Abstract
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.
Highlights
Cutaneous malignant melanoma (MM), represents the most common cause of death from skin cancer, and, apart from female lung cancer, it is the tumor entity with the highest increase in incidence worldwide [1]
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
Summary
Cutaneous malignant melanoma (MM), represents the most common cause of death from skin cancer, and, apart from female lung cancer, it is the tumor entity with the highest increase in incidence worldwide [1]. According to the AJCC 2009 classification [3], the findings of vertical tumor thickness [4], tumor ulceration [5], and sentinel node biopsy [6] represent the most dominant prognostic factors. In stage pT1 melanomas (#1.00 thickness), the mitotic rate (histologically defined as mitoses/mm2) has to be considered as additional prognostic parameter [3]. 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). Predictive molecular marker profiles for risk stratification and therapy optimization are not yet available for routine clinical assessment
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