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 identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival. CONCLUSION: Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
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 identification of tumor-infiltrating lymphocytes was not a significant independent predictor of survival. CONCLUSION: Intratumoral CD8+ lymphocyte infiltration can be readily assessed on paraffin-embedded tissue, is independently associated with improved MCC-specific survival, and therefore, may provide prognostic information that enhances established MCC staging protocols.
Authors: M Ashburner; C A Ball; J A Blake; D Botstein; H Butler; J M Cherry; A P Davis; K Dolinski; S S Dwight; J T Eppig; M A Harris; D P Hill; L Issel-Tarver; A Kasarskis; S Lewis; J C Matese; J E Richardson; M Ringwald; G M Rubin; G Sherlock Journal: Nat Genet Date: 2000-05 Impact factor: 38.330
Authors: Bianca D Lemos; Barry E Storer; Jayasri G Iyer; Jerri Linn Phillips; Christopher K Bichakjian; L Christine Fang; Timothy M Johnson; Nanette J Liegeois-Kwon; Clark C Otley; Kelly G Paulson; Merrick I Ross; Siegrid S Yu; Nathalie C Zeitouni; David R Byrd; Vernon K Sondak; Jeffrey E Gershenwald; Arthur J Sober; Paul Nghiem Journal: J Am Acad Dermatol Date: 2010-06-19 Impact factor: 11.527
Authors: Roland Houben; Masahiro Shuda; Rita Weinkam; David Schrama; Huichen Feng; Yuan Chang; Patrick S Moore; Jürgen C Becker Journal: J Virol Date: 2010-05-05 Impact factor: 5.103
Authors: C M Balch; A C Buzaid; S J Soong; M B Atkins; N Cascinelli; D G Coit; I D Fleming; J E Gershenwald; A Houghton; J M Kirkwood; K M McMasters; M F Mihm; D L Morton; D S Reintgen; M I Ross; A Sober; J A Thompson; J F Thompson Journal: J Clin Oncol Date: 2001-08-15 Impact factor: 44.544
Authors: Phyu P Aung; Edwin Roger Parra; Souptik Barua; Dawen Sui; Jing Ning; Barbara Mino; Debora Alejandra Ledesma; Jonathan L Curry; Priyadharsini Nagarajan; Carlos A Torres-Cabala; Eleni Efstathiou; Anh G Hoang; Michael K Wong; Jennifer A Wargo; Alexander J Lazar; Arvind Rao; Victor G Prieto; Ignacio Wistuba; Michael T Tetzlaff Journal: Clin Cancer Res Date: 2019-02-26 Impact factor: 12.531
Authors: Rikke Lyngaa; Natasja Wulff Pedersen; David Schrama; Charlotte Albæk Thrue; Dafina Ibrani; Ozcan Met; Per Thor Straten; Paul Nghiem; Jürgen C Becker; Sine Reker Hadrup Journal: Clin Cancer Res Date: 2014-02-13 Impact factor: 12.531
Authors: Aude G Chapuis; Olga K Afanasiev; Jayasri G Iyer; Kelly G Paulson; Upendra Parvathaneni; Joo Ha Hwang; Ivy Lai; Ilana M Roberts; Heather L Sloan; Shailender Bhatia; Kendall C Shibuya; Ted Gooley; Cindy Desmarais; David M Koelle; Cassian Yee; Paul Nghiem Journal: Cancer Immunol Res Date: 2014-01 Impact factor: 11.151