title: Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival.
abstract: Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging.
authors.affiliation: Cancer Institute and Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Dusan
authors.initials: D
authors.lastname: Bogunovic
authors.forename: David W
authors.initials: DW
authors.lastname: O'Neill
authors.forename: Ilana
authors.initials: I
authors.lastname: Belitskaya-Levy
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vacic
authors.forename: Yi-Lo
authors.initials: YL
authors.lastname: Yu
authors.forename: Sylvia
authors.initials: S
authors.lastname: Adams
authors.forename: Farbod
authors.initials: F
authors.lastname: Darvishian
authors.forename: Russell
authors.initials: R
authors.lastname: Berman
authors.forename: Richard
authors.initials: R
authors.lastname: Shapiro
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Stefano
authors.initials: S
authors.lastname: Lonardi
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008545:Melanoma / Q000175:diagnosis* / Q000235:genetics* / Q000276:immunology / Q000556:secondary; D008940:Mitotic Index / Q000379:methods; D009367:Neoplasm Staging / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016019:Survival Analysis