Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
Fam Cancer. 2023 Apr;22(2):193-202. doi: 10.1007/s10689-022-00310-3. Epub 2022 Aug 3.
Uveal melanoma (UM) is a rare tumor originating from melanocytic cells in the eye. Familial aggregation of UM is rare and can occur as part of the tumor predisposition syndrome BAP1-TPDS. However, family history alone will only identify a subset of patients with BAP1-TPDS. In the present study, we used sequential testing of tumor and blood DNA from UM patients for differential diagnosis of BAP1-TPDS. The study group was an unselected prospective cohort of patients from whom UM tissue was available. First, chromosome 3 status in tumor DNA was determined in all 140 patients who consented to participate. As tumors with disomy 3 rarely show BAP1 alterations, sequence analysis of this gene was performed in the 72 tumors with monosomy 3 (M3) or partial M3 only. We identified oncogenic BAP1 alterations in 52 of these tumors (72%). Targeted sequencing of DNA from matched peripheral blood showed pathogenic variants in two patients (3.8%) thus proving BAP1-TPDS. Only one of these two patients also had a medical history suggestive of this syndrome. Conversely, in three patients known to have had additional tumors before diagnosis of UM, constitutional heterozygosity for a BAP1 mutation was excluded. Altogether, in 50 patients we could exclude BAP1-TPDS with high diagnostic certainty. The results of our study support that genetic testing for BAP1-TPDS should be offered to all patients with UM. Moreover, as genetic information from the tumor can help exclude heritable risk, the strategy for analysis should include efforts to obtain tumor samples for testing.
葡萄膜黑色素瘤（UM）是一种罕见的肿瘤，起源于眼睛中的黑色素细胞。UM 的家族聚集现象很少见，可能是肿瘤易感性综合征 BAP1-TPDS 的一部分。然而，仅家族史只能识别出一部分具有 BAP1-TPDS 的患者。在本研究中，我们使用 UM 患者的肿瘤和血液 DNA 进行连续检测，以对 BAP1-TPDS 进行鉴别诊断。研究组是一个未经选择的前瞻性队列，从该队列的患者中获得了 UM 组织。首先，对同意参与的 140 名患者的肿瘤 DNA 中的 3 号染色体状态进行了确定。由于具有二倍体 3 号染色体的肿瘤很少显示 BAP1 改变，因此仅对具有单体型 3 号染色体（M3）或部分 M3 的 72 个肿瘤进行了该基因的序列分析。我们在这些肿瘤中的 52 个肿瘤（72%）中发现了致癌性 BAP1 改变。对匹配的外周血 DNA 进行靶向测序显示，有两个患者（3.8%）存在致病性变体，从而证实了 BAP1-TPDS。这两个患者中只有一个有提示该综合征的病史。相反，在三个已知在诊断 UM 之前就已经有其他肿瘤的患者中，排除了 BAP1 突变的种系杂合性。总的来说，我们可以在 50 名患者中以高诊断确定性排除 BAP1-TPDS。我们的研究结果支持应对所有 UM 患者提供 BAP1-TPDS 的基因检测。此外，由于肿瘤的遗传信息可以帮助排除遗传性风险，因此分析策略应包括努力获取肿瘤样本进行检测。
