Genetic landscape of uveal melanoma in Southeast Asia: high 1q gains and unique patterns of metastasis risk

Abstract

<p><strong>Purpose: </strong>This retrospective cohort study aims to investigate chromosomal aberrations in Southeast Asian (SEA) uveal melanoma (UM) patients, evaluate their impact on clinical outcomes, and compare findings with the TCGA-Uveal Melanoma (TCGA-UM) dataset to explore potential genetic differences.</p><p><strong>Methods: </strong>Formalin-fixed paraffin-embedded (FFPE) tumour samples from 20 UM patients diagnosed between 2004 and 2018 were initially analysed using the OncoScan™ CNV Array to detect chromosomal aberrations, with 14 samples yielding valid results for cytogenetic analysis. BAP1 immunohistochemistry was performed on all 20 samples to assess BAP1 protein expression using automated immunostaining techniques validated in the Clinical Pathology Laboratory of the Singapore General Hospital. Clinical data were retrospectively reviewed, and chromosomal aberration frequencies were compared with the TCGA-UM dataset.</p><p><strong>Results: </strong>A total of 78 chromosomal gains, 48 losses, and two cases of copy-neutral loss of heterozygosity (CN-LOH) were identified. Compared to the TCGA-UM cohort, SEA patients exhibited a lower frequency of monosomy 3 (14% vs. 53%) and a higher incidence of chromosome 1q gains (20% vs. 6%). Gains in chromosome 1q were significantly associated (P = 0.0289) with shorter progression-free survival (PFS). In comparison, gains in chromosome 9q were correlated with longer PFS in SEA patients, a trend not observed in the TCGA-UM cohort. BAP1 loss was detected in 20% of cases and was associated with reduced survival rates, consistent with TCGA data.</p><p><strong>Conclusions: </strong>This study highlights significant genetic differences between SEA and Western UM patients, particularly the lower incidence of monosomy 3 in SEA patients. This preliminary observation raises concerns about the reliability of using BAP1 loss alone, assessed through gene expression or immunostaining, as a sole marker for metastasis surveillance and risk stratification in Asian UM patients. These findings underscore the need for further research to determine whether additional genetic markers are required to improve prognostic accuracy in this population. Expanding molecular profiling in SEA would improve risk stratification and inform treatment strategies, while collaborative research with larger cohorts is essential to validate these findings and refine prognostic models globally.</p>