Unknown,Transcriptomics,Genomics,Proteomics

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Gene Expression Changes in Non-Dysplastic Mucosa from Patients with Ulcerative Colitis Harboring Remote Neoplastic Lesions

ABSTRACT: Background and Aims: Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer, although underlying mechanisms are incompletely understood. We sought to identify a potential gene expression signature in non-dysplastic distal mucosa that as a “genetic field effect” could be a marker for remote neoplastic lesions. Results: 468 genes were significantly up-regulated and 541 genes were significantly down-regulated >2-fold in UC patients with neoplasia compared to UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly up-regulated from controls to quiescent non-dysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increases in tissue expression of S100A9 and REG1 in UC-associated cancer and in non-dysplastic tissue from UC patients harboring remote neoplasia, compared to UC patients without dysplasia and normal controls. Conclusions: Gene expression changes occur as a field effect in UC patients without active inflammation who harbor a remote dysplastic lesion. Further characterization of these genes and proteins might elucidate pathways of carcinogenesis in IBD and lead to the development of more accurate, less invasive markers of dysplasia in those at increased risk. Microarray assay were conducted on 20 RNA samples isolated from colon mucosa of 20 patients. Of these patients, 5 were normal controls, 4 had quiescent UC, and 11 had UC with neoplasia. Patients were included if they had a previous clinical diagnosis of UC confirmed by an expert GI pathologist, a disease duration > 7 years, and an extent of disease >20 cm proximal to the anal verge.

ORGANISM(S): Homo sapiens

SUBMITTER: Yong Huang

PROVIDER: E-GEOD-37283 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Inflammatory bowel diseases (IBD) are chronic inflammatory disorders that can be categorized as ulcerative colitis (UC), Crohn’s disease (CD) and indeterminate colitis (IC). Deep remission has been shown to improve disease outcome. There may be a lack of concordance between endoscopic and histologic remission. IBD patients with long standing colitis are at risk of developing dysplasia and colorectal cancer (CRC). However, it can be challenging to diagnose dysplasia in IBD patients during colonoscopy, as dysplasia frequently manifests as non-pedunculated lesions that present with only subtle visible changes or are even invisible due to the surrounding inflammation, scarring, pseudopolyps, or hyperplasia. Although white light endoscopy and chromoendoscopy are the current standard modality of imaging, there is still a gap to be bridged, in terms of improving endoscopic diagnosis of dysplasia and improving concordance of endoscopic and histologic remission. Raman spectroscopy is an inelastic light scattering technique provide specific fingerprints of molecular compositions and structures of biological tissues. It may be able to provide additional diagnostic information over standard endoscopy. A second-generation Raman endoscope system for improving in vivo tissue characterization and diagnosis during colonoscopy has been developed (SPECTRA IMDx system). Preliminary data suggested its utility in the diagnosis of colorectal neoplasia during colonoscopy. There is currently a lack of data concerning the application of this novel technology in the context of IBD. Specifically, whether the spectral signals generated can be used to better classify disease remission, and thus achieve higher concordance with histology when compared to standard endoscopy. It is also unclear whether this technology can be used to differentiate dysplastic mucosa from non-dysplastic mucosal in IBD patients. Hypotheses 1. Raman spectroscopy based artificial intelligence system has the potential to be used to differentiate disease remission from active mucosal inflammation and hence improve concordance between endoscopic and histologic remission, with the potential to decrease the need for random biopsies real-time during colonoscopy. 2. Raman spectroscopy based artificial intelligence system has the potential to differentiate dysplastic mucosa in IBD patients (low grade and high grade dysplasia; colorectal cancer) from non-dysplastic mucosa. real-time during colonoscopy.

Project description:The aim of the study was to address the concept of field cancerization in oral cancer. The presence of genomic aberrations, indicative of chromosomal instability (CIN), in oral distant fields (ODFs) of visually normal and non-dysplastic mucosa at the mirror image from concomitant oral potentially malignant lesions (OPMLs) was investigated. This pilot study comprised 16 OPMLs (8 without dysplasia, nd-OPMLs; 8 with dysplasia, d-OPMLs) and 16 ODFs. DNA diploid (DNA Index, DI=1) and aneuploid (DIM-bM-^IM- 1) sublines were detected by high resolution DNA-flow cytometry (FCM) at (hr DNA-FCM) using DAPI stained nuclei suspensions. Nuclei with different DIs were FCM-sorted in order to enrich the epithelial component and to obtain genomic DNA for high resolution oligonucleotide array-Comparative Genomic Hybridization (a-CGH) analysis to provide a genome-wide measurement of DNA copy number aberrations (CNAs). The frequencies of DNA aneuploidy in ODFs and OPMLs were 6.2% and 43.8%, respectively (p=0.037). ODFs and nd-OPMLs were all near-diploid (DIM-bM-^IM- 1 and DIM-bM-^IM-$1.4), while d-OPMLs were also high-aneuploid (DI>1.4). CNA averages were 2.3 in ODFs (1.5 for nd-OPMLs and 3.1 for d-OPMLs), and 7.325 in OPMLs (3.0 in nd-OPMLs; 11.6 in d-OPMLs). CNAs were present in the DNA diploid sublines and often the same CNAs were observed in both ODFs and corresponding OPMLs DNA aneuploid sublines and CNAs in the present series of 16 ODFs are likely to represent early events of the natural history of oral carcinogenesis and to indicate an early onset of the field effect cancerization. Moreover, gains within 20q13.33-qter, 7p22.2-pter and 16p13.3-pter chromosomal regions in ODFs and in the relative OPMLs suggest that specific genes localized in these regions (RTEL1, MAD1L1 and TEL2) might contribute to the ODF/d-OPML transition. We analyzed: 8 samples of oral potentially malignant lesions with dysplasia, 8 samples of oral potentially malignant lesions without dysplasia and for each patient a corresponding oral distant field of visually normal mucosa.

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Gene Expression Changes in Non-Dysplastic Mucosa from Patients with Ulcerative Colitis Harboring Remote Neoplastic Lesions

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