Transcriptome-Wide Studies of Merkel Cell Carcinoma and Validation of Intratumoral CD8+ Lymphocyte Invasion As an Independent Predictor of Survival

作者：Kelly G. Paulson, Jayasri G. Iyer, Andrew Tegeder, Renee Thibodeau, Janell M. Schelter, S Koba, David Schrama, William Simonson, Bianca D. Lemos, David R. Byrd, David M. Koelle, Denise A. Galloway, J. Helen Leonard, Margaret M. Madeleine, Zsolt B. Argényi, Mary L. Disis, Juergen C. Becker, Michele A. Cleary, Paul Nghiem · 发表于：Journal of Clinical Oncology · 年份：2011 · DOI：10.1200/jco.2010.30.6308 · 被引用次数：299 · 研究领域：Polyomavirus and related diseases、Nonmelanoma Skin Cancer Studies、Animal Virus Infections Studies

PURPOSE: Merkel cell carcinoma (MCC) is a polyomavirus-associated skin cancer that is frequently lethal and lacks established prognostic biomarkers. This study sought to identify biomarkers that improve prognostic accuracy and provide insight into MCC biology. PATIENTS AND METHODS: Gene expression profiles of 35 MCC tumors were clustered based on prognosis. The cluster of genes overexpressed in good-prognosis tumors was tested for biologic process enrichment. Relevant mRNA expression differences were confirmed by quantitative polymerase chain reaction and immunohistochemistry. An independent set of 146 nonoverlapping MCC tumors (median follow-up, 25 months among 116 living patients) was employed for biomarker validation. Univariate and multivariate Cox regression analyses were performed. RESULTS: Immune response gene signatures were prominent in patients with good prognoses. In particular, genes associated with cytotoxic CD8+ lymphocytes were overexpressed in tumors from patients with favorable prognoses. In the independent validation set, cases with robust intratumoral CD8+ lymphocyte infiltration had improved outcomes (100% MCC-specific survival, n = 26) compared with instances characterized by sparse infiltration (60% survival, n = 120). Only stage and intratumoral CD8 infiltration (but not age, sex, or CD8+ lymphocytes localized to the tumor-stroma interface) were significant in both univariate and multivariate Cox regression analyses. Notably, traditional histologic iden...