Maria Chiara Gelmi, Laurien E Houtzagers, Annemijn P A Wierenga, Mieke Versluis, Bastiaan T Heijmans, Gregorius P M Luyten, Peter de Knijff, Marije Te Raa, Rick H de Leeuw, Martine J Jager
{"title":"葡萄膜黑色素瘤患者的存活率与 HERC2 SNP rs12913832 的遗传变异有关。","authors":"Maria Chiara Gelmi, Laurien E Houtzagers, Annemijn P A Wierenga, Mieke Versluis, Bastiaan T Heijmans, Gregorius P M Luyten, Peter de Knijff, Marije Te Raa, Rick H de Leeuw, Martine J Jager","doi":"10.1016/j.ophtha.2024.09.001","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Uveal melanoma (UM) is a rare disease, with the highest incidence in people with fair skin and light eyes. Eye color is largely genetically determined and is defined by a set of single nucleotide polymorphisms (SNPs). We set out to determine whether we could identify a SNP related to prognosis.</p><p><strong>Design: </strong>We sequenced DNA from peripheral blood mononuclear cells of 392 patients with UM and obtained the genotype of 6 common eye color-related SNPs. Clinical and histopathologic tumor characteristics, tumor chromosome status, and patient survival were compared among patients with different genotypes.</p><p><strong>Participants: </strong>Three hundred ninety-two patients who underwent enucleation for UM at the Leiden University Medical Center, Leiden, The Netherlands.</p><p><strong>Methods: </strong>We isolated DNA from peripheral blood leukocytes of 392 patients with UM and performed sequencing, using 6 eye color SNPs from the HIrisPlex-S assay (Erasmus MC, Walsh lab). The genotypes extracted from the sequencing data were uploaded onto the HIrisPlexwebtool (https://hirisplex.erasmusmc.nl/) for eye color prediction. We tested the association of eye color SNPs with tumor characteristics and chromosome aberrations using Pearson's chi-square test and the Mann-Whitney U test and evaluated survival with Kaplan-Meier curves with the log-rank test and Cox regression.</p><p><strong>Main outcome measures: </strong>Uveal melanoma-related survival.</p><p><strong>Results: </strong>Of 392 patients with analyzable genotype data, 307 patients (78%) were assigned blue eyes, 74 patients (19%) were assigned brown eyes, and 11 patients (3%) could not be assigned to either blue or brown. Patients with a genetically blue eye color showed worse survival (P = 0.04). This was related to 1 genotype: patients with the G/G genotype of rs12913832 (HERC2), which codes for blue eye color showed a worse prognosis (P = 0.017) and more often had high-risk tumors (monosomy of chromosome 3; P = 0.04) than in patients with an A/G or A/A genotype.</p><p><strong>Conclusions: </strong>The G/G genotype of rs12913832 (HERC2), which is related to blue eye color, not only is a genetic factor related to the risk of UM develop, but also is linked to a worse prognosis because of an association with a higher risk of a high-risk UM developing (carrying monosomy of chromosome 3).</p><p><strong>Financial disclosure(s): </strong>The author(s) have no proprietary or commercial interest in any materials discussed in this article.</p>","PeriodicalId":19533,"journal":{"name":"Ophthalmology","volume":null,"pages":null},"PeriodicalIF":13.1000,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Survival in Patients with Uveal Melanoma Is Linked to Genetic Variation at HERC2 Single Nucleotide Polymorphism rs12913832.\",\"authors\":\"Maria Chiara Gelmi, Laurien E Houtzagers, Annemijn P A Wierenga, Mieke Versluis, Bastiaan T Heijmans, Gregorius P M Luyten, Peter de Knijff, Marije Te Raa, Rick H de Leeuw, Martine J Jager\",\"doi\":\"10.1016/j.ophtha.2024.09.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Uveal melanoma (UM) is a rare disease, with the highest incidence in people with fair skin and light eyes. Eye color is largely genetically determined and is defined by a set of single nucleotide polymorphisms (SNPs). We set out to determine whether we could identify a SNP related to prognosis.</p><p><strong>Design: </strong>We sequenced DNA from peripheral blood mononuclear cells of 392 patients with UM and obtained the genotype of 6 common eye color-related SNPs. Clinical and histopathologic tumor characteristics, tumor chromosome status, and patient survival were compared among patients with different genotypes.</p><p><strong>Participants: </strong>Three hundred ninety-two patients who underwent enucleation for UM at the Leiden University Medical Center, Leiden, The Netherlands.</p><p><strong>Methods: </strong>We isolated DNA from peripheral blood leukocytes of 392 patients with UM and performed sequencing, using 6 eye color SNPs from the HIrisPlex-S assay (Erasmus MC, Walsh lab). The genotypes extracted from the sequencing data were uploaded onto the HIrisPlexwebtool (https://hirisplex.erasmusmc.nl/) for eye color prediction. We tested the association of eye color SNPs with tumor characteristics and chromosome aberrations using Pearson's chi-square test and the Mann-Whitney U test and evaluated survival with Kaplan-Meier curves with the log-rank test and Cox regression.</p><p><strong>Main outcome measures: </strong>Uveal melanoma-related survival.</p><p><strong>Results: </strong>Of 392 patients with analyzable genotype data, 307 patients (78%) were assigned blue eyes, 74 patients (19%) were assigned brown eyes, and 11 patients (3%) could not be assigned to either blue or brown. Patients with a genetically blue eye color showed worse survival (P = 0.04). This was related to 1 genotype: patients with the G/G genotype of rs12913832 (HERC2), which codes for blue eye color showed a worse prognosis (P = 0.017) and more often had high-risk tumors (monosomy of chromosome 3; P = 0.04) than in patients with an A/G or A/A genotype.</p><p><strong>Conclusions: </strong>The G/G genotype of rs12913832 (HERC2), which is related to blue eye color, not only is a genetic factor related to the risk of UM develop, but also is linked to a worse prognosis because of an association with a higher risk of a high-risk UM developing (carrying monosomy of chromosome 3).</p><p><strong>Financial disclosure(s): </strong>The author(s) have no proprietary or commercial interest in any materials discussed in this article.</p>\",\"PeriodicalId\":19533,\"journal\":{\"name\":\"Ophthalmology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":13.1000,\"publicationDate\":\"2024-09-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ophthalmology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.ophtha.2024.09.001\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ophthalmology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ophtha.2024.09.001","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的:葡萄膜黑色素瘤(UM)是一种罕见疾病,在皮肤白皙、眼睛明亮的人群中发病率最高。眼睛的颜色主要由基因决定,并由一组单核苷酸多态性(SNPs)定义。我们的目的是确定是否能找出与预后有关的 SNP:设计:我们对 392 名 UM 患者外周血单核细胞中的 DNA 进行了测序,并获得了 6 个常见眼色相关 SNP 的基因型。比较了不同基因型患者的临床和组织病理学肿瘤特征、肿瘤染色体状态和患者生存率:荷兰莱顿市莱顿大学医学中心接受 UM 去核手术的 392 名患者:我们从 392 名 UM 患者的外周血白细胞中分离出 DNA,并使用 HIrisPlex-S 检测方法中的 6 个眼色 SNPs 进行测序。从测序数据中提取的基因型被上传到Hirisplex网络工具(https://hirisplex.erasmusmc.nl/),用于眼色预测。我们使用皮尔逊卡方检验(Pearson's chi-square test)和曼-惠特尼U检验(Mann-Whitney U test)检验了眼色SNP与肿瘤特征和染色体畸变的相关性,并使用卡普兰-梅耶曲线(Kaplan-Meier curves)、对数秩检验(log-rank test)和考克斯回归(Cox regression)检验了生存率:结果:在392名有可分析基因型数据的患者中,307人(78%)被指定为蓝眼睛,74人(19%)为棕色眼睛,11人(3%)不能被指定为蓝眼睛或棕色眼睛。具有蓝眼基因的患者生存率较低(p = 0.04)。这与一种基因型有关:rs12913832(HERC2)的G/G基因型编码蓝色眼睛的患者预后较差(p = 0.017),这与高危肿瘤(3号染色体单体,p = 0.04)多于A/G或A/A基因型的患者有关:rs12913832(HERC2)的G/G基因型与蓝眼睛的颜色有关,它不仅是一个与荨麻疹发病风险有关的遗传因素,而且还与较差的预后有关,因为它与高危荨麻疹(携带3号染色体单体)的发病风险较高有关。
Survival in Patients with Uveal Melanoma Is Linked to Genetic Variation at HERC2 Single Nucleotide Polymorphism rs12913832.
Purpose: Uveal melanoma (UM) is a rare disease, with the highest incidence in people with fair skin and light eyes. Eye color is largely genetically determined and is defined by a set of single nucleotide polymorphisms (SNPs). We set out to determine whether we could identify a SNP related to prognosis.
Design: We sequenced DNA from peripheral blood mononuclear cells of 392 patients with UM and obtained the genotype of 6 common eye color-related SNPs. Clinical and histopathologic tumor characteristics, tumor chromosome status, and patient survival were compared among patients with different genotypes.
Participants: Three hundred ninety-two patients who underwent enucleation for UM at the Leiden University Medical Center, Leiden, The Netherlands.
Methods: We isolated DNA from peripheral blood leukocytes of 392 patients with UM and performed sequencing, using 6 eye color SNPs from the HIrisPlex-S assay (Erasmus MC, Walsh lab). The genotypes extracted from the sequencing data were uploaded onto the HIrisPlexwebtool (https://hirisplex.erasmusmc.nl/) for eye color prediction. We tested the association of eye color SNPs with tumor characteristics and chromosome aberrations using Pearson's chi-square test and the Mann-Whitney U test and evaluated survival with Kaplan-Meier curves with the log-rank test and Cox regression.
Main outcome measures: Uveal melanoma-related survival.
Results: Of 392 patients with analyzable genotype data, 307 patients (78%) were assigned blue eyes, 74 patients (19%) were assigned brown eyes, and 11 patients (3%) could not be assigned to either blue or brown. Patients with a genetically blue eye color showed worse survival (P = 0.04). This was related to 1 genotype: patients with the G/G genotype of rs12913832 (HERC2), which codes for blue eye color showed a worse prognosis (P = 0.017) and more often had high-risk tumors (monosomy of chromosome 3; P = 0.04) than in patients with an A/G or A/A genotype.
Conclusions: The G/G genotype of rs12913832 (HERC2), which is related to blue eye color, not only is a genetic factor related to the risk of UM develop, but also is linked to a worse prognosis because of an association with a higher risk of a high-risk UM developing (carrying monosomy of chromosome 3).
Financial disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
期刊介绍:
The journal Ophthalmology, from the American Academy of Ophthalmology, contributes to society by publishing research in clinical and basic science related to vision.It upholds excellence through unbiased peer-review, fostering innovation, promoting discovery, and encouraging lifelong learning.