Human melanoma samples comparing nevi and primary and metastatic melanoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Lawrence Kwong
PROVIDER: E-GEOD-46517 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Despite malignant cutaneous melanoma is relatively rare compared to other skin cancers, it is still responsible for 80% of all skin cancer-related deaths. To identify molecular signatures of melanoma progression, excisional biopsies from 18 common melanocytic nevi (CMN), 8 primary radial growth phase melanomas (RGPM), 15 primary vertical growth phase melanomas (VGPM) and 5 melanoma metastases (MTS) were profiled using whole genome oligo-microarrays. Differentially expressed genes for each progression step were identified, and validation of selected transcripts by qRT-PCR was performed on an independent cohort of fixed samples. The comparison between CMN and RGPM showed an enrichment of Gene Ontology (GO) terms related to inter and intra-cellular junctions, whereas the transition from RGPM to VGPM was characterized by the deregulation of WNT3, MAPK and AKT pathways. 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This suggests that DN is not an intermediate step within melanoma progression, but a separate entity with an independent risk of progression to melanoma Experiment Overall Design: In order to identify genes implicated during the course of melanoma development and progression, a total of 57 excisional biopsies from common melanocytic nevi (n = 18), dysplastic nevi (n = 11), primary radial growth phase malignant melanomas (n = 8), primary vertical growth phase malignant melanomas (n = 15) and melanoma metastases (n = 5) were analyzed. Total RNA was isolated by using RNeasy Mini Kit (Qiagen, Dusseldorf, Germany). TotRNA quality was checked by means of RNA 6000 pico chip assays (Agilent Technologies, Palo Alto, CA) run on the Agilent 2100 bioanalyzer. RNA isolated from each fresh tissue and from the human universal reference (BD™ Human Universal Reference Total RNA, Clontech, Palo Alto, CA) was amplified by means of the Amino Allyl MessageAmp II aRNA Kit (Ambion) to obtain amino allyl antisense RNA (aaRNA) following the method developed by Eberwine and coworkers. Two rounds of amplification were performed to obtain the necessary quantity of aaRNA for labeling. Briefly: mRNA was reverse transcribed in cDNA single strand; after the second strand synthesis (in the second round of amplification), cDNA was in vitro transcribed in aaRNA including amino allyl modified nucleotides (aaUTP). Both dsDNA and aaRNA underwent a purification step using columns provided with the kit. Labeling was performed using NHS ester Cy3 or Cy5 dyes (Amersham Biosciences, Buckinghamshire UK) able to react with the modified RNA. mRNA quality was checked by means of RNA 6000 nano chip assays (Agilent Technologies). At least 5 ug of mRNA for each sample were labeled and purified with columns. Equal amounts (0.75 ug) of labeled specimens from sample and reference were put together, fragmented and hybridized to oligonucleotide glass arrays representing 41K human unique genes and transcripts (Human Whole Genome Oligo Microarray Array, Agilent Technologies). All steps were performed using the In Situ Hybridization kit-plus (Agilent Technologies) and following the 60-mer oligo microarray processing protocol (Agilent Technologies). Then, slides were washed with the SSPE wash procedure and scanned with the dual-laser microarray scanner Agilent G2505B. For each sample, a dye-swap replicate was performed. To visually inspect the relationships among samples, unsupervised clustering analysis was applied to the ratios between each DN, RGPM , VGPM or MTS sample and the average profile of all the CMN included into the study, just selecting transcripts with p-value less than 0.01 in at least half of the samples considered. Transcripts modulated in each progression step were then selected by applying a cut-off of 2 for the B value yielded by the limma procedure applied on original ratios (sample over common reference). Initially, DN were included into either the CMN class or the RGPM one, according to the degree of their cyto-architectural atypia However, the presence of such lesions among either CMN or RGPM made the distinction between these two classes and between RGPM and VGPM much less clear. 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