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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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Dot blot of risk scores for the various histological subtypes of melanoma as classified by the ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision).SSM, superficial spreading melanoma; LMM, lentigo maligna melanoma; NM, nodular melanoma; NOS, not otherwise specificed; ALM, acral lentiginous melanoma. Horizontal lines represent median risk scores for each subgroup.The aim of this study was to provide a maximum of prognostic and therapeutically relevant information by a minimum of markers combined in a clear signature. For the sake of clinical feasibility and cost saving, an IHC marker set suitable for routine clinical assessment should be based on a limited number of antibodies. Accordingly, the nine-marker signature was reduced by the risk marker with the lowest Cox regression coefficient β, i.e. MLH1 (β = 0.254).
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pone-0038222-g004: Dot blot of risk scores for the various histological subtypes of melanoma as classified by the ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision).SSM, superficial spreading melanoma; LMM, lentigo maligna melanoma; NM, nodular melanoma; NOS, not otherwise specificed; ALM, acral lentiginous melanoma. Horizontal lines represent median risk scores for each subgroup.The aim of this study was to provide a maximum of prognostic and therapeutically relevant information by a minimum of markers combined in a clear signature. For the sake of clinical feasibility and cost saving, an IHC marker set suitable for routine clinical assessment should be based on a limited number of antibodies. Accordingly, the nine-marker signature was reduced by the risk marker with the lowest Cox regression coefficient β, i.e. MLH1 (β = 0.254).

Mentions: Comparing high-risk with low-risk patients (Table 2) based on their seven-marker risk score showed a significant difference in tumor thickness (p<0.001) and Clark level (p<0.001) and no difference in nodal status (p = 0.08), sex (p = 1) and age (p = 0.26). Risk scores significantly increased with increasing Clark levels (Figures 3A and 3B). Patients with nodular malignant melanomas (NM) showed the highest risk scores. Dot blots of risk scores for the various histological subtypes of malignant melanoma as classified by the ICD-10 are given in Figure 4.


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)

Dot blot of risk scores for the various histological subtypes of melanoma as classified by the ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision).SSM, superficial spreading melanoma; LMM, lentigo maligna melanoma; NM, nodular melanoma; NOS, not otherwise specificed; ALM, acral lentiginous melanoma. Horizontal lines represent median risk scores for each subgroup.The aim of this study was to provide a maximum of prognostic and therapeutically relevant information by a minimum of markers combined in a clear signature. For the sake of clinical feasibility and cost saving, an IHC marker set suitable for routine clinical assessment should be based on a limited number of antibodies. Accordingly, the nine-marker signature was reduced by the risk marker with the lowest Cox regression coefficient β, i.e. MLH1 (β = 0.254).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038222-g004: Dot blot of risk scores for the various histological subtypes of melanoma as classified by the ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th revision).SSM, superficial spreading melanoma; LMM, lentigo maligna melanoma; NM, nodular melanoma; NOS, not otherwise specificed; ALM, acral lentiginous melanoma. Horizontal lines represent median risk scores for each subgroup.The aim of this study was to provide a maximum of prognostic and therapeutically relevant information by a minimum of markers combined in a clear signature. For the sake of clinical feasibility and cost saving, an IHC marker set suitable for routine clinical assessment should be based on a limited number of antibodies. Accordingly, the nine-marker signature was reduced by the risk marker with the lowest Cox regression coefficient β, i.e. MLH1 (β = 0.254).
Mentions: Comparing high-risk with low-risk patients (Table 2) based on their seven-marker risk score showed a significant difference in tumor thickness (p<0.001) and Clark level (p<0.001) and no difference in nodal status (p = 0.08), sex (p = 1) and age (p = 0.26). Risk scores significantly increased with increasing Clark levels (Figures 3A and 3B). Patients with nodular malignant melanomas (NM) showed the highest risk scores. Dot blots of risk scores for the various histological subtypes of malignant melanoma as classified by the ICD-10 are given in Figure 4.

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