Jennifer Erdrich1, Kristel Lourdault2, Alex Judd3, David Kaufman4, Ke Wei Gong5, Melanie Gainsbury6, Nan Deng4, Wonwoo Shon4, Richard Essner2. 1. University of Arizona, Tucson, Arizona. 2. Saint John's Cancer Institute, Santa Monica, California. 3. University of Arizona, Tucson, Arizona. Electronic address: alexjudd@email.arizona.edu. 4. Cedars Sinai Medical Center, Los Angeles, California. 5. David Geffen School of Medicine at UCLA, Los Angeles, California. 6. Kaiser Permanente, Santa Clara, California.
Abstract
INTRODUCTION: Histologic characteristics cannot adequately predict which patients are at risk of developing metastatic disease after excision of primary cutaneous melanoma. The aim of this study was to identify immunomodulatory genes in primary tumors associated with development of distant metastases. MATERIALS AND METHODS: Thirty-seven patients with primary melanoma underwent surgical excision. RNA was extracted from the primary tumor specimens. cDNA was synthesized and used with Human Gene Expression microarray. Differential expression of 74 immunomodulatory genes was compared between patients who developed distant metastases and those who did not. RESULTS: Six of 37 patients developed distant metastases during the time of the study. Differential expression of microarray data showed upregulation of four immunomodulatory genes in this group. These four genes-c-CBL, CD276, CXCL1, and CXCL2-were all significantly overexpressed in the metastatic group with differential expression fold change of 1.15 (P = 0.01), 1.16 (P = 0.04), 2.51 (P < 0.001), and 1.68 (P < 0.02), respectively. CXCL1 had particularly high predictive value with an area under the curve of 0.80. Multivariate analysis showed only expression of CXCL1 (P = 0.01) remains predictive of distant metastases in melanoma patients. This result was confirmed using quantitative real-time polymerase chain reaction. CONCLUSIONS: CXCL1, CXCL2, c-CBL, and CD276 are immunomodulatory genes present in primary melanoma that are strongly associated with development of metastatic disease. Identification of their presence, particularly CXCL1, in the primary tumor could be used as a predictor of future risk of metastatic disease and thereby to identify patients who might benefit early from immunotherapy.
INTRODUCTION: Histologic characteristics cannot adequately predict which patients are at risk of developing metastatic disease after excision of primary cutaneous melanoma. The aim of this study was to identify immunomodulatory genes in primary tumors associated with development of distant metastases. MATERIALS AND METHODS: Thirty-seven patients with primary melanoma underwent surgical excision. RNA was extracted from the primary tumor specimens. cDNA was synthesized and used with Human Gene Expression microarray. Differential expression of 74 immunomodulatory genes was compared between patients who developed distant metastases and those who did not. RESULTS: Six of 37 patients developed distant metastases during the time of the study. Differential expression of microarray data showed upregulation of four immunomodulatory genes in this group. These four genes-c-CBL, CD276, CXCL1, and CXCL2-were all significantly overexpressed in the metastatic group with differential expression fold change of 1.15 (P = 0.01), 1.16 (P = 0.04), 2.51 (P < 0.001), and 1.68 (P < 0.02), respectively. CXCL1 had particularly high predictive value with an area under the curve of 0.80. Multivariate analysis showed only expression of CXCL1 (P = 0.01) remains predictive of distant metastases in melanoma patients. This result was confirmed using quantitative real-time polymerase chain reaction. CONCLUSIONS: CXCL1, CXCL2, c-CBL, and CD276 are immunomodulatory genes present in primary melanoma that are strongly associated with development of metastatic disease. Identification of their presence, particularly CXCL1, in the primary tumor could be used as a predictor of future risk of metastatic disease and thereby to identify patients who might benefit early from immunotherapy.
Authors: James Larkin; Vanna Chiarion-Sileni; Rene Gonzalez; Jean-Jacques Grob; Piotr Rutkowski; Christopher D Lao; C Lance Cowey; Dirk Schadendorf; John Wagstaff; Reinhard Dummer; Pier F Ferrucci; Michael Smylie; David Hogg; Andrew Hill; Ivan Márquez-Rodas; John Haanen; Massimo Guidoboni; Michele Maio; Patrick Schöffski; Matteo S Carlino; Céleste Lebbé; Grant McArthur; Paolo A Ascierto; Gregory A Daniels; Georgina V Long; Lars Bastholt; Jasmine I Rizzo; Agnes Balogh; Andriy Moshyk; F Stephen Hodi; Jedd D Wolchok Journal: N Engl J Med Date: 2019-09-28 Impact factor: 91.245
Authors: Deryk Loo; Ralph F Alderson; Francine Z Chen; Ling Huang; Wenjun Zhang; Sergey Gorlatov; Steve Burke; Valentina Ciccarone; Hua Li; Yinhua Yang; Tom Son; Yan Chen; Ann N Easton; Jonathan C Li; Jill R Rillema; Monica Licea; Claudia Fieger; Tony W Liang; Jennie P Mather; Scott Koenig; Stanford J Stewart; Syd Johnson; Ezio Bonvini; Paul A Moore Journal: Clin Cancer Res Date: 2012-05-21 Impact factor: 12.531
Authors: J Luan; R Shattuck-Brandt; H Haghnegahdar; J D Owen; R Strieter; M Burdick; C Nirodi; D Beauchamp; K N Johnson; A Richmond Journal: J Leukoc Biol Date: 1997-11 Impact factor: 4.962
Authors: Magdalena Paolino; Axel Choidas; Stephanie Wallner; Blanka Pranjic; Iris Uribesalgo; Stefanie Loeser; Amanda M Jamieson; Wallace Y Langdon; Fumiyo Ikeda; Juan Pablo Fededa; Shane J Cronin; Roberto Nitsch; Carsten Schultz-Fademrecht; Jan Eickhoff; Sascha Menninger; Anke Unger; Robert Torka; Thomas Gruber; Reinhard Hinterleitner; Gottfried Baier; Dominik Wolf; Axel Ullrich; Bert M Klebl; Josef M Penninger Journal: Nature Date: 2014-02-19 Impact factor: 49.962