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Title: Conjunctival melanoma : a multicentre study correlating baseline clinical features with histology and genetics
Author: Kenawy, N.
ISNI:       0000 0004 7428 4157
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2017
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Conjunctival melanoma (CoM) is a rare, but potentially fatal, malignancy constituting about 2% of all ocular cancers. Despite successful local primary CoM treatment, an estimated 60% recur locally within 5 years, and are fatal in 26% at 10 years. Because of CoM rarity, management of patients varies between centres, and the protocols are based on limited case series and reports rather than randomised clinical trials. Further, the mechanisms behind disease pathogenesis and genetics are largely unknown. The scope of the work presented in this thesis was to understand the genetic aberrations in CoM in a large series within a mutlicentre collaboration. Chapter 1 provides an overview of CoM. The aim of chapter 2 was to determine gene copy number variations (CNVs) and their correlation with clinical or histological CoM characteristics, in an attempt to identify potential genetic biomarkers for pathogenesis and metastasis. Regional and focal gains of 6p and losses of 7q were the most common aberrations in CoM, whether primary or recurrent, but not related to any particular tumour features. Most important were the 10q deletions, which commonly recurred in metastasising CoM, and were also associated with lymphatic invasion and increased thickness. In chapter 3, BRAF and NRAS mutations, which are the most common in cutaneous melanoma, were investigated in addition to their associated CNVs. BRAF and NRAS mutational frequencies in CoM were 34% and 13%, respectively, similar to skin melanoma. Apart from BRAF-mutant CoM tending to occur in younger patients (median age 58 years) than NRAS-mutant or Wild-type tumours, there were no other significant associations between BRAF/NRAS mutational status and the tumour features and/or the clinical outcome. In addition, 10q and 19q deletions were commonly seen in the BRAF- and NRAS-mutant tumours, respectively. The focus of chapter 4 was to assess the prognostic value of the AJCC/Tumor-NodeMetastasis (TNM) system for a cohort of 220 CoM patients (follow up 0.36-35 years). This was achieved by comparing the 6th and 7th TNM staging systems. The 7th TNM staging was more accurate than the 6th, and better conformed to the literature-reported patients' outcomes. However, some deficiencies of the 7th staging system were also highlighted in the chapter, and suggestions were proposed for improvements in future editions. Notably the 8th TNM staging system for all cancers was only very recently released, and some relevant alterations have been made. In conclusion, the multicentre study on CoM presented in this MD thesis provides further insight into CoM genetics. It is a first step towards bridging the significant knowledge gap in CoM (when compared to its skin and intraocular counterparts). The work presented here provides basis for several future projects outlines potential future work that could be taken forward to improve this rare cancer's treatment & prognostication.
Supervisor: Coupland, S. E. ; Damato, B. E. ; Lake, S. L. ; Sacco, J. Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral