We compared transcript expression, and chromosomal changes on a series of tumors and surrounding tissues to determine if there is evidence of field cancerization in colorectal cancer. Epithelial cells were isolated from tumors and areas adjacent to the tumors ranging from 1 to 10cm. Tumor abnormalities mirrored those previously reported for colon cancer and while the number and size of the chromosomal abnormalities were greatly reduced in cells from surrounding regions, many chromosome abnormalities were discernable. Interestingly, these abnormalities were not consistent across the field in the same patient samples suggesting a field of chromosomal instability surrounding the tumor. A mutator phenotype has been proposed to account for this instability which states that the genotypes of cells within a tumor would not be identical, but would share at least a single mutation in any number of genes, or a selection of genes affecting a specific pathway which provide a proliferative advantage.
BackgroundStudies using microarray analysis of colorectal cancer have been generally beleaguered by the lack of a normal cell population of the same lineage as the tumor cell. One of the main objectives of this study was to generate a reference gene expression data set for normal colonic epithelium which can be used in comparisons with diseased tissues, as well as to provide a dataset that could be used as a baseline for studies in alternative splicing.ResultsWe present a dependable expression reference data set for non-neoplastic colonic epithelial cells. An enriched population of fresh colon epithelial cells were obtained from non-neoplastic, colectomy specimens and analyzed using Affymetrix GeneChip EXON 1.0 ST arrays. For demonstration purposes, we have compared the data derived from these cells to a publically available set of tumor and matched normal colon data. This analysis allowed an assessment of global gene expression alterations and demonstrated that adjacent normal tissues, with a high degree of cellular heterogeneity, are not always representative of normal cells for comparison to tumors which arise from the colon epithelium. We also examined alternative splicing events in tumors compared to normal colon epithelial cells.ConclusionsThe findings from this study represent the first comprehensive expression profile for non-neoplastic colonic epithelial cells reported. Our analysis of splice variants illustrate that this is a very labor intensive procedure, requiring vigilant examination of the data. It is projected that the contribution of this set of data derived from pure colonic epithelial cells will enhance studies in colon-related disease and offer a vital baseline for studies aimed at elucidating the mechanisms of alternative splicing.
Recent trials have shown remarkable efficacy from combined trastuzumab and chemotherapy in the adjuvant setting of breast cancer. In spite of these successes, refractory breast cancer has emerged as a clinically problematic outcome for a subset of patients managed this way. In an effort to clarify and optimize the treatment regimens for breast cancer patients who are candidates to receive trastuzumab, we sought to analyze whether a distinctive genetic signature could be characterized that would reliably predict the treatment outcome. The ability to predict who will respond and who will become refractory to this agent will allow for improved, rational clinical management of these patients and further stratify the personalized nature of this treatment regimen. In this study, 41 consecutive cases of breast carcinoma with well-documented amplification of the human epidermal growth factor receptor-2 gene and corresponding banked fresh-frozen tissue were identified and divided into two separate groups based on whether they received trastuzumab or not. The first group consisted of 12 patients who had received trastuzumab in the adjuvant setting, of which three later experienced tumor recurrence. The second group consisted of 10 patients not treated with trastuzumab, of which 6 were later found to have recurrence. Differentially expressed genetic profiles were determined using human genomewide Illumina Bead Microarrays. The differentially expressed genes for non-recurrence vs recurrence in the trastuzumab-treated group were distinct from those in the same comparison group in the untreated group. Differential expression of key genes indentified in this study might offer an insight into a possible mechanism of trastuzumab resistance in breast carcinoma, and may emerge as potential predictive biomarkers indicative of trastuzumab resistance.
The absence of mutations in exon 17 of CD117+ SCLC suggests this tumour may respond to therapy with TKI.
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