Natasha M van Poppelen1, Jolanda Vaarwater1, Hardeep S Mudhar2, Karen Sisley3, Ian G Rennie4, Paul Rundle4, Tom Brands5, Quincy C C van den Bosch5, Hanneke W Mensink6, Annelies de Klein5, Emine Kiliç7, Robert M Verdijk8. 1. Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. 2. National Specialist Ophthalmic Pathology Service, Department of Histopathology, Royal Hallamshire Hospital, Sheffield, United Kingdom. 3. Department of Oncology & Metabolism, The University of Sheffield, Sheffield, United Kingdom. 4. Ocular Oncology Clinic, Department of Ophthalmology, Royal Hallamshire Hospital, Sheffield, United Kingdom. 5. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands. 6. Department of Ocular Oncology, The Rotterdam Eye Hospital, Rotterdam, The Netherlands. 7. Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands. 8. Department of Ocular Oncology, The Rotterdam Eye Hospital, Rotterdam, The Netherlands; Department of Pathology, Section Ophthalmic Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands. Electronic address: r.verdijk@erasmusmc.nl.
Abstract
PURPOSE: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi. DESIGN: Multicenter, retrospective case series. PARTICIPANTS: Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment. METHODS: Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53, and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples. MAIN OUTCOME MEASURES: Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis. RESULTS: In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11. Furthermore, 13 of 30 BAP1, 5 of 30 EIF1AX, and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3 BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT, and TP53 were detected in 6 iris melanomas and 4 iris nevi. CONCLUSIONS: Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential.
PURPOSE: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Iris melanoma comprises 4% to 10% of all UMs and has a lower mortality rate. The genetic changes in iris melanoma are not as well characterized as ciliary body or choroidal melanoma. The aim of this study was to gain more insight into the genetic background of iris melanoma and iris nevi. DESIGN: Multicenter, retrospective case series. PARTICIPANTS: Patients diagnosed with iris melanoma or iris nevi who underwent surgical intervention as primary or secondary treatment. METHODS: Next-generation sequencing of GNAQ, GNA11, EIF1AX, SF3B1, BAP1, NRAS, BRAF, PTEN, c-Kit, TP53, and TERT was performed on 30 iris melanomas and 7 iris nevi. Copy number status was detected using single nucleotide polymorphisms (SNPs) included in the next-generation sequencing (NGS) panel, SNP array, or fluorescent in situ hybridization. BAP1 immunohistochemistry was performed on all samples. MAIN OUTCOME MEASURES: Mutation and copy number status were analyzed. Results of BAP1 immunohistochemistry were used for survival analysis. RESULTS: In 26 of the 30 iris melanoma and all iris nevi, at least 1 mutation was identified. Multiple mutations were detected in 23 iris melanoma and 5 nevi, as well as mutations in GNAQ and GNA11. Furthermore, 13 of 30 BAP1, 5 of 30 EIF1AX, and 2 of 30 SF3B1 mutations were identified in iris melanoma. No correlation between BAP1 status and disease-free survival was found. The iris nevi showed 1 EIF1AX and 3BAP1 mutations. Two of the nevi, with a BAP1 mutation, were histologically borderline malignant. Mutations in NRAS, BRAF, PTEN, c-KIT, and TP53 were detected in 6 iris melanomas and 4 iris nevi. CONCLUSIONS: Mutations that are often found in uveal and cutaneous melanoma were identified in this cohort of iris melanomas and iris nevi. Therefore, iris melanomas harbor a molecular profile comparable to both choroidal melanoma and cutaneous melanoma. These findings may offer adjuvant targeted therapies for iris melanoma. There was no prognostic significance of BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential.
Authors: Natasha M van Poppelen; Daniël P de Bruyn; Tolga Bicer; Rob Verdijk; Nicole Naus; Hanneke Mensink; Dion Paridaens; Annelies de Klein; Erwin Brosens; Emine Kiliҫ Journal: Int J Mol Sci Date: 2020-12-30 Impact factor: 5.923
Authors: Natasha M van Poppelen; Jolique A van Ipenburg; Quincy van den Bosch; Jolanda Vaarwater; Tom Brands; Bert Eussen; Frank Magielsen; Hendrikus J Dubbink; Dion Paridaens; Erwin Brosens; Nicole Naus; Annelies de Klein; Emine Kiliç; Robert M Verdijk Journal: Int J Mol Sci Date: 2021-05-28 Impact factor: 5.923
Authors: Laurien E Houtzagers; Annemijn P A Wierenga; Aleid A M Ruys; Gregorius P M Luyten; Martine J Jager Journal: Int J Mol Sci Date: 2020-09-28 Impact factor: 5.923