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

<h4>Background</h4>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...

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Autores principales:	Stefanie Meyer, Thomas J Fuchs, Anja K Bosserhoff, Ferdinand Hofstädter, Armin Pauer, Volker Roth, Joachim M Buhmann, Ingrid Moll, Nikos Anagnostou, Johanna M Brandner, Kristian Ikenberg, Holger Moch, Michael Landthaler, Thomas Vogt, Peter J Wild
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2bc143f0d8524d2b8a33c655470f7061
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spelling	oai:doaj.org-article:2bc143f0d8524d2b8a33c655470f70612021-11-18T07:16:06ZA seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.1932-620310.1371/journal.pone.0038222https://doaj.org/article/2bc143f0d8524d2b8a33c655470f70612012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22685558/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.Stefanie MeyerThomas J FuchsAnja K BosserhoffFerdinand HofstädterArmin PauerVolker RothJoachim M BuhmannIngrid MollNikos AnagnostouJohanna M BrandnerKristian IkenbergHolger MochMichael LandthalerThomas VogtPeter J WildPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 6, p e38222 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefanie Meyer Thomas J Fuchs Anja K Bosserhoff Ferdinand Hofstädter Armin Pauer Volker Roth Joachim M Buhmann Ingrid Moll Nikos Anagnostou Johanna M Brandner Kristian Ikenberg Holger Moch Michael Landthaler Thomas Vogt Peter J Wild A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
description	<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.
format	article
author	Stefanie Meyer Thomas J Fuchs Anja K Bosserhoff Ferdinand Hofstädter Armin Pauer Volker Roth Joachim M Buhmann Ingrid Moll Nikos Anagnostou Johanna M Brandner Kristian Ikenberg Holger Moch Michael Landthaler Thomas Vogt Peter J Wild
author_facet	Stefanie Meyer Thomas J Fuchs Anja K Bosserhoff Ferdinand Hofstädter Armin Pauer Volker Roth Joachim M Buhmann Ingrid Moll Nikos Anagnostou Johanna M Brandner Kristian Ikenberg Holger Moch Michael Landthaler Thomas Vogt Peter J Wild
author_sort	Stefanie Meyer
title	A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
title_short	A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
title_full	A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
title_fullStr	A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
title_full_unstemmed	A seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
title_sort	seven-marker signature and clinical outcome in malignant melanoma: a large-scale tissue-microarray study with two independent patient cohorts.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/2bc143f0d8524d2b8a33c655470f7061
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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.

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