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Saeed AlWadani, Laura Asnaghi, Hind Alkatan, Hilal Al -Hussain, Deepak Edward, Charles Eberhart; Molecular Profiling of Ocular Surface Squamous Neoplasia Identifies Multiple DNA Copy Number Alterations Including Recurring 8p11.22 Amplicons. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5434.
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© ARVO (1962-2015); The Authors (2016-present)
To uncover novel diagnostic biomarkers and molecular pathways, which can be targeted using new therapies in Conjunctival squamous cell carcinoma (cSCC). Very little is known about the molecular pathways, which drive the formation and growth of ocular surface squamous neoplasia.
We analyzed DNA extracted from 14 snap frozen cSCC tumor specimens using Agilent 180K high density oligonucleotide array-based Comparative Genomic Hybridization (aCGH), with 12 samples giving high quality hybridizations. 11 cases with DNA remaining were used to confirm chromosomal alterations by nanostring analysis.
Of these 12 tumors, the number of clear regions of DNA loss ranged from 1 to 24 per tumor, while gains ranged from 2 to 14 per tumor. Two of the 12 tumors were recurrent, and these had the highest number of copy number gains/amplifications 9 and 14, and 8 and 11 losses among the cohort. These recurring aberrations were observed in chromosome 6, where the region 6p22.1-p21.32 was lost in 33%, in chromosome 14, where the locus 14q13.2 was lost in 42%, and in chromosome 22, where 5 samples showed DNA loss and one DNA gain at 22q11.22. However, the most frequent alteration was observed in chromosome 8, where the locus 8p11.22 was amplified in 75% and lost in 25%. This region contains a group of genes coding for “a disintegrin and metalloprotease” (ADAM) proteins, known to be involved in the activation of oncogenic receptors and tumor formation. We observed the most profound DNA alterations in the region of 8p11.22 which contains part or all of the ADAM1B, 3A, and 5p genes. We are now investigating mRNA expression at the 8p11.22 loci with PCR.
Recurrent cSCC tumors were found to have significant chromosomal alteration in region 8p11.22, suggesting that increased numbers of DNA alterations may be associated with more aggressive clinical behavior and/or tumor progression. In contrast, case with fewer gains and losses was somewhat distinct microscopically, and noted to be relatively undifferentiated with adnexal features. The ADAM genes discovered in this study could be related to ocular tumors and previously reported ADAM9 alterations associated with oral mucosa neoplasia, suggest that ADAM family members may be involved in the pathogenesis of several types of mucosal squamous neoplasia, and could be potential therapeutic target.
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