PMID- 35356600
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230202
IS  - 2296-4681 (Print)
IS  - 2296-4657 (Electronic)
IS  - 2296-4657 (Linking)
VI  - 8
IP  - 1
DP  - 2022 Feb
TI  - Single Time Frame Overview of the Genetic Changes in Conjunctival Melanoma from 
      Intraepithelial Disease to Invasive Melanoma: A Study of 4 Exenteration Specimens 
      Illustrating the Potential Role of Cyclin D1.
PG  - 52-63
LID - 10.1159/000520953 [doi]
AB  - INTRODUCTION: Despite advances in the understanding of the molecular pathogenesis 
      of cutaneous melanoma, relatively little is known about the genetic changes that 
      occur in the progression of conjunctival melanocytic intraepithelial lesions to 
      invasive conjunctival melanoma. METHODS: We exposed 4 exenteration specimens that 
      each contained varying grades of intraepithelial conjunctival melanocytic 
      neoplasia and invasive neoplasia to a combination of various techniques, 
      including array comparative genomic hybridization (aCGH), ribonucleic acid 
      sequencing (RNA-seq), fluorescence in situ hybridization (FISH), and 
      immunohistochemistry. RESULTS: Three out of 4 of the invasive melanomas showed 
      gains in 11q13 (CCND1 locus) by aCGH. FISH demonstrated CCND1 gain in invasive 
      melanoma and in conjunctival melanocytic intraepithelial lesions (CMILs) of all 
      grades (low-grade CMILs and in situ melanoma), and this was paralleled by 
      increased expression of Cyclin D1 protein within the atypical melanocytes by 
      immunohistochemistry, using a double-staining method with a red end point for 
      Melan A cytoplasmic staining and a brown end point for nuclear Cyclin D1 
      expression. Higher grades of melanocytic intraepithelial lesions showed more 
      cells expressing Cyclin D1 than lower grade melanocytic intraepithelial lesions. 
      The Cyclin D1 protein expression was in the same location as the amplified CCND1 
      signal by FISH. One out of 3 of these cases also showed the amplification of the 
      12q13-15 locus corresponding to MDM2 and FISH confirmed gains in the conjunctival 
      melanocytic intraepithelial neoplasia and invasive melanoma. The remaining fourth 
      case showed a homozygous deletion of 9p21 (CDKN2A) by aCGH only, with 
      immunohistochemistry showing clonal loss of p16 protein expression in the 
      invasive and conjunctival melanocytic intraepithelial lesion. Two out of 4 of the 
      invasive melanomas harboured classical driver mutations in NRAS and NF-1, 
      respectively. None of the cases showed mutations in BRAF, KIT, and TERT 
      mutations. RNA-seq data showed secondary mutations in ARAF, PLCB4, MET, EZH2, 
      MAP2K2, CTNNB1, CIITA, NF2, TP53, and MEN1, some of which are implicated in the 
      MAPK pathway. CONCLUSION: CMILs harbour amplifications of CCND1 (3 cases), MDM2 
      (1 case), and loss of CDKN2A (1 case), which are also present when the lesion 
      progresses to invasive melanoma, implicating these amplifications in the early 
      pathogenesis of CMILs. This study represents the first attempt to capture the 
      mutational landscape of all stages of conjunctival melanoma in a single tissue 
      excision.
CI  - Copyright (c) 2021 by S. Karger AG, Basel.
FAU - Mudhar, Hardeep Singh
AU  - Mudhar HS
AD  - Department of Histopathology, National Specialist Ophthalmic Pathology Service 
      (NSOPS), Sheffield, United Kingdom.
FAU - Salvi, Sachin S
AU  - Salvi SS
AD  - Department of Ophthalmology, Sheffield Ocular Oncology Service, Sheffield, United 
      Kingdom.
FAU - Pissaloux, Daniel
AU  - Pissaloux D
AD  - Department of Biopathologie, Centre Leon Berard, Lyon, France.
AD  - University of Lyon, Universite Claude Bernard Lyon 1, CNRS UMR 5286, INSERM 
      U1052, Cancer Research Centre of Lyon, Lyon, France.
FAU - de La Fouchardiere, Arnaud
AU  - de La Fouchardiere A
AD  - Department of Biopathologie, Centre Leon Berard, Lyon, France.
AD  - University of Lyon, Universite Claude Bernard Lyon 1, CNRS UMR 5286, INSERM 
      U1052, Cancer Research Centre of Lyon, Lyon, France.
LA  - eng
PT  - Journal Article
DEP - 20211117
PL  - Switzerland
TA  - Ocul Oncol Pathol
JT  - Ocular oncology and pathology
JID - 101656139
PMC - PMC8914236
OTO - NOTNLM
OT  - Array comparative genomic hybridization
OT  - Conjunctival melanoma
OT  - Cyclin D1
OT  - Fluorescence in situ hybridization
OT  - Genetic landscape
OT  - Immunohistochemistry
COIS- The authors have no conflicts of interest to declare.
EDAT- 2022/04/01 06:00
MHDA- 2022/04/01 06:01
PMCR- 2023/02/01
CRDT- 2022/03/31 05:34
PHST- 2021/08/17 00:00 [received]
PHST- 2021/11/15 00:00 [accepted]
PHST- 2022/03/31 05:34 [entrez]
PHST- 2022/04/01 06:00 [pubmed]
PHST- 2022/04/01 06:01 [medline]
PHST- 2023/02/01 00:00 [pmc-release]
AID - oop-0008-0052 [pii]
AID - 10.1159/000520953 [doi]
PST - ppublish
SO  - Ocul Oncol Pathol. 2022 Feb;8(1):52-63. doi: 10.1159/000520953. Epub 2021 Nov 17.