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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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Related in: MedlinePlus

Immunohistochemically stained TMA specimens illustrating the Seven-Marker Signature for a patient with a high-risk and another patient with a low-risk melanoma.The low-risk melanoma (Column C) showed a strong cytoplasmic staining for β-Catenin and MTAP, respectively. Immunoreactivity of these two protective markers was not found in the high-risk melanoma (Column D). In contrast, the high-risk melanoma demonstrated a moderate to strong cytoplasmic staining for Bax, Bcl-X, PTEN, COX-2, and infiltration with CD20 positive B-lymphocytes.
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pone-0038222-g007: Immunohistochemically stained TMA specimens illustrating the Seven-Marker Signature for a patient with a high-risk and another patient with a low-risk melanoma.The low-risk melanoma (Column C) showed a strong cytoplasmic staining for β-Catenin and MTAP, respectively. Immunoreactivity of these two protective markers was not found in the high-risk melanoma (Column D). In contrast, the high-risk melanoma demonstrated a moderate to strong cytoplasmic staining for Bax, Bcl-X, PTEN, COX-2, and infiltration with CD20 positive B-lymphocytes.

Mentions: In this retrospective study of 364 melanoma patients, we identified an independent seven-marker signature of prognosis. Notably, the predictive power of the signature was carefully validated and confirmed on a secondary independent external test cohort (n = 225). With a total of 27,055 specimens of primary MMs analyzed by IHC, this TMA study is unmatched in the literature. An individual patient’s risk score can easily be calculated given the immunoreactivity scores for the seven markers and the estimated coefficients (Figure 5H). Figure 7 shows stained TMA specimens illustrating the Seven-Marker Signature for a patient with a high-risk and another patient with a low-risk melanoma.


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)

Immunohistochemically stained TMA specimens illustrating the Seven-Marker Signature for a patient with a high-risk and another patient with a low-risk melanoma.The low-risk melanoma (Column C) showed a strong cytoplasmic staining for β-Catenin and MTAP, respectively. Immunoreactivity of these two protective markers was not found in the high-risk melanoma (Column D). In contrast, the high-risk melanoma demonstrated a moderate to strong cytoplasmic staining for Bax, Bcl-X, PTEN, COX-2, and infiltration with CD20 positive B-lymphocytes.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0038222-g007: Immunohistochemically stained TMA specimens illustrating the Seven-Marker Signature for a patient with a high-risk and another patient with a low-risk melanoma.The low-risk melanoma (Column C) showed a strong cytoplasmic staining for β-Catenin and MTAP, respectively. Immunoreactivity of these two protective markers was not found in the high-risk melanoma (Column D). In contrast, the high-risk melanoma demonstrated a moderate to strong cytoplasmic staining for Bax, Bcl-X, PTEN, COX-2, and infiltration with CD20 positive B-lymphocytes.
Mentions: In this retrospective study of 364 melanoma patients, we identified an independent seven-marker signature of prognosis. Notably, the predictive power of the signature was carefully validated and confirmed on a secondary independent external test cohort (n = 225). With a total of 27,055 specimens of primary MMs analyzed by IHC, this TMA study is unmatched in the literature. An individual patient’s risk score can easily be calculated given the immunoreactivity scores for the seven markers and the estimated coefficients (Figure 5H). Figure 7 shows stained TMA specimens illustrating the Seven-Marker Signature for a patient with a high-risk and another patient with a low-risk melanoma.

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