Intratumor Heterogeneity in Uveal Melanoma BAP-1 Expression

SIMPLE SUMMARY: Uveal 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. ABSTRACT: 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.