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A 3D Organotypic Melanoma Spheroid Skin Model

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Melanoma prognostic model using tissue microarrays and genetic algorithms.

Bonnie E Gould Rothberg¹, Aaron J Berger, Annette M Molinaro

¹Department of Pathology, Yale University School of Medicine, New Haven, CT 06520-8023, USA.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology

|November 4, 2009

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A new molecular assay identifies stage II melanoma patients at high risk for recurrence. This prognostic tool uses five protein markers to improve patient selection for adjuvant therapy, potentially improving survival outcomes.

Area of Science:

Oncology
Molecular Biology
Biomarker Discovery

Background:

Stage II melanoma management relies on observation due to limitations in predicting metastatic disease.
Current clinicopathologic parameters fail to accurately identify 20%-60% of stage II melanoma patients at risk for recurrence.
Adjuvant therapies for stage II melanoma have a questionable risk-to-benefit ratio, necessitating better patient stratification.

Purpose of the Study:

To develop and validate a multimarker molecular prognostic assay for stage II melanoma.
To identify patients at increased risk of recurrence who may benefit from adjuvant therapy.
To improve the selection of stage II melanoma patients for adjuvant treatment based on molecular profiling.

Main Methods:

Protein expression of 38 melanoma oncogenesis candidates was assessed using automated quantitative analysis (AQUA) on formalin-fixed, paraffin-embedded primary melanomas.

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A genetic algorithm was employed to build a prognostic assay using immunofluorescence-based immunohistochemistry data from 192 melanomas (1959-1994).

The assay was validated on an independent cohort of 246 primary melanomas (1997-2004).

Main Results:

A consistent five-marker molecular signature was identified using a genetic algorithm.
The assay incorporates ATF2, p21(WAF1), p16(INK4A), beta-catenin, and fibronectin expression levels and localization.
High-risk patients (meeting ≤3 of 5 criteria) exhibited significantly reduced survival (HR=2.84, P=.002 discovery; HR=2.72, P=.027 validation), independent of clinicopathologic factors.

Conclusions:

The developed multimarker prognostic assay is an independent determinant of melanoma survival.
This assay can aid in identifying stage II melanoma patients who are at increased risk of recurrence.
Improved patient selection for adjuvant therapy may be achieved, potentially enhancing treatment efficacy and outcomes.