Prognostic parameters in uveal melanoma and their association with BAP1 expression

Abstract

Aim To determine whether BAP1 gene and protein expression associates with different prognostic parameters in uveal melanoma and whether BAP1 expression correctly identifies patients as being at risk for metastases, following enucleation of the primary tumour. Methods Thirty cases of uveal melanoma obtained by enucleation between 1999 and 2004 were analysed for a variety of prognostic markers, including histological characteristics, chromosome aberrations obtained by fluorescence in situ hybridisation (FISH) and single nucleotide polymorphism (SNP) analysis and gene expression profiling. These parameters were compared with BAP1 gene expression and BAP1 immunostaining. Results The presence of monosomy of chromosome 3 as identified by the different chromosome 3 tests showed significantly increased HRs (FISH on isolated nuclei cut-off 30%: HR 11.6, p=0.002; SNP analysis: HR 20.3, p=0.004) for death due to metastasis. The gene expression profile class 2, based on the 15-gene expression profile, similarly provided a significantly increased HR for a poor outcome (HR 8.5, p=0.005). Lower BAP1 gene expression and negative BAP1 immunostaining (50% of 28 tumours were immunonegative) were both associated with these markers for prognostication: FISH cut-off 30% monosomy 3 (BAP1 gene expression: p=0.037; BAP1 immunostaining: p=0.001), SNP-monosomy 3 (BAP1 gene expression: p=0.008; BAP1 immunostaining: p=0.002) and class 2 profile (BAP1 gene expression: p<0.001; BAP1 immunostaining: p=0.001) and were themselves associated with an increased risk of death due to metastasis (BAP1 gene expression dichotomised: HR 8.7, p=0.006; BAP1 immunostaining: HR 4.0, p=0.010). Conclusions Loss of BAP1 expression associated well with all of the methods currently used for prognostication and was itself predictive of death due to metastasis in uveal melanoma after enucleation, thereby emphasising the importance of further research on the role of BAP1 in uveal melanoma.

Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Mucosal Melanomas

“…A flat or nodular black gray mucosal lesion is most often identified on the palate or gingiva [8,9,17,18]. Lesions are often detected by the patient or on oral [2,3] Cutaneous [4,5] Ocular (uveal) [6] examination during a dental procedure and require differentiation from amalgam tattoos: metal "pigment" from prior dental work accumulating in macrophages. Up to 1/3 of lesions may show ulceration.…”

Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma

“…More recently, mutations occurring in UM have been identified in several genes, including GNAQ , GNA11 , BAP1 , SF3B1 , EIF1AX , PLCB4 , and CYSLTR2 11, 18, 19, 20, 21, 22. In particular, inactivating BAP1 mutations are associated with a poor outcome, being present in ∼84% of all UMs that went on to produce metastases 19, 23, 24. BAP1 mutations similarly correspond with a significantly worse prognosis in renal clear cell carcinoma 25 and cholangiocarcinoma 26, whilst in mesothelioma BAP1 inactivation is associated with a good prognosis 27.…”

BAP1 Immunostaining in Uveal Melanoma: Potentials and Pitfalls

“…Several studies have shown promising results, in particular an excellent correlation of BAP1 immunostaining with genetic analysis (although in some cases discrepancies were observed) [1,3,4], as well as the identification of a subgroup of "atypical" poor-prognosis disomy 3 patients [2]. Thus, BAP1 immunohistochemical screening was suggested as the routine staining for UM molecular work-up [2,3].…”

“…Recently, its prognostic role in uveal melanoma (UM) has been further elucidated by several independent groups showing that somatic BAP1 mutations are associated with a higher risk for metastasis [1][2][3][4][5]. While genetic testing is expensive and time-consuming, immunohistochemical staining can be easily performed on formalin-fixed paraffin-embedded tissue, and was therefore proposed as a good alternative [3].…”

“…cells, inflammatory cells, or intratumoral vessels can be used [1,4]. In the absence of such an internal positive control, it is difficult to assess the reliability of BAP1 nuclear expression in a tumor.…”