Manuel Rodrigues, MD, PhD; Khadija Ait Rais, BSc; Flore Salviat, MD; Nathalie Algret; Fatoumata Simaga, MSc; Raymond Barnhill, MD; Sophie Gardrat, MD; Vincent Servois, MD; Pascale Mariani, MD; Sophie Piperno-Neumann, MD; Sergio Roman-Roman, PharmD, PhD; Olivier Delattre, MD, PhD; Nathalie Cassoux, MD, PhD; Alexia Savignoni, MD, PhD; Marc-Henri Stern, MD, PhD; Gaëlle Pierron, PhD
Objective To examine the association of partial chromosome 3 deletion in UMs with metastasis-free survival.
Design, Setting, and Participants This retrospective cohort study of 1088 consecutive comparative genomic hybridization arrays performed from May 1, 2006, to July 31, 2015, assessed patients presenting with UMs with and without partial loss of chromosome 3 at a referral center. Data analysis was performed from September 1, 2017, to November 30, 2017.
Exposure Uveal melanoma with or without partial loss of chromosome 3.
Main Outcomes and Measures Metastasis-free survival and overall survival at 60 months.
Results Of the 1088 consecutive comparative genomic hybridization arrays that were performed, 43 UMs (4.0%) in 43 patients (median age, 58 years [range, 12-79 years]; 22 [51%] female) carried partial deletions of chromosome 3. Median follow-up was 66 months (range, 1.2-126.2 months). Metastasis-free survival at 60 months was 33.6% (95% CI, 15.8%-71.4%) for UMs that carried a deletion of the BAP1 (BRCA1 associated protein 1) locus (BAP1del; 24 tumors) and 80.5% (95% CI, 64.8%-100%) for UMs without the loss of the BAP1 locus (BAP1 normal [BAP1nl]; 19 tumors) (log-rank P = .001). Overall survival at 60 months was 64.5% (95% CI, 43.5%-95.8%) in the BAP1del group vs 84.1% (95% CI, 69.0%-100%) in the BAP1nl group (log-rank P < .001). In these 43 cases, metastasis-free survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 70.0% (95% CI, 50.5%-96.9%) for UMs that carried 1 of these alterations, and 12.5% (95% CI, 2.1%-73.7%) for those that carried both (log-rank P < .001). Similarly, overall survival at 60 months was 100% for UMs without loss of the BAP1 locus or 8q gain, 80.8% (95% CI, 63.3%-100%) for UMs that carried 1 of these alterations, and 46.7% (95% CI, 23.3%-93.6%) for those that carried both (log-rank P < .001).
Conclusions and Relevance These findings suggest that partial deletion of chromosome 3 encompassing the BAP1 locus is associated with poor prognosis. A cytogenetic classification of UMs could be proposed based on the status of the BAP1 locus instead of the chromosome 3 locus, while also taking chromosome 8q into account.
Sarah E. Coupland, MBBS, PhD, FRCPath; Sophie Thornton, BSc, PhD; Helen Kalirai, BSc, PhD
Close to 30 years ago, 3 research groups independently described chromosomal abnormalities in primary uveal melanoma, with all 3 highlighting the presence of monosomy 3 in some of the examined cases. All groups proposed that monosomy 3 may play an important role in uveal melanoma progression. This theory was later confirmed by Prescher and colleagues,1 who examined the outcome of 54 patients with primary uveal melanoma, 30 (55%) of whom had monosomy 3 tumors, with 17 of these 30 patients (57%) dying of the disease within 3 years. In the meantime, numerous research groups have confirmed the significance of monosomy 3 loss in primary uveal melanoma. Damato et al2 used cytogenetic testing of consented patients with primary uveal melanoma to stratify these patients into risk groups with respect to metastasis development and to assess liver surveillance management. In the meantime, molecular genetic testing has been incorporated into algorithms that integrate other known strong prognostic factors to refine metastatic risk.3 During the past decade, understanding of the underlying mutations present in primary uveal melanoma and how these may be associated with the described chromosomal alterations has advanced significantly.4 Of particular importance is the gene BAP1 (3p21.31-p21.2) and its temporal and functional association with the loss of 1 copy of chromosome 3.