Emory University School of Medicine, Atlanta, Georgia, USA.
Departments of Ophthalmology and Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.
Sci Rep. 2021 Apr 26;11(1):8923. doi: 10.1038/s41598-021-88390-6.
Uveal melanoma is the most common primary intraocular malignancy. A vast majority of metastasizing tumors have mutations in the BAP1 gene. Here, we investigate the spatiotemporal timing of these mutations. The size of 177 uveal melanomas and 8.3 million individual tumor cells was measured. BAP1 sequencing results and BAP1 IHC were available and for 76 (43%) and 101 (57%) of these, respectively. Tumors with a BAP1 mutation had significantly larger volume (2109 vs. 1552 mm, p = 0.025). Similarly, tumor cells with loss of BAP1 protein expression had significantly larger volume (2657 vs. 1593 μm, p = 0.027). Using observations of the time elapsed between mitoses, the BAP1 mutation was calculated to occur when the primary tumor had a size of a few malignant cells to 6 mm, 0.5 to 4.6 years after tumor initiation and at least 9 years before diagnosis. We conclude that BAP1 mutations occur early in the growth of uveal melanoma, well before the average tumor is diagnosed. Its timing coincides with the seeding of micrometastases.
葡萄膜黑色素瘤是最常见的原发性眼内恶性肿瘤。绝大多数转移性肿瘤都存在 BAP1 基因突变。在这里，我们研究了这些突变的时空时间。测量了 177 个葡萄膜黑色素瘤和 830 万个肿瘤细胞的大小。获得了 BAP1 测序结果和 BAP1 IHC 结果，分别为 76 个（43%）和 101 个（57%）。具有 BAP1 突变的肿瘤体积明显更大（2109 与 1552mm，p=0.025）。同样，BAP1 蛋白表达缺失的肿瘤细胞体积明显更大（2657 与 1593μm，p=0.027）。根据有丝分裂之间时间流逝的观察，BAP1 突变发生在原发性肿瘤的大小为几个恶性细胞到 6mm 之间时，肿瘤发生后 0.5 到 4.6 年，至少在诊断前 9 年。我们得出结论，BAP1 突变发生在葡萄膜黑色素瘤生长的早期，远在平均肿瘤被诊断之前。其时间与微转移的播种相吻合。
