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


RESULTS
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.
Department of Dermatology, University Hospital of Regensburg, Regensburg, Germany.
Stefanie
S
Meyer
Thomas J
TJ
Fuchs
Anja K
AK
Bosserhoff
Ferdinand
F
Hofstädter
Armin
A
Pauer
Volker
V
Roth
Joachim M
JM
Buhmann
Ingrid
I
Moll
Nikos
N
Anagnostou
Johanna M
JM
Brandner
Kristian
K
Ikenberg
Holger
H
Moch
Michael
M
Landthaler
Thomas
T
Vogt
Peter J
PJ
Wild
D000328:Adult; D000368:Aged; D018951:Antigens, CD20 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D046888:Tissue Array Analysis / Q000379:methods*; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D018951:Antigens, CD20; D014408:Biomarkers, Tumor; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D051059:PTEN Phosphohydrolase