Kowalik Artur, Karpinski Pawel, Markiewicz Anna, Orlowska-Heitzman Jolanta, Romanowska-Dixon Bozena, Donizy Piotr, Hoang Mai P
Department of Molecular Diagnostics, Holy Cross Cancer Center.
Division of Medical Biology, Institute of Biology, Jan Kochanowski University, Kielce.
Melanoma Res. 2023 Apr 1;33(2):104-115. doi: 10.1097/CMR.0000000000000874. Epub 2023 Jan 30.
There is no published data regarding the molecular alterations of Polish patients with primary uveal melanoma. We performed whole exome sequencing of 20 primary uveal melanomas (UMs), 10 metastasizing and 10 non-metastasizing cases to identify significant molecular alterations. We detected mutations and copy number variants in the BAP1 gene in 50% (10 cases) of the cases. GNA11 mutations were detected in 50% (10 cases) including nine p.Q209L and one p.R183C. GNAQ mutations gene were detected in 40% (8 cases) and all were p.Q209P. SF3B1, EIF1AX, PLCB4 , and PALB2 mutations were detected in one case each. Genetic aberrations of FBXW7 were detected in 55% of cases, with copy number loss of 10 and missense mutation in one. Gain or loss of copy number was observed in 60%, 60%, and 10% of cases in MYC, MLH1 , and CDKN2A genes, respectively. BAP1 and GNAQ tumor suppressor genes are more often mutated in UM with metastasis, while GNA11 mutations are more frequently detected in non-metastasizing tumors. MYC copy gain was present twice as frequently (80% versus 40%) in cases with versus those without metastases. BAP1 mutation correlated with worse overall survival; while GNA11 mutation and CDKN2A loss correlated with better and worse progression-free survival, respectively. We have confirmed BAP1 prognostic potential and documented frequent MYC amplification in metastasizing cases. Although GNA11 mutation and CDKN2A loss significantly correlated with progression-free survival in our study, our sample size is small. The prognostic significance of GNAQ/GNA11 mutation and CDKN2A loss would require further investigation.
目前尚无关于波兰原发性葡萄膜黑色素瘤患者分子改变的公开数据。我们对20例原发性葡萄膜黑色素瘤（UMs）进行了全外显子测序，其中10例发生转移，10例未发生转移，以确定显著的分子改变。我们在50%（10例）的病例中检测到BAP1基因的突变和拷贝数变异。在50%（10例）的病例中检测到GNA11突变，其中包括9例p.Q209L和1例p.R183C。在40%（8例）的病例中检测到GNAQ基因突变，且均为p.Q209P。SF3B1、EIF1AX、PLCB4和PALB2基因的突变各在1例中检测到。在55%的病例中检测到FBXW7的基因畸变，其中10号染色体拷贝数丢失且有1例错义突变。分别在60%、60%和10%的病例中观察到MYC、MLH1和CDKN2A基因的拷贝数增加或减少。BAP1和GNAQ肿瘤抑制基因在发生转移的UM中更常发生突变，而GNA11突变在未发生转移的肿瘤中更频繁地被检测到。MYC拷贝数增加在发生转移的病例中的出现频率是未发生转移病例的两倍（80%对40%）。BAP1突变与较差的总生存期相关；而GNA11突变和CDKN2A缺失分别与较好和较差的无进展生存期相关。我们证实了BAP1的预后潜力，并记录了转移病例中频繁出现的MYC扩增。虽然在我们的研究中GNA11突变和CDKN2A缺失与无进展生存期显著相关，但我们的样本量较小。GNAQ/GNA11突变和CDKN2A缺失的预后意义需要进一步研究。
