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Multiple genes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression

ABSTRACT: Chromosomal instability (CIN) is the hallmark of colorectal adenoma to carcinoma progression in 85% of cases, with 20q gain as the most prominent aberration. Yet, the oncogenes at this chromosomal gain are still largely unknown. Here, we aimed to identify oncogenes at 20q involved in colorectal adenoma to carcinoma progression by measuring the effect of 20q gain on gene expression in this amplicon. Segmentation of DNA copy number changes on 20q was performed by array CGH in 67 colorectal adenomas and carcinomas. Additionally, robust analysis of mRNA expression in these segments was performed in 68 adenomas and carcinomas. This approach revealed seven genes to be important in CIN related adenoma to carcinoma progression. These genes may both serve as highly specific biomarkers for presence of high-risk precursor lesions as well as potential targets for pharmaceutical intervention. Keywords: Integration of array CGH and expression microarrays in colorectal cancer progression We performed array CGH on a panel of 41 progressed adenomas, from which the adenoma and carcinoma components were separately analysed (total, 82 samples). The DNA obtained from these samples was extracted from formalin-fixed, paraffin-embedded material. Additionally we analysed a series of independent frozen adenomas and carcinomas by array CGH (34 adenomas and 33 carcinomas) and expression microarrays (37 adenomas and 31 carcinomas). For array-CGH we used as reference DNA for all samples, a pool of 10 normal individuals. For expression microarrays we used as reference a commercial available RNA (pool of different cancer cell lines), from Strategene. No replicates nor dye swaps were done.

ORGANISM(S): Homo sapiens

SUBMITTER: Carvalho B

PROVIDER: S-ECPF-GEOD-8067 | biostudies-other | 2009 Jan

REPOSITORIES: biostudies-other

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Project description:BackgroundOne prominent event associated with colorectal adenoma-to-carcinoma progression is genomic instability. Approximately 85% of colorectal cancer cases exhibit chromosomal instability characterized by accumulation of chromosome copy number aberrations (CNAs). Adenomas with gain of chromosome 8q, 13q, and/or 20q are at high risk of progression to cancer. Tumor progression is also associated with expansion of the extracellular matrix (ECM) and the activation of non-malignant cells within the tumor stroma. The glycoproteins versican and lumican are overexpressed at the mRNA level in colon carcinomas compared to adenomas, and are associated with the formation of tumor stroma.PurposeThe aim of this study was to characterize versican and lumican protein expression in tumor progression and investigate their association with CNAs commonly associated with adenoma-to-carcinoma progression.MethodsTissue microarrays were constructed with colon adenomas and carcinomas that were characterized for MSI-status and DNA copy number gains of chromosomes 8q, 13q and 20q. Sections were immunohistochemically stained for lumican and versican. Protein expression levels were evaluated using digitized slides, and scores were finally dichotomized into a positive or negative score per sample.ResultsLumican and versican expression were both observed in neoplastic cells and in the tumor stroma of colon adenomas and carcinomas. Lumican expression was more frequently present in epithelial cells of carcinomas than adenomas (49% versus 18%; P = 0.0001) and in high-risk adenomas and carcinomas combined compared to low-risk adenomas (43% versus 16%; P = 0.005). Versican staining in the tumor stroma was more often present in high-risk adenomas combined with carcinomas compared to low-risk adenomas (57% versus 36%; P = 0.03) and was associated with the presence of gain of 13q (71% versus 44%; P = 0.04).ConclusionEpithelial lumican and stromal versican protein expression are increased during colorectal adenoma-to-carcinoma progression.

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Multiple genes at the chromosome 20q amplicon contribute to colorectal adenoma to carcinoma progression

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