Prognostic impact of chromosomal aberrations and GNAQ GNAQ , GNA GNA 11 and BAP BAP 1 mutations in uveal melanoma

摘要

Abstract Purpose To evaluate clinico‐pathological and molecular prognostic factors in a well‐defined series of posterior uveal melanoma ( UM ) with focus on chromosomal aberrations and mutations in the GNAQ , GNA 11 and BRCA1‐associated protein 1 (BAP1) genes. Methods Formalin‐fixed paraffin‐embedded (FFPE) tissue samples were obtained from 50 consecutive eyes enucleated for UM between 1993 and 2005. The material was tested for loss of chromosome 3 and gain of chromosome 8q gene signatures by selective molecular gene markers using multiplex ligation‐dependent probe amplification (MLPA), and for DNA mutations in the GNAQ , GNA 11 and BAP 1 genes. Results After a mean follow‐up of 83?months (range, 8–205?months), 21 patients had died of metastatic UM and 16 patients of other causes. Tumour diameter, ciliary body involvement, mixed/epithelioid cell types, mitotic index, Ki‐67 proliferation index, loss of chromosome 3 and gain of chromosome 8q showed statistically significant associations with metastatic disease. There were no significant differences in the prevalence of GNAQ and GNA 11 mutations between patients with or without metastatic disease. Mutational analysis of the BAP 1 gene was performed in 32 primary UM and in five UM liver metastases. Nine different BAP 1 missense mutations were identified. BAP 1 mutations were not more common in metastasizing than in nonmetastasizing UM . Conclusion The molecular gene markers showing loss of chromosome 3 and gain of 8q gene signatures were associated with an increased risk of metastatic disease. BRCA1‐associated protein 1 (BAP1) gene mutation status had no prognostic significance. The frequency and spectrum of BAP 1 mutations in UM may be more dependent on ethnicity and demographic variables than hitherto considered.