Abstract
Simple SummaryUveal melanoma is the most common primary eye malignancy. In this paper, we examine how the expression of the tumor suppressor BRCA1 associated protein 1 (BAP-1) varies across different parts of these tumors. We find that there are considerable differences, but that these do not matter as long as proper rules for interpretation are applied. Further, we show that analysis of BAP-1 expression adds significant prognostic information to both tumor size and gene expression classifications.Malignant tumors are rarely homogenous on the morphological, genome, transcriptome or proteome level. In this study, we investigate the intratumor heterogeneity of BAP-1 expression in uveal melanoma with digital image analysis of 40 tumors. The proportion of BAP-1 positive cells was measured in full tumor sections, hot spots, cold spots and in scleral margins. The mean difference between hot spots and cold spots was 41 percentage points (pp, SD 29). Tumors with gene expression class 1 (associated with low metastatic risk) and 2 (high metastatic risk) had similar intratumor heterogeneity. Similarly, the level of intratumor heterogeneity was comparable in tumors from patients that later developed metastases as in patients that did not. BAP-1 measured in any tumor region added significant prognostic information to both American Joint Committee on Cancer (AJCC) tumor size category (p ≤ 0.001) and gene expression class (p ≤ 0.04). We conclude that there is substantial intratumor heterogeneity in uveal melanoma BAP-1 expression. However, it is of limited prognostic importance. Regardless of region, analysis of BAP-1 expression adds significant prognostic information beyond tumor size and gene expression class.
Highlights
Uveal melanoma is the most common primary intraocular malignancy [1]
Several methods for early prognostication have implemented in clinical practice: Gene expression classification and evaluation of mutations in BRCA associated protein 1 (BAP1), a tumor suppressor located on chromosome 3p, are two of the strongest prognostic predictors [5,6,7,8,9]
In the sequence of mutations, the BAP-1 mutation has been assumed to occur relatively late, preceded by smaller genomic alterations in G-protein subunits including GNA11 or GNAQ that are present in virtually all uveal melanomas [5]
Summary
Uveal melanoma is the most common primary intraocular malignancy [1]. Two to four percent of patients have detectable metastases at the time of diagnosis [2]. At a later stage more than one third of patients develop unvaryingly fatal metastatic disease [3,4]. Several methods for early prognostication have implemented in clinical practice: Gene expression classification and evaluation of mutations in BRCA associated protein 1 (BAP1), a tumor suppressor located on chromosome 3p, are two of the strongest prognostic predictors [5,6,7,8,9]. In the sequence of mutations, the BAP-1 mutation has been assumed to occur relatively late, preceded by smaller genomic alterations in G-protein subunits including GNA11 or GNAQ that are present in virtually all uveal melanomas [5]. It is thought that these G-protein mutations are not sufficient for progression to metastatic disease. BAP-1 mutations are thought to appear after the GNA11 or GNAQ mutations, after which the risk for metastatic seeding increases greatly
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