Genetic and genomic characterization of uveal melanoma (UM).

Choroidal UM is the most common form of intraocular primary malignancies in adults but is a rare tumor with an incidence rate of 5.6 cases per million person-years (~500 new cases a year in France). Prognosis is dismal when the disease spreads, frequently to the liver. A better understanding of the disease is an urgent need, considering the rapidly unfavorable evolution and lack of effective chemotherapy in its metastatic form (1).

• In collaboration with R. Marais (Cancer Research UK), we have shown the low mutational burden and lack of ultra-violet radiation signature in UM, in contrast to cutaneous melanoma (2). We also described recurrent mutations of the splicing gene SF3B1 (2).
• We then deciphered the consequences of SF3B1 mutations on splicing (11-13). More recently, a pan-cancer analysis using cloud computing (in collaboration with Seven Bridges, USA) allowed us to identify SUGP1 mutations as a genocopy of SF3B1 (3). Oncogenic consequences of these mutations are actively searched for in collaboration with the translational research group led by S. Alsafadi.
• We hypothesized splicing abnormalities as a possible source of neoantigens, hypothesis that we validated in collaboration with O. Lantz’s team, Inserm U932 (4). Patent : 20305477.This opens the possibility of immunotherapeutic intervention, including vaccination, in this disease.
• UM has an unusual epidemiology, as the disease occurs mostly in individuals of European ancestry. In the hypothesis of predisposing alleles in this population, we initiated the first pan-genomic association study (GWAS) for uveal melanoma. We identified risk variants in the TERT/CLPTM1L region (5). This study is currently being expanded to search for new risk loci (collaboration with CeRePP, CNG, IARC and CLB; Mobuchon et al., submitted).
• We participated in the TCGA project to describe primary UM at the –omics level (6) and we are key players in the Horizon2020 project aiming to better understand and target metastatic UM (7). We analyzed the mechanisms of metastatic progression and resistance to chemotherapy of these metastases and showed that mutational heterogeneity is very limited and does not explain the therapeutic resistance, whereas metastatic progression is mainly associated with the acquisition of recurrent genomic gains and losses (8). We actively collaborate with M.-L. Yaspo’s team (Max Planck Institute, Berlin) on the epigenetic characterization of UM (Risch et al., submitted).
• Exploring a UM metastatic patient with an outlier response to immune checkpoint inhibitors, we discovered the role of MBD4 inactivation in a new genetic instability (9). We further explored UM progression in MBD4 deficient tumors, showed the continuous acquisition of mutations in the course of the disease, and used this biological clock to reconstruct the natural history of the disease (8). We recently demonstrated the predisposing role of germline MBD4 mutations in uveal melanoma (10). We are presently coordinating the INCa PRT-K19 TREAT-MBD4 project for better defining the spectrum of this novel cancer predisposition syndrome, to develop diagnostic tools and to take advantage of MBD4 deficiency for targeted therapies.

1.    Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers 2020;6(1):24.

2.    Furney SJ, Pedersen M, Gentien D, et al. SF3B1 mutations are associated with alternative splicing in uveal melanoma. Cancer Discov 2013;3(10):1122-1129.

3.    Alsafadi S, Dayot S, Tarin M, et al. Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers. Oncogene 2021;40(1):85-96.

4.    Bigot J, Lalanne AI, Lucibello F, et al. Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes. Cancer Discov 2021; 10.1158/2159-8290.CD-20-0555.

5.    Mobuchon L, Battistella A, Bardel C, et al. A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus. NPJ Genom Med 2017;2(1):5.

6.    Robertson AG, Shih J, Yau C, et al. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell 2017;32(2):204-220 e15.

7.    Rodrigues M, Koning L, Coupland SE, et al. So Close, yet so Far: Discrepancies between Uveal and Other Melanomas. A Position Paper from UM Cure 2020. Cancers (Basel) 2019;11(7):1032.

8.    Rodrigues M, Mobuchon L, Houy A, et al. Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations. Clin Cancer Res 2019;25(18):5513-5524.

9.    Rodrigues M, Mobuchon L, Houy A, et al. Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nat Commun 2018;9(1):1866.

10.  Derrien AC, Rodrigues M, Eeckhoutte A, et al. Germline MBD4 Mutations and Predisposition to Uveal Melanoma. J Natl Cancer Inst 2021;113(1):80-87.

11.  Gentien D, Kosmider O, Nguyen-Khac F, et al. A common alternative splicing signature is associated with SF3B1 mutations in malignancies from different cell lineages. Leukemia 2014;28(6):1355-7.

12.  Alsafadi S, Houy A, Battistella A, et al. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nat Commun 2016;7:10615.

13.  Canbezdi C, Tarin M, Houy A, et al. Functional and conformational impact of cancer-associated SF3B1 mutations depends on the position and the charge of amino acid substitution. Comput Struct Biotechnol J 2021;19:1361-1370.