TY - JOUR
T1 - PRAME as an independent biomarker for metastasis in uveal melanoma
AU - Field, Matthew G.
AU - Decatur, Christina L.
AU - Kurtenbach, Stefan
AU - Gezgin, Gülçin
AU - Van Der Velden, Pieter A.
AU - Jager, Martine J.
AU - Kozak, Kaleigh N.
AU - Harbour, J. William
N1 - Funding Information:
Grant Support This work was supported by grants to J.W.H. from the National Cancer Institute (R01 CA125970 and CA161870), Research to Prevent Blindness, Inc. Senior Scientific Investigator Award, and Melanoma Research Alliance, to J.W.H. andM.G.F. from theMelanoma Research Foundation, toM.G.F. from the Sheila and David Fuente Graduate Program in Cancer Biology, Sylvester Comprehensive Cancer Center, to S.K. by the 2015 AACR-Ocular Melanoma Foundation Fellowship, in honor of Robert C. Allen, MD, Grant Number 15-40-39-KURT, and to the Bascom Palmer Eye Institute from NIH Core Grant P30EY014801, Research to Prevent Blindness Unrestricted Grant, and Department of Defense Grant #W81XWH-09-1-0675. The funding organizations had no role in the design or conduct of this research.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Purpose: Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1. Nevertheless, a small percentage of Class 1 tumors give rise to metastatic disease. The purpose of this study was to identify biomarkers of metastasis in Class 1 tumors. Experimental Design: A total of 389 consecutive patients with UM were assigned to Class 1 or Class 2 using a prospectively validated 12-gene prognostic classifier. Selected tumorswere further analyzed using global GEP and single nucleotide polymorphism microarrays. PRAME (preferentially expressed antigen in melanoma) mRNA expression was analyzed in 64 Class 1 tumors by qPCR. Results: Among Class 1 UMs, the most significant predictor of metastasis was PRAME mRNA expression (P = 0.0006). The 5-year actuarial rate of metastasis was0%for Class1PRAME-, 38% for Class1PRAME+, and 71% for Class 2 tumors. Median metastasisfree survival for Class1PRAME+ patients was 88 months, compared to 32 months for Class 2 patients. Findings were validated using three independent datasets, including one using disomy 3 to identify low-risk UM. Chromosome copy number changes associated with Class1PRAME+ tumors included gain of 1q, 6p, 8q, and 9q and loss of 6q and 11q. PRAME expression was associated with larger tumor diameter (P = 0.05) and SF3B1 mutations (P = 0.003). Conclusions: PRAME is an independent prognostic biomarker in UM, which identifies increased metastatic risk in patients with Class 1 or disomy 3 tumors. This finding may further enhance the accuracy of prognostic testing and precision medicine for UM. Clin Cancer Res; 22(5); 1234-42.
AB - Purpose: Uveal melanoma (UM) can be classified by gene expression profiling (GEP) into Class 1 (low metastatic risk) and Class 2 (high metastatic risk), the latter being strongly associated with mutational inactivation of the tumor suppressor BAP1. Nevertheless, a small percentage of Class 1 tumors give rise to metastatic disease. The purpose of this study was to identify biomarkers of metastasis in Class 1 tumors. Experimental Design: A total of 389 consecutive patients with UM were assigned to Class 1 or Class 2 using a prospectively validated 12-gene prognostic classifier. Selected tumorswere further analyzed using global GEP and single nucleotide polymorphism microarrays. PRAME (preferentially expressed antigen in melanoma) mRNA expression was analyzed in 64 Class 1 tumors by qPCR. Results: Among Class 1 UMs, the most significant predictor of metastasis was PRAME mRNA expression (P = 0.0006). The 5-year actuarial rate of metastasis was0%for Class1PRAME-, 38% for Class1PRAME+, and 71% for Class 2 tumors. Median metastasisfree survival for Class1PRAME+ patients was 88 months, compared to 32 months for Class 2 patients. Findings were validated using three independent datasets, including one using disomy 3 to identify low-risk UM. Chromosome copy number changes associated with Class1PRAME+ tumors included gain of 1q, 6p, 8q, and 9q and loss of 6q and 11q. PRAME expression was associated with larger tumor diameter (P = 0.05) and SF3B1 mutations (P = 0.003). Conclusions: PRAME is an independent prognostic biomarker in UM, which identifies increased metastatic risk in patients with Class 1 or disomy 3 tumors. This finding may further enhance the accuracy of prognostic testing and precision medicine for UM. Clin Cancer Res; 22(5); 1234-42.
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U2 - 10.1158/1078-0432.CCR-15-2071
DO - 10.1158/1078-0432.CCR-15-2071
M3 - Article
C2 - 26933176
AN - SCOPUS:84962231578
VL - 22
SP - 1234
EP - 1242
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 5
ER -