Tissue Microarray Analysis of Methylthioadenosine Phosphorylase Protein Expression in Melanocytic Skin Tumors

Wild, Peter J.; Meyer, Stefanie; Bataille, Frauke; Woenckhaus, Matthias; Ameres, Markus; Vogt, Thomas; Landthaler, Míchael; Pauer, Armin; Klinkhammer‐Schalke, Monika; Hofstaedter, Ferdinand; Bosserhoff, Anja‐Katrin

doi:10.1001/archderm.142.4.471

Cited by 18 publications

(24 citation statements)

References 11 publications

(21 reference statements)

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“…MTAP plays a critical role in the salvage pathway of adenine and methionine and has previously been reported to be lost in several tumors including melanoma (33). Our results demonstrate lower expression of MTAP in SSM relative to NM which was significantly correlated with SSM-specific genomic deletions in the region of 9p21.3.…”

Section: Discussionmentioning

confidence: 99%

Integrative Genomics Identifies Molecular Alterations that Challenge the Linear Model of Melanoma Progression

et al. 2011

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Superficial spreading melanoma (SSM) and nodular melanoma (NM) are believed to represent sequential phases of linear progression from radial to vertical growth. Several lines of clinical, pathologic, and epidemiologic evidence suggest, however, that SSM and NM might be the result of independent pathways of tumor development. We utilized an integrative genomic approach that combines single nucleotide polymorphism array (6.0; Affymetrix) with gene expression array (U133A 2.0; Affymetrix) to examine molecular differences between SSM and NM. Pathway analysis of the most differentially expressed genes between SSM and NM (N ¼ 114) revealed significant differences related to metabolic processes. We identified 8 genes (DIS3, FGFR1OP, G3BP2, GALNT7, MTAP, SEC23IP, USO1, and ZNF668) in which NM/SSM-specific copy number alterations correlated with differential gene expression (P < 0.05; Spearman's rank). SSM-specific genomic deletions in G3BP2, MTAP, and SEC23IP were independently verified in two external data sets. Forced overexpression of metabolism-related gene MTAP (methylthioadenosine phosphorylase) in SSM resulted in reduced cell growth. The differential expression of another metabolic-related gene, aldehyde dehydrogenase 7A1 (ALDH7A1), was validated at the protein level by using tissue microarrays of human melanoma. In addition, we show that the decreased ALDH7A1 expression in SSM may be the result of epigenetic modifications. Our data reveal recurrent genomic deletions in SSM not present in NM, which challenge the linear model of melanoma progression. Furthermore, our data suggest a role for altered regulation of metabolism-related genes as a possible cause of the different clinical behavior of SSM and NM. Cancer Res; 71(7); 2561-71. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Integrative Genomics Identifies Molecular Alterations that Challenge the Linear Model of Melanoma Progression

et al. 2011

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“…TMAs were constructed as described previously [12] and based on primary melanoma material, collected between 1994 and 2006. TMA 1, the primary cohort, contained single tissue punch samples from 364 consecutive (non-selected), formalin-fixed, paraffin-embedded MMs of 364 different patients and were from the Department of Dermatology, University Hospital of Regensburg, Germany.…”

Section: Methodsmentioning

confidence: 99%

“…The candidate markers were chosen because of their described role in MM in the literature [10], [11], [14] or on the basis of previous studies by our group [12], [15].…”

Section: Methodsmentioning

confidence: 99%

A Seven-Marker Signature and Clinical Outcome in Malignant Melanoma: A Large-Scale Tissue-Microarray Study with Two Independent Patient Cohorts

et al. 2012

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BackgroundCurrent 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 FindingsUsing 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.ConclusionsThe 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 second TMA ( TMA-2 ) was constructed as described by Wild et al [26] and contained a total of 350 formalin-fixed, paraffin-embedded human tissues: 88 (25.1%) primary malignant melanomas, 101 (28.9%) metastases, and 161 (46.0%) benign nevi. H&E-stained slides of all tumors were evaluated by two surgical pathologists (T.V., P.J.W.).…”

Section: Methodsmentioning

confidence: 99%

Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma

et al. 2010

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Using tissue microarrays (TMAs) we studied COX2/PPARG immunoreactivity in a broad spectrum of tumors focussing on clinicopathological correlations and the outcome of patients with malignant melanoma (MM). TMA-1 contained normal and tumor tissues (n = 3448) from 47 organs including skin neoplasms (n = 323); TMA-2 88 primary MM, 101 metastases, and 161 benign nevi. Based on a biomodulatory approach combining COX/PPAR-targeting with metronomic low-dose chemotherapy metastases of 36 patients participating in a randomized trial with metastatic (stage IV) melanoma were investigated using TMA-3. COX2/PPARG immunoreactivity significantly increased from nevi to primary MM and metastases; COX2 positivity was associated with advanced Clark levels and shorter recurrence-free survival. Patients with PPARG-positive metastases and biomodulatory metronomic chemotherapy alone or combined with COX2/PPARG-targeting showed a significantly prolonged progression-free survival. Regarding primary MM, COX2 expression indicates an increased risk of tumor recurrence. In metastatic MM, PPARG expression may be a predicitive marker for response to biomodulatory stroma-targeted therapy.

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Tissue Microarray Analysis of Methylthioadenosine Phosphorylase Protein Expression in Melanocytic Skin Tumors

Cited by 18 publications

References 11 publications

Integrative Genomics Identifies Molecular Alterations that Challenge the Linear Model of Melanoma Progression

Integrative Genomics Identifies Molecular Alterations that Challenge the Linear Model of Melanoma Progression

A Seven-Marker Signature and Clinical Outcome in Malignant Melanoma: A Large-Scale Tissue-Microarray Study with Two Independent Patient Cohorts

Cyclooxygenase 2 (COX2) and Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Are Stage-Dependent Prognostic Markers of Malignant Melanoma

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