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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 Seven-Marker Signature and Survival of 362 Patients with Primary MM.Panels A and B show Kaplan-Meier estimates of overall and recurrence-free survival for high risk patients (red) and low risk patients (green) from the primary cohort according to the final seven-marker signature (Panels A, B). Equality in survival expectance of the subgroups is assessed by the log-rank test. The difference between high risk patients and low risk patients is highly significant (p<0.001) for the seven-marker signature. Panel C shows the IHC expression profiles of 362 tumor specimens from the primary cohort ordered by their predicted risk score. Each column represents an individual patient consisting of the expression values of the seven-marker signature (5 risk markers and 2 protective markers). The magnitude of the corresponding risk score is plotted below for 181 low risk patients (green) and 181 high risk patients (red). IHC expression values were scaled between 0 (light blue) and 1 (dark blue) for plotting only. White cells represent missing values (n.a.).
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pone-0038222-g002: The Seven-Marker Signature and Survival of 362 Patients with Primary MM.Panels A and B show Kaplan-Meier estimates of overall and recurrence-free survival for high risk patients (red) and low risk patients (green) from the primary cohort according to the final seven-marker signature (Panels A, B). Equality in survival expectance of the subgroups is assessed by the log-rank test. The difference between high risk patients and low risk patients is highly significant (p<0.001) for the seven-marker signature. Panel C shows the IHC expression profiles of 362 tumor specimens from the primary cohort ordered by their predicted risk score. Each column represents an individual patient consisting of the expression values of the seven-marker signature (5 risk markers and 2 protective markers). The magnitude of the corresponding risk score is plotted below for 181 low risk patients (green) and 181 high risk patients (red). IHC expression values were scaled between 0 (light blue) and 1 (dark blue) for plotting only. White cells represent missing values (n.a.).

Mentions: Among the 362 patients of the primary cohort, patients with a high-risk seven-marker signature had a shorter median overall survival than the patients with a low-risk seven-marker signature (88 months versus not reached) and the difference between the two patient groups was significant (p<0.00001) (Figure 2A). The high-risk seven-marker signature was associated with a median recurrence-free survival of 33 months, whereas the low-risk seven-marker signature was associated with a median recurrence-free survival of 88 months (p<0.001) (Figure 2B). The heatmap in Figure 2C shows the IHC expression profiles of these 362 tumor specimens from the primary cohort ordered by their predicted risk score, indicating no high correlation between the selected markers. Figure S4 depicts all correlations between the markers of interest. Having the same sign, risk markers are naturally slightly correlated, but the maximal correlation between Bcl-X and COX-2 is only 0.36.


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 Seven-Marker Signature and Survival of 362 Patients with Primary MM.Panels A and B show Kaplan-Meier estimates of overall and recurrence-free survival for high risk patients (red) and low risk patients (green) from the primary cohort according to the final seven-marker signature (Panels A, B). Equality in survival expectance of the subgroups is assessed by the log-rank test. The difference between high risk patients and low risk patients is highly significant (p<0.001) for the seven-marker signature. Panel C shows the IHC expression profiles of 362 tumor specimens from the primary cohort ordered by their predicted risk score. Each column represents an individual patient consisting of the expression values of the seven-marker signature (5 risk markers and 2 protective markers). The magnitude of the corresponding risk score is plotted below for 181 low risk patients (green) and 181 high risk patients (red). IHC expression values were scaled between 0 (light blue) and 1 (dark blue) for plotting only. White cells represent missing values (n.a.).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038222-g002: The Seven-Marker Signature and Survival of 362 Patients with Primary MM.Panels A and B show Kaplan-Meier estimates of overall and recurrence-free survival for high risk patients (red) and low risk patients (green) from the primary cohort according to the final seven-marker signature (Panels A, B). Equality in survival expectance of the subgroups is assessed by the log-rank test. The difference between high risk patients and low risk patients is highly significant (p<0.001) for the seven-marker signature. Panel C shows the IHC expression profiles of 362 tumor specimens from the primary cohort ordered by their predicted risk score. Each column represents an individual patient consisting of the expression values of the seven-marker signature (5 risk markers and 2 protective markers). The magnitude of the corresponding risk score is plotted below for 181 low risk patients (green) and 181 high risk patients (red). IHC expression values were scaled between 0 (light blue) and 1 (dark blue) for plotting only. White cells represent missing values (n.a.).
Mentions: Among the 362 patients of the primary cohort, patients with a high-risk seven-marker signature had a shorter median overall survival than the patients with a low-risk seven-marker signature (88 months versus not reached) and the difference between the two patient groups was significant (p<0.00001) (Figure 2A). The high-risk seven-marker signature was associated with a median recurrence-free survival of 33 months, whereas the low-risk seven-marker signature was associated with a median recurrence-free survival of 88 months (p<0.001) (Figure 2B). The heatmap in Figure 2C shows the IHC expression profiles of these 362 tumor specimens from the primary cohort ordered by their predicted risk score, indicating no high correlation between the selected markers. Figure S4 depicts all correlations between the markers of interest. Having the same sign, risk markers are naturally slightly correlated, but the maximal correlation between Bcl-X and COX-2 is only 0.36.

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