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Whole genome methylation profiles as independent markers of survival in stage IIIC melanoma patients.

Sigalotti L, Covre A, Fratta E, Parisi G, Sonego P, Colizzi F, Coral S, Massarut S, Kirkwood JM, Maio M - J Transl Med (2012)

Bottom Line: A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.A discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients.Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy. lsigalotti@cro.it

ABSTRACT

Background: The clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis. This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.

Methods: Genome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients. Unsupervised K-means partitioning clustering was exploited to sort patients into 2 groups based on their methylation profiles. Methylation patterns related to the discovered groups were determined using the nearest shrunken centroid classification algorithm. The impact of genome-wide methylation patterns on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analyses.

Results: Unsupervised K-means partitioning by whole genome methylation profiles identified classes with significantly different OS in stage IIIC CM patients. Patients with a "favorable" methylation profile had increased OS (P = 0.001, log-rank = 10.2) by Kaplan-Meier analysis. Median OS of stage IIIC patients with a "favorable" vs. "unfavorable" methylation profile were 31.5 and 10.4 months, respectively. The 5 year OS for stage IIIC patients with a "favorable" methylation profile was 41.2% as compared to 0% for patients with an "unfavorable" methylation profile. Among the variables examined by multivariate Cox regression analysis, classification defined by methylation profile was the only predictor of OS (Hazard Ratio = 2.41, for "unfavorable" methylation profile; 95% Confidence Interval: 1.02-5.70; P = 0.045). A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.

Conclusions: A discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients. Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.

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Prognostic methylation signatures identified by the “nearest shrunken centroid” algorithm in stage IIIC CM patients. Pre-processed genome-wide methylation data from stage IIIC CM patients under study was analyzed through nearest shrunken centroids algorithm to identify genes best characterizing the k-means defined prognostic methylation groups. Panel a, Shrunken differences for the 17 methylation markers, having at least 1 non-zero difference, selected as signature for LM (blue) and HM (red) groups. Lines to the left indicate relatively reduced levels of methylation; lines to the right indicate relatively increased levels of methylation. Genes defining the signature have been reported as Gene Symbol on the left of the panel. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Panel b, the methylation values of the 17 genes composing the methylation signature in the patients’ population have been reported as a heatmap. Genes defining the signature have been reported as Gene Symbol on the right of the heatmap, while patient identifier numbers and the k-means-defined groups have been reported on foot of the heatmap. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Each color patch represents the methylation level of one gene in each patient, with a continuum of methylation levels from dark blue (completely unmethylated, β = 0) to dark red (completely methylated, β = 1).
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Figure 3: Prognostic methylation signatures identified by the “nearest shrunken centroid” algorithm in stage IIIC CM patients. Pre-processed genome-wide methylation data from stage IIIC CM patients under study was analyzed through nearest shrunken centroids algorithm to identify genes best characterizing the k-means defined prognostic methylation groups. Panel a, Shrunken differences for the 17 methylation markers, having at least 1 non-zero difference, selected as signature for LM (blue) and HM (red) groups. Lines to the left indicate relatively reduced levels of methylation; lines to the right indicate relatively increased levels of methylation. Genes defining the signature have been reported as Gene Symbol on the left of the panel. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Panel b, the methylation values of the 17 genes composing the methylation signature in the patients’ population have been reported as a heatmap. Genes defining the signature have been reported as Gene Symbol on the right of the heatmap, while patient identifier numbers and the k-means-defined groups have been reported on foot of the heatmap. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Each color patch represents the methylation level of one gene in each patient, with a continuum of methylation levels from dark blue (completely unmethylated, β = 0) to dark red (completely methylated, β = 1).

Mentions: To define the methylation signature representing the minimal number of methylation markers characterizing LM and HM patient groups, we applied the “nearest shrunken centroid” algorithm[16] (Figure3). A methylation signature of 17 genes (Figure3, Table4), that allowed to correctly sort stage IIIC patients into groups LM and HM (overall error rate = 0), was identified. A dramatic difference in the methylation status of the genes included in the signature is evident between the good prognosis LM and the bad prognosis HM groups of patients (Figure3).


Whole genome methylation profiles as independent markers of survival in stage IIIC melanoma patients.

Sigalotti L, Covre A, Fratta E, Parisi G, Sonego P, Colizzi F, Coral S, Massarut S, Kirkwood JM, Maio M - J Transl Med (2012)

Prognostic methylation signatures identified by the “nearest shrunken centroid” algorithm in stage IIIC CM patients. Pre-processed genome-wide methylation data from stage IIIC CM patients under study was analyzed through nearest shrunken centroids algorithm to identify genes best characterizing the k-means defined prognostic methylation groups. Panel a, Shrunken differences for the 17 methylation markers, having at least 1 non-zero difference, selected as signature for LM (blue) and HM (red) groups. Lines to the left indicate relatively reduced levels of methylation; lines to the right indicate relatively increased levels of methylation. Genes defining the signature have been reported as Gene Symbol on the left of the panel. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Panel b, the methylation values of the 17 genes composing the methylation signature in the patients’ population have been reported as a heatmap. Genes defining the signature have been reported as Gene Symbol on the right of the heatmap, while patient identifier numbers and the k-means-defined groups have been reported on foot of the heatmap. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Each color patch represents the methylation level of one gene in each patient, with a continuum of methylation levels from dark blue (completely unmethylated, β = 0) to dark red (completely methylated, β = 1).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3539917&req=5

Figure 3: Prognostic methylation signatures identified by the “nearest shrunken centroid” algorithm in stage IIIC CM patients. Pre-processed genome-wide methylation data from stage IIIC CM patients under study was analyzed through nearest shrunken centroids algorithm to identify genes best characterizing the k-means defined prognostic methylation groups. Panel a, Shrunken differences for the 17 methylation markers, having at least 1 non-zero difference, selected as signature for LM (blue) and HM (red) groups. Lines to the left indicate relatively reduced levels of methylation; lines to the right indicate relatively increased levels of methylation. Genes defining the signature have been reported as Gene Symbol on the left of the panel. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Panel b, the methylation values of the 17 genes composing the methylation signature in the patients’ population have been reported as a heatmap. Genes defining the signature have been reported as Gene Symbol on the right of the heatmap, while patient identifier numbers and the k-means-defined groups have been reported on foot of the heatmap. Duplicate Gene Symbol entries refer to methylation data read for the same gene from different probes. Each color patch represents the methylation level of one gene in each patient, with a continuum of methylation levels from dark blue (completely unmethylated, β = 0) to dark red (completely methylated, β = 1).
Mentions: To define the methylation signature representing the minimal number of methylation markers characterizing LM and HM patient groups, we applied the “nearest shrunken centroid” algorithm[16] (Figure3). A methylation signature of 17 genes (Figure3, Table4), that allowed to correctly sort stage IIIC patients into groups LM and HM (overall error rate = 0), was identified. A dramatic difference in the methylation status of the genes included in the signature is evident between the good prognosis LM and the bad prognosis HM groups of patients (Figure3).

Bottom Line: A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.A discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients.Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy. lsigalotti@cro.it

ABSTRACT

Background: The clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis. This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.

Methods: Genome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients. Unsupervised K-means partitioning clustering was exploited to sort patients into 2 groups based on their methylation profiles. Methylation patterns related to the discovered groups were determined using the nearest shrunken centroid classification algorithm. The impact of genome-wide methylation patterns on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analyses.

Results: Unsupervised K-means partitioning by whole genome methylation profiles identified classes with significantly different OS in stage IIIC CM patients. Patients with a "favorable" methylation profile had increased OS (P = 0.001, log-rank = 10.2) by Kaplan-Meier analysis. Median OS of stage IIIC patients with a "favorable" vs. "unfavorable" methylation profile were 31.5 and 10.4 months, respectively. The 5 year OS for stage IIIC patients with a "favorable" methylation profile was 41.2% as compared to 0% for patients with an "unfavorable" methylation profile. Among the variables examined by multivariate Cox regression analysis, classification defined by methylation profile was the only predictor of OS (Hazard Ratio = 2.41, for "unfavorable" methylation profile; 95% Confidence Interval: 1.02-5.70; P = 0.045). A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.

Conclusions: A discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients. Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.

Show MeSH
Related in: MedlinePlus