van Engen-van Grunsven Adriana C H, Baar Marjolein P, Pfundt Rolph, Rijntjes Jos, Küsters-Vandevelde Heidi V N, Delbecq Ann-Laure, Keunen Jan E, Klevering Jeroen B, Wesseling Pieter, Blokx Willeke A M, Groenen Patricia J T A
Departments of aPathology bHuman Genetics cOphthalmology, Radboud University Medical Center dDepartment of Pathology, Canisius Wilhelmina Hospital, Nijmegen eDepartment of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Melanoma Res. 2015 Jun;25(3):200-9. doi: 10.1097/CMR.0000000000000152.
To further elucidate the genetic underpinnings of uveal melanoma (UM) and identify new markers that correlate with disease outcome, archival formalin-fixed, paraffin-embedded enucleation specimens from 25 patients with UM and a mean follow-up of 14 years were analyzed for whole-genome copy-number alterations using OncoScan analysis. Copy-number alterations of chromosomes 1, 3, 6, and 8 were also analyzed in these tumors using multiplex ligation-dependent probe-amplification, and mutations in GNAQ, GNA11, and BAP1 were searched for by Sanger sequencing. Our study confirms the previously reported GNAQ and GNA11 mutation frequencies in UMs as well as the presence of monosomy 3 as a factor strongly indicating poor prognosis. Two cases with metastatic disease, but without monosomy of chromosome 3, showed loss of a small region in the distal part of chromosome 2p. Also, UMs leading to metastatic disease had more chromosomal aberrations than those without metastases. Three UMs lacking a GNAQ or a GNA11 mutation showed a gain of chromosome 8q; one of these cases showed extensive chromothripsis. Another case (with suspect lung metastasis) showed focal chromothripsis. Our whole-genome copy-number analysis shows that focal loss of chromosome 2p may be involved in the metastatic spread of UMs without monosomy 3; metastatic UMs carry more chromosomal aberrations than those without metastases; and chromothripsis may play a role in the oncogenesis of UMs, but does not necessarily indicate a poor prognosis. The clinical and particularly diagnostic utility of these findings needs to be corroborated in a larger set of patients with UM.
为进一步阐明葡萄膜黑色素瘤（UM）的遗传基础并鉴定与疾病预后相关的新标志物，我们使用OncoScan分析对来自25例UM患者的存档福尔马林固定、石蜡包埋眼球摘除标本进行了全基因组拷贝数改变分析，这些患者的平均随访时间为14年。还使用多重连接依赖探针扩增分析了这些肿瘤中1、3、6和8号染色体的拷贝数改变，并通过Sanger测序寻找GNAQ、GNA11和BAP1中的突变。我们的研究证实了先前报道的UM中GNAQ和GNA11的突变频率以及3号染色体单体性的存在，其作为一个强烈提示预后不良的因素。两例发生转移但无3号染色体单体性的病例显示2号染色体短臂远端的一个小区域缺失。此外，导致转移的UM比未发生转移的UM有更多的染色体畸变。三例缺乏GNAQ或GNA11突变的UM显示8号染色体长臂增加；其中一例显示广泛的染色体碎裂。另一例（怀疑有肺转移）显示局灶性染色体碎裂。我们的全基因组拷贝数分析表明，2号染色体短臂的局灶性缺失可能参与了无3号染色体单体性的UM的转移扩散；转移性UM比非转移性UM携带更多的染色体畸变；染色体碎裂可能在UM的肿瘤发生中起作用，但不一定表明预后不良。这些发现的临床，特别是诊断效用需要在更大一组UM患者中得到证实。
