Characterization of somatic mutations in sporadic uveal melanoma and uveal melanoma in patients with germline BAP1 pathogenic variants

Abstract

Genetic analyses were conducted on tumor samples from 88 patients with uveal melanoma (UM), 6 of whom carry pathogenic germline variants in BAP1. We assessed the frequency, pattern, and prognostic significance of somatic aberrations, and investigated differences between germline BAP1 variant carriers compared to sporadic cases. The frequency of the main oncogenic driver mutations was not significantly different between these groups. Patients with germline BAP1 variants did not have significantly different overall survival compared to the wildtype or somatic BAP1 mutation groups. Patients with a somatic BAP1 mutation (n = 24) had a significantly worse prognosis compared to wildtype (n = 58). All patients with stage III tumors and a somatic BAP1 mutation (n = 7) developed metastasis, however four of 28 stage I-II tumors without metastasis had somatic BAP1 mutations, with observation time >5 years. The tumor from one germline BAP1 carrier (stage IIIC) with a somatic EIF1AX splice variant, has not developed metastasis within a 22-year observation time.

Introduction

Uveal melanoma (UM) is the most frequent adult primary tumor of the eye, with an incidence of 2–8 per million in Europe [1]. UM has a greater incidence in countries with higher latitude in Europe and North America, and meta-analysis has shown increased risk with light skin color and blue or green eye color [2]. UM occurs in the choroid, ciliary body or iris, and only the latter is potentially exposed to UV-radiation. However, the molecular profiles of UM and cutaneous melanoma (CM) are different, with a distinctive mutation spectrum in UM and no UV-mutation signatures described in choroidal or ciliary body UM [3]. The vast majority of UM have a somatic gain-of-function Gα_q pathway mutation in either GNAQ, GNA11, CYSLTR2 or PLCB4 [4–6]. Additionally, somatic chromosomal aberrations including monosomy 3, 8q gain, and loss of 1p, are frequent and associated with poor prognosis [7, 8]. Recently, extensive somatic mutation profiling has divided UM into 4 classes [3], with the most significant factor associated with adverse prognosis and high metastatic risk being BAP1 mutation/loss [9–13].

Recent advances in treatment of CM have shown enormous improvement in patient outcome [14], however, this success has not been translated to UM [15]. Around 50% of UM metastasize, preferentially to the liver [16] and at present no curable treatment has been identified. On average, patients survive 3.9 months after diagnosis of liver metastasis [17]. A recent retrospective study of UM patients with metastases treated with immune checkpoint inhibitors showed that germline and/or somatic MBD4 mutations are highly predictive of response [18]. Such mutations are rare but illustrates the importance of further molecular subdivision of UM [18, 19].

Here, we assessed the frequency, pattern, and prognostic significance of somatic mutations in a Danish cohort of UM patients, and investigated differences between germline BAP1 variant carriers compared to sporadic cases.

Results

Molecular data were obtained from 80 primary UM tumors and 8 metastases. Clinical data for the 88 patients is presented in S1 Table. Of the 82 patients with sporadic UM, 33 (40%) did not develop metastasis (minimum follow-up time of 5 years, range 5–36 years), while 49 (60%) developed metastasis. Five of the six patients with a germline BAP1 pathogenic variant (PV) developed metastases. None of the patients with a germline BAP1 PV had received presymptomatic testing or surveillance, as their variants were identified following their UM diagnosis. The tumor from the germline BAP1 PV carrier with a stage IIIC UM, and no metastasis (observation time 22 years) had an EIF1AX splice mutation (c.429+1G>A). This tumor has been reported to have loss of the wildtype BAP1 allele [20]. Of the 6 BAP1 germline PV carriers, two tumors carried a less frequently reported GNA11 mutation (R183C), and one tumor the less frequent variant p.Q209H in GNAQ, whereas the others had the frequent GNA11/GNAQ hotspot mutations at codon 209. The frequency of germline or somatic BAP1 mutations is significantly higher in the metastasis group (46%) compared to the non-metastasis group (15%) (p = 0.0005).

Of sporadic UM patients, 24 (29%) carried a BAP1 somatic mutation classified as pathogenic or likely pathogenic. One patient carried the BAP1 variant c.2057-4G>T previously reported likely benign [21–23], resulting in this patient being categorized in the wild-type BAP1 group. In sporadic UM patients with tumors that had somatic BAP1 pathogenic mutations, age at diagnosis (average 60 years), was not significantly older compared to the total cohort (average 57 years) or to patients with wild-type BAP1 (average 56 years), but significantly older than cases with SF3B1 mutations (average 52 years) (p = 0.03) (Fig 1).

[Figure omitted. See PDF.]

Individuals with somatic BAP1 mutation were significantly older at diagnosis than individuals with SF3B1 mutation (p = 0.03).

Sporadic UM patients with a BAP1-mutant tumor, had significantly worse overall survival (OS) (p = 0.005, Cox log-rank test) compared to those with wildtype BAP1 (Fig 2). Patients with germline BAP1 PVs (n = 6) did not have significantly different OS compared to the wildtype BAP1 (p = 0.09) or the somatic BAP1 mutation group (p = 0.99) (Fig 2). No significant differences in OS were seen in relation to GNAQ, GNA11 or SF3B1 mutations (p = 0.1, p = 0.9, p = 0.9, respectively).

[Figure omitted. See PDF.]

X-axis represents years after UM diagnosis, Y-axis represents the survival fraction. P-values were derived from Cox log-rank test (p = 0.008) and Cox regression between the three groups, showing significantly worse OS of somatic BAP1 mutation carriers than wildtype BAP1 carriers (p = 0.005).

Sporadic UM patients who developed metastasis (n = 47) were significantly older at time of diagnosis if their tumors had a somatic BAP1 mutation (n = 20, average 61 years) compared to wildtype BAP1 (n = 27, average 53 years) (p = 0.04) and shorter time to death from diagnosis, which was on average 4.1 years in the BAP1 somatic mutation group, compared to 6.4 years in tumors with no somatic BAP1 mutation (p = 0.02) (Fig 3). This result was despite quite comparable AJCC clinical staging of the tumors, with a median stage of IIIA in the BAP1 wildtype group, and IIB in the BAP1 somatic mutation group (data not available for 9 patients: 5 in the BAP1 somatic mutation group and 4 in non-BAP1 somatic mutation group). No mutations in BAP1 were found in stage III tumors with no metastasis, whereas 4 of 28 stage I-II tumors without metastasis had BAP1 mutations. These patients have been observed for 5 †, 7 †, 10, and 16 years.

[Figure omitted. See PDF.]

Patients with somatic BAP1 mutation had significantly older age at diagnosis (p = 0.04) (A) and shorter time to death from UM diagnosis (p = 0.02); (B) despite comparable AJCC clinical stage in the two groups.

Fig 4 shows mutations in tumors from each of the 88 patients, clustered by those with or without metastasis. Somatic mutations in the Gα_q signaling pathway genes (i.e. GNAQ, GNA11, PLCB4, CYSLTR2), as well as SF3B1 and EIF1AX, were mutually exclusive. The frequency of GNA11 and GNAQ mutations was not significantly different between tumors with and without BAP1 mutation (p = 0.14, chi² test) or between tumors with germline or somatic BAP1 mutations (p = 0.08, chi² test).

[Figure omitted. See PDF.]

Individual genes are represented as rows. Individual patients are represented as columns. The mutation type is shown by the color. One patient with family history of UM is marked by “X”.

Rare variants and mutations identified in the study that are not normally seen in UM include a germline RB1 VUS (variant of uncertain significance) (p.A488T), a KIT p.V422M VUS, previously described germline, in this dataset unknown if germline or somatic, a NRAS p.E63V VUS, not previously reported germline and unknown somatic or germline in this dataset. Further, a tumor with a CDKN2A mutation c.233_234delTC, also harbored a truncating BAP1 and a GNA11 driver mutation. These rare variants were each identified in one patient (S1 Table).

Discussion

In this study we assessed the frequency, pattern, and prognostic significance of somatic aberrations in 82 sporadic UM and 6 UM from germline pathogenic BAP1 variant carriers. EIF1AX is mutated in approximately 20% of UM [24] and such UM have been shown to rarely metastasize and have better prognosis compared to UM without EIF1AX mutation [13, 24]. One germline BAP1 pathogenic variant carrier has not developed metastasis after 22 years of observation and we speculate this is because the tumor had a somatic splice mutation in EIF1AX. To our knowledge, no other studies have evaluated somatic EIF1AX mutations in germline BAP1 PV carriers. In the other five germline BAP1 variant carriers we found only GNAQ and GNA11 somatic mutations.

As expected from previous studies [25, 26], we found a significantly worse prognosis associated with somatic BAP1 mutations compared to wildtype (Fig 2). The Kaplan-Meier curve as well suggests worse OS of germline BAP1 variant carriers compared to wildtype but analysis is limited by small sample size (n = 6). A study by Ewens et al., 2018 [25] directly compared the risk of UM metastasis between tumors with germline BAP1 variants, somatic BAP1 mutations and wild type BAP1 tumors. They found tumors with somatic BAP1 mutations metastasized significantly more often compared to both germline and wildtype. Patients with germline BAP1 variants did not show significantly different prognosis than patients with wildtype BAP1 tumors, which however could be due to low numbers, i.e. of the six BAP1 germline variant carriers in this cohort, five died within 0–4 years following UM diagnosis and one was a long-term survivor (22 years). No significant alterations in survival were seen in relation to GNAQ, GNA11 or SF3B1 mutations (p = 0.1, p = 0.9, p = 0.9, respectively), in keeping with previous findings [9, 10, 13].

We found a significantly older age at diagnosis in patients with tumors that had BAP1 somatic mutations (n = 24) compared to patients with tumors with SF3B1 mutations (n = 17, p = 0.03, Fig 1). It has been reported by Ewens et al. 2018 [25], as well as others [26, 27], that patients with UM somatic BAP1 mutations have a significantly older age at diagnosis compared to wildtype, in agreement with our study, although not significantly different. As pointed out by others [9], performing BAP1 exonic sequencing, will not identify all BAP1 mutations, but unfortunately due to lack of tumor tissue we were not able to perform BAP1 IHC or chromosome copy number analysis on the tumors, which would have made the analysis more complete. We did however find a significantly shorter time to death in patients who developed metastasis and carry a BAP1 somatic mutation compared to patients who developed metastasis without a somatic BAP1 mutation.

Finally, we identified somatic BAP1 mutations in stage I-II tumors from patients who have not developed metastasis, whereas we do not find any BAP1 somatic mutations in stage III-IV tumors with no metastasis, speculatively indicating perhaps the existence of a threshold: i.e., in stage I-II tumors metastasis may develop if a somatic BAP1 mutation is found, but in stage III-IV metastasis is inevitable if somatic BAP1 mutations are present.

Materials and methods

Patient

Tumors from 100 persons with primary uveal melanoma treated with enucleation from 1986 to 2011 were selected and permissions granted from the Ethics committee of the Capital region of Copenhagen. H-15005619. In the retrospective cohort clinical data from participants was obtained from 1 September 2015 to 31 October 2020. During the study period the authors could identify individual participants. The Ethics committee waived the requirement for informed consent.

The UM included those from four known germline BAP1 mutation carriers, 48 samples of metastatic UM and 48 UM with no metastasis and at least 5 years follow-up. Of the 100 samples, molecular genetic results were obtained from 81 samples. During the duration of the project four patients developed metastasis and their group status was changed. In one patient a KRAS p.G12V mutation was found, and pathology reexamination was performed and a uveal metastasis from an undetected cutaneous melanoma could not be excluded, thus the patient was omitted from the dataset. In total, molecular data were obtained from primary tumors of four UM cases with germline BAP1 mutation, 41 samples of UM (metastasized) and 35 samples of UM with no metastasis.

In addition to the 80 patients, sequencing data from metastases from 8 patients (1 germline BAP1 PV) were included from a clinical pipeline. Materials and methods performed included whole-exome sequencing on germline DNA from blood samples and DNA from matched tumor biopsies, and have been described elsewhere [28] and Regulatory approvals from the Regional Ethics Committee and the Danish Data Protection Agency were obtained (Danish Ethical Committee, file number: 1300530). All patients provided signed informed written consent. Information on AJCC clinical staging of the tumors was not available for these 8 patients.

Clinical data regarding the 88 patients are presented in S1 Table.

Samples

FFPE tissue blocks from 100 UM where cut in 8 μm sections; 5 slides from each tumor unstained on glass and one slide from each tumor stained with H&E using a standard protocol. Under a microscope the samples were dissected and normal tissue separated from tumor tissue.

DNA extraction and sequencing

DNA and RNA were extracted from the tumor and normal tissue using Allprep DNA/RNA FFPE extraction kit (Qiagen, catalog number 80234). DNA was submitted to quality control using FFPE DNA Library Prep QC Kit (Illumina, catalog number FC-121-9999) and only tumor samples with delta CT of 10 or less were selected for sequencing library preparation. Libraries were prepared from tumor DNA using TruSeq custom amplicon low input kit (Illumina) and sequenced on a NextSeq500 (Illumina). The custom gene panel comprised the following genes: GNA11, GNAQ, BAP1, SF3B1, EIF1AX, EGFR, NRAS, ARID2, KIT, FBXW7, NF1, CDK4, CDKN2A, TP53, RAC1, RB1, KRAS, STK11, CTNNB1.

Sanger sequencing of PLCB4 (D630Y) and CYSLTR2 (L129Q), in tumors without a GNA11, GNAQ, or BAP1 variant (n = 8).

Statistical analyses

Continuous variables were compared using the t-test. The overall survival (OS) curves were generated by the Kaplan-Meier method, and OS between groups compared using Cox regression. A p < 0.05 was deemed statistically significant in all calculations. Kaplan-Meier, log-rank test and Cox regression were carried out with the R software version 4.3.

Supporting information

S1 Table. Clinical data and genetic results from the 88 patients.

Germline data shown with color brown.

https://doi.org/10.1371/journal.pone.0306386.s001

(XLSX)

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Citation: Wadt KAW, Harbst K, Sjøl MMB, Rosengren F, Yde CW, Rohrberg KS, et al. (2024) Characterization of somatic mutations in sporadic uveal melanoma and uveal melanoma in patients with germline BAP1 pathogenic variants. PLoS ONE 19(10): e0306386. https://doi.org/10.1371/journal.pone.0306386

About the Authors:

Karin A. W. Wadt

Roles: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing

E-mail: [email protected]

Affiliations: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

ORICD: https://orcid.org/0000-0003-2882-6798

Katja Harbst

Roles: Data curation, Formal analysis, Methodology, Validation, Writing – review & editing

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University Cancer Center, Lund University, Lund, Sweden

Mette M. B. Sjøl

Roles: Data curation, Investigation, Validation

Affiliation: Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Frida Rosengren

Roles: Formal analysis, Writing – review & editing

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University Cancer Center, Lund University, Lund, Sweden

Christina Westmose Yde

Roles: Data curation, Formal analysis, Methodology, Writing – review & editing

Affiliation: Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Kristoffer Staal Rohrberg

Roles: Investigation, Supervision, Writing – review & editing

Affiliations: Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Marlene Richter Jensen

Roles: Formal analysis, Visualization, Writing – review & editing

Affiliation: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Steffen Heegaard

Roles: Data curation, Methodology, Writing – review & editing

Affiliations: Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Pathology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Jens Folke Kiilgaard

Roles: Conceptualization, Supervision, Writing – review & editing

Affiliation: Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark

Anne-Marie Gerdes

Roles: Conceptualization, Supervision, Writing – review & editing

Affiliations: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

Nicholas Hayward

Contributed equally to this work with: Nicholas Hayward, Göran B. Jönsson

Roles: Conceptualization, Investigation, Supervision, Writing – review & editing

Affiliation: QIMR Berghofer Medical Research Institute, Herston, QLD, Australia

Göran B. Jönsson

Contributed equally to this work with: Nicholas Hayward, Göran B. Jönsson

Roles: Conceptualization, Formal analysis, Funding acquisition, Supervision, Writing – review & editing

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University Cancer Center, Lund University, Lund, Sweden

References

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2. Weis E, Shah CP, Lajous M, Shields JA, Shields CL. The Association Between Host Susceptibility Factors and Uveal Melanoma: A Meta-analysis. Arch Ophthalmol. 2006;124:54–60. pmid:16401785

3. Robertson AG, Shih J, Yau C, Gibb EA, Oba J, Mungall KL, et al. Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. Cancer Cell. 2017;32:204–20. pmid:28810145

4. Johansson P, Aoude LG, Wadt K, Glasson WJ, Warrier SK, Hewitt AW, et al. Deep sequencing of uveal melanoma identifies a recurrent mutation in PLCB4. Oncotarget. 2016;7:4624–31. pmid:26683228

5. Moore AR, Ceraudo E, Sher JJ, Guan Y, Shoushtari AN, Chang MT, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet [Internet]. 2016;48(6):675–80. Available from: pmid:27089179

6. Johansson PA, Brooks K, Newell F, Palmer JM, Wilmott JS, Pritchard AL, et al. Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours. Nat Commun [Internet]. 2020;11(1):1–8. Available from: http://dx.doi.org/10.1038/s41467-020-16276-8

7. Horsthemke B, Prescher G, Bornfeld N, Becher R. Loss of chromosome 3 alleles and multiplication of chromosome 8 alleles in uveal melanoma. Genes Chromosom Cancer. 1992;4(3):217–21. pmid:1382562

8. Dogrusöz M, Bagger M, Van Duinen SG, Kroes WG, Ruivenkamp CAL, Böhringer S, et al. The prognostic value of AJCC staging in uveal melanoma is enhanced by adding chromosome 3 and 8q status. Investig Ophthalmol Vis Sci. 2017;58(2):833–42. pmid:28159971

9. Field MG, Durante MA, Anbunathan H, Cai LZ, Decatur CL, Bowcock AM, et al. Punctuated evolution of canonical genomic aberrations in uveal melanoma. Nat Commun [Internet]. 2018;9(116). Available from: pmid:29317634

10. Staby KM, Gravdal K, Mørk SJ, Heegaard S, Vintermyr OK, Krohn J. Prognostic impact of chromosomal aberrations and GNAQ, GNA11 and BAP1 mutations in uveal melanoma. Acta Ophthalmol. 2018;96:31–8. pmid:28444874

11. Silva-Rodríguez P, Fernández-Díaz D, Bande M, Pardo M, Loidi L, Blanco-Teijeiro MJ. GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma. Cancers (Basel). 2022;14(13).

12. Griewank KG, Van De Nes J, Schilling B, Moll I, Sucker A, Kakavand H, et al. Genetic and clinico-pathologic analysis of metastatic uveal melanoma. Mod Pathol [Internet]. 2014;27(2):175–83. Available from: pmid:23887304

13. Martin M, Maßhöfer L, Temming P, Rahmann S, Metz C, Bornfeld N, et al. Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3. Nat Genet. 2013;45(8):933–6. pmid:23793026

14. Pasquali S, Hadjinicolaou A V., Chiarion Sileni V, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev. 2018;2(2). pmid:29405038

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