few cases showed infiltrating CD20 positive B-lymphocytes (Figure 2E), comprising a very narrow dynamic range of this marker. However, even a six-marker signature without CD20 was significantly associated with overall and recurrence-free survival (Figures 9A and 9B).


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)

The Six-Marker Signature (without CD20) and Survival of Patients with Malignant Melanoma.Kaplan-Meier estimates show a significantly lower overall (p<0.00001, Panel A) and recurrence-free survival (p<0.01, Panel B) for melanoma patients with high-risk score.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038222-g009: The Six-Marker Signature (without CD20) and Survival of Patients with Malignant Melanoma.Kaplan-Meier estimates show a significantly lower overall (p<0.00001, Panel A) and recurrence-free survival (p<0.01, Panel B) for melanoma patients with high-risk score.
Mentions: Presence of CD20-positive B-lymphocytes within or adjacent to MM tissue (Figures 8A–D ) was among the top seven biomarkers. However, the role of B-lymphocyte infiltration in MM is unknown and needs further investigation. The CD20-antigen is known to be an effective therapeutic target in the treatment of patients with CD20-positive B-Cell-Non-Hodgkin-Lymphomas. The monoclonal chimeric antibody Rituximab is indicated for alternative immunotherapy [32]. In MM, several subpopulations - some with stem cell-like characteristics - have been described including one with expression of CD20 (reviewed in [33]). In our study, only very few cases showed infiltrating CD20 positive B-lymphocytes (Figure 2E), comprising a very narrow dynamic range of this marker. However, even a six-marker signature without CD20 was significantly associated with overall and recurrence-free survival (Figures 9A and 9B).

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