A Prognostic Test to Predict the Risk of Metastasis in Uveal Melanoma Based on a 15-Gene Expression Profile
Uveal (ocular) melanoma is an aggressive cancer that metastasizes in up to half of patients. Uveal melanoma spreads preferentially to the liver, and the metastatic disease is almost always fatal. There are no effective therapies for advanced metastatic disease, so the most promising strategy for improving survival is to detect metastasis at an earlier stage or to treat high-risk patients in an adjuvant setting. An accurate test for identifying high-risk patients would allow for such personalized management as well as for stratification of high-risk patients into clinical trials of adjuvant therapy.
We developed a gene expression profile (GEP) that distinguishes between primary uveal melanomas that have a low metastatic risk (class 1 tumors) and those with a high metastatic risk (class 2 tumors). We migrated the GEP from a high-density microarray platform to a 15-gene, qPCR-based assay that is now performed in a College of American Pathologists (CAP)-accredited Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory on a routine clinical basis on very small samples obtained by fine needle aspiration and on archival formalin-fixed specimens. We collaborated with several centers to show that our specimen collection protocol was easily learned and performed and that it allowed samples to be safely and reliably transported from distant locations with a very low failure rate. Finally, we showed in a multicenter, prospective study that our GEP assay is highly accurate for predicting which patients will develop metastatic disease, and it was significantly superior to the previous gold standard, chromosome 3 testing for monosomy 3. This is the only prognostic test in uveal melanoma ever to undergo such extensive validation, and it is currently being used in a commercial format under the trade name DecisionDx-UM in over 100 centers in the USA and Canada.
Key wordsUveal melanoma Metastasis Prognosis Gene expression profiling Support vector machine Machine learning algorithm
- 5.Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, Hawkins BS, Hayman JA, Jaiyesimi I, Jampol LM, Kirkwood JM, Koh WJ, Robertson DM, Shaw JM, Straatsma BR, Thoma J (2005) Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol 123:1639–1643CrossRefPubMedGoogle Scholar
- 9.Folberg R, Pe’er J, Gruman LM, Woolson RF, Jeng G, Montague PR, Moninger TO, Yi H, Moore KC (1992) The morphologic characteristics of tumor blood vessels as a marker of tumor progression in primary human uveal melanoma: a matched case-control study. Hum Pathol 23:1298–1305CrossRefPubMedGoogle Scholar
- 29.Naus NC, van Drunen E, de Klein A, Luyten GP, Paridaens DA, Alers JC, Ksander BR, Beverloo HB, Slater RM (2001) Characterization of complex chromosomal abnormalities in uveal melanoma by fluorescence in situ hybridization, spectral karyotyping, and comparative genomic hybridization. Genes Chromosomes Cancer 30:267–273CrossRefPubMedGoogle Scholar
- 36.Tschentscher F, Husing J, Holter T, Kruse E, Dresen IG, Jockel KH, Anastassiou G, Schilling H, Bornfeld N, Horsthemke B, Lohmann DR, Zeschnigk M (2003) Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Cancer Res 63:2578–2584PubMedGoogle Scholar
- 38.Petrausch U, Martus P, Tonnies H, Bechrakis NE, Lenze D, Wansel S, Hummel M, Bornfeld N, Thiel E, Foerster MH, Keilholz U (2007) Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases. Eye 22:997–1007CrossRefPubMedGoogle Scholar
- 41.Onken M, Worley L, Char D, Augsburger J, Correa Z, Nudleman E, Aaberg TM Jr, Altaweel M, Bardenstein D, Finger P, Gallie B, Harocopos G, Hovland P, McGowan H, Milman T, Mruthyunjaya P, Simpson E, Smith M, Wilson D, Wirostko W, Harbour J (2012) Collaborative Ocular Oncology Group Report No. 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 119(8):1596–1603. doi: 10.1016/j.ophtha.2012.02.017 CrossRefPubMedGoogle Scholar
- 47.Bott M, Brevet M, Taylor BS, Shimizu S, Ito T, Wang L, Creaney J, Lake RA, Zakowski MF, Reva B, Sander C, Delsite R, Powell S, Zhou Q, Shen R, Olshen A, Rusch V, Ladanyi M (2011) The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat Genet 43:668–672CrossRefPubMedGoogle Scholar
- 48.Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M (2011) Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet 43:1022–1025CrossRefPubMedGoogle Scholar
- 49.Wiesner T, Obenauf AC, Murali R, Fried I, Griewank KG, Ulz P, Windpassinger C, Wackernagel W, Loy S, Wolf I, Viale A, Lash AE, Pirun M, Socci ND, Rutten A, Palmedo G, Abramson D, Offit K, Ott A, Becker JC, Cerroni L, Kutzner H, Bastian BC, Speicher MR (2011) Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet 43:1018–1021CrossRefPubMedGoogle Scholar
- 50.Njauw CN, Kim I, Piris A, Gabree M, Taylor M, Lane AM, Deangelis MM, Gragoudas E, Duncan LM, Tsao H (2012) Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS One 7(4):e35295. doi: 10.1371/journal.pone.0035295 CrossRefPubMedGoogle Scholar
- 51.Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, Leng N, Pavia-Jimenez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SW, Grishin N, Laurent M, Xie XJ, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J (2012) BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44(7):751–759. doi: 10.1038/ng.2323 CrossRefPubMedGoogle Scholar
- 53.Yoshikawa Y, Sato A, Tsujimura T, Emi M, Morinaga T, Fukuoka K, Yamada S, Murakami A, Kondo N, Matsumoto S, Okumura Y, Tanaka F, Hasegawa S, Nakano T, Hashimoto-Tamaoki T (2012) Frequent inactivation of the BAP1 gene in epithelioid-type malignant mesothelioma. Cancer Sci 103:868–874CrossRefPubMedGoogle Scholar