PMID- 35085662 OWN - NLM STAT- MEDLINE DCOM- 20220524 LR - 20220622 IS - 1549-4713 (Electronic) IS - 0161-6420 (Linking) VI - 129 IP - 6 DP - 2022 Jun TI - Mutational Landscape and Outcomes of Conjunctival Melanoma in 101 Patients. PG - 679-693 LID - S0161-6420(22)00068-9 [pii] LID - 10.1016/j.ophtha.2022.01.016 [doi] AB - PURPOSE: To evaluate targetable mutations and molecular genetic pathways in conjunctival melanoma with clinical correlation. DESIGN: Observational case series. PARTICIPANTS: Patients with conjunctival melanoma. MAIN OUTCOME MEASURES: Mutational profile of the tumor by next-generation sequencing (NGS), alternative lengthening of telomeres (ALT) by fluorescence in situ hybridization (FISH), and ATRX immunohistochemistry. Outcomes at 2 years and 5 years of tumor-related metastasis and death were recorded. RESULTS: Of the 101 patients, mean age at presentation was 60 years, 52% were male, and 88% were White. The NGS panels initially targeted BRAF only (n = 6, 6%), BRAF/NRAS (n = 17, 17%), and BRAF/NRAS/NF1 (n = 10, 10%). Sixty-eight tumors were tested with the expanded 592-gene panel. Next-generation sequencing identified high-frequency mutations in NF1 (29/74, 39%), BRAF (31/101, 31%), NRAS (25/95, 26%), and ATRX (17/68, 25%). Of those with an ATRX mutation, 12 (71%) had an additional NF1 mutation. A subset analysis of 21 melanomas showed that the ATRX mutation was associated with loss of ATRX protein expression and ALT. Loss of ATRX expression and ALT were present in both intraepithelial and invasive tumors, suggesting that an ATRX mutation is an early event in conjunctival melanoma progression. The NF1 and ATRX mutations were associated with tarsal (vs. nontarsal) tumors (NF1: 28% vs. 9%, P = 0.035, ATRX: 41% vs. 14%, P = 0.021) and orbital (vs. nonorbital) tumors (ATRX: 24% vs. 2%, P = 0.007). ATRX(MUT) (vs. ATRX(WT)) tumors were associated with a lower 2-year rate of metastasis (0% vs. 24%, P = 0.005). NRAS(MUT) (vs. NRAS(WT)) tumors were associated with a greater 2-year rate of metastasis (28% vs. 14%, P = 0.07) and death (16% vs. 4%, P = 0.04), with a 5-fold increased risk of death (relative risk, 5.45 [95% confidence interval, 1.11-26.71], P = 0.039). CONCLUSIONS: This study confirms the high frequency of previously documented BRAF and NRAS mutations and recently reported ATRX and NF1 mutations in conjunctival melanoma. An NRAS mutation implied increased risk for metastasis and death. Loss of ATRX and ALT may be early events in conjunctival melanoma development. CI - Copyright (c) 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved. FAU - Lally, Sara E AU - Lally SE AD - Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: sara@shields.md. FAU - Milman, Tatyana AU - Milman T AD - Department of Pathology, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. FAU - Orloff, Marlana AU - Orloff M AD - Department of Medical Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. FAU - Dalvin, Lauren A AU - Dalvin LA AD - Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota. FAU - Eberhart, Charles G AU - Eberhart CG AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Heaphy, Christopher M AU - Heaphy CM AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Boston University School of Medicine, Boston, Massachusetts. FAU - Rodriguez, Fausto J AU - Rodriguez FJ AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. FAU - Lin, Chun-Chieh AU - Lin CC AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. FAU - Dockery, Philip W AU - Dockery PW AD - Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. FAU - Shields, Jerry A AU - Shields JA AD - Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. FAU - Shields, Carol L AU - Shields CL AD - Ocular Oncology Service, Wills Eye Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania. LA - eng PT - Journal Article PT - Observational Study PT - Research Support, Non-U.S. Gov't DEP - 20220124 PL - United States TA - Ophthalmology JT - Ophthalmology JID - 7802443 RN - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) SB - IM MH - *Conjunctival Neoplasms/genetics/pathology MH - DNA Mutational Analysis MH - Female MH - Humans MH - In Situ Hybridization, Fluorescence MH - Male MH - *Melanoma/genetics/pathology MH - Mutation MH - Proto-Oncogene Proteins B-raf/genetics MH - *Skin Neoplasms/pathology OTO - NOTNLM OT - ATRX OT - Alternative lengthening of telomeres OT - BRAF OT - Biomarker OT - Conjunctiva OT - Fluorescence in situ hybridization OT - Melanoma OT - Mutation OT - NF1 OT - NRAS OT - Next-generation sequencing EDAT- 2022/01/28 06:00 MHDA- 2022/05/25 06:00 CRDT- 2022/01/27 20:12 PHST- 2021/05/20 00:00 [received] PHST- 2022/01/12 00:00 [revised] PHST- 2022/01/14 00:00 [accepted] PHST- 2022/01/28 06:00 [pubmed] PHST- 2022/05/25 06:00 [medline] PHST- 2022/01/27 20:12 [entrez] AID - S0161-6420(22)00068-9 [pii] AID - 10.1016/j.ophtha.2022.01.016 [doi] PST - ppublish SO - Ophthalmology. 2022 Jun;129(6):679-693. doi: 10.1016/j.ophtha.2022.01.016. Epub 2022 Jan 24.