[Frontiers in Bioscience E4, 2723-2733, June 1, 2012]

An organ system-based approach to prognosis in advanced melanoma

Shernan G. Holtan1, Aaron S. Mansfield1,2, Douglas J. Creedon3, Wendy K. Nevala4, Paul Haluska2, Alexey A. Leontovich5, Svetomir N. Markovic1,2,4

1Department of Medicine, Division of Hematology, Mayo Clinic Graduate School of Medicine, 200 First Street SW, Rochester, MN 55905, USA, 2Department of Oncology, Mayo Clinic Graduate School of Medicine, 200 First Street SW, Rochester, MN 55905, USA, 3Department of Obstetrics and Gynecology, Mayo Clinic Graduate School of Medicine, 200 First Street SW, Rochester, MN 55905, USA, 4Department of Immunology, Mayo Clinic Graduate School of Medicine, 200 First Street SW, Rochester, MN 55905, USA, 5Department of Biomedical Statistics and Informatics, Mayo Clinic Graduate School of Medicine, 200 First Street SW, Rochester, MN 55905, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods 3.1. Ethics statement
3.2. Tumor microarray construction and immunohistochemistry scoring
3.3. Statistical analyses 4. Results 4.1. Survival analyses
4.2. Unsupervised hierarchical clustering of immunohistochemical staining patterns
4.3. Exploratory pathway enrichment
5. Discussion
5.1. CD58
5.2. Galectin-9
5.3. CD44
5.4. TIMP2
6. Conclusion
7. Acknowledgment
8. References

1. ABSTRACT

Previous models to study the biology of melanoma have focused on individual factors, such as proliferative and invasive capacity, the microenvironment, angiogenesis, or systemic immune dysfunction. However, all of these factors contribute to melanoma progression in concert. One physiologic phenomenon that typifies the coordination of these processes is placental development, characterized by trophoblast proliferation, invasion into decidual tissues, angiogenesis, and transient organ system-based immune evasion. Herein, we explore expression of 34 proteins involved in placentation and determine their association with an established prognostic factor, tumor infiltrating lymphocytes (TILs), in a 118-patient tumor microarray (TMA). Melanoma expression of CD58 and galectin-9 independently predicted for a favorable prognosis. Patients could be categorized into three clusters based upon patterns of protein expression and TILs. Patients in Cluster 2 demonstrated frequent TILs and superior overall survival. Pathway enrichment using MetaCore™ from GeneGo, a Thompson Reuters company, showed that TIMP2 and CD44 were expressed more frequently within Cluster 2 patients, suggesting a potential association with TILs. A subset of melanoma patients appear to lack an organized immune response to the tumor, which portends a poor prognosis.