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The expression profile of 5-fluorouracil pathway genes in colorectal carcinoma

ABSTRACT: This study addressed involvement of fourteen 5-fluorouracil pathway genes in the prognosis of colorectal carcinoma patients. The major goal of our study was to investigate associations of gene expression of enzymes metabolizing 5-fluorouracil with therapy response and survival of colorectal carcinoma patients Downregulation of DPYD and upregulation of PPAT, UMPS, RRM2, and SLC29A1 transcripts were found in tumors compared to adjacent mucosas in testing and validation sets of patients. Low RRM2 transcript level significantly associated with poor response to the first-line palliative 5-FU-based chemotherapy in the testing set and with poor disease-free interval of patients in the validation set.

ORGANISM(S): Homo sapiens

PROVIDER: GSE67111 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA278973

REPOSITORIES: GEO

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Project description:Background: Colorectal cancer is the third most common and the fourth most lethal cancer in the world. In the majority of cases, patients are diagnosed at an advanced stage or even metastatic, thus explaining the high mortality. The standard protocol for treating patients with locally advanced non-metastatic colorectal cancer (CRC) is neoadjuvant radio-chemotherapy (NRCT) with 5-fluorouracil (5-FU), but the resistance rate to this treatment remains high with approximately 30% of non-responders. The lack of evidence available in clinical practice to predict NRCT resistance to 5-FU and to guide clinical practice therefore encourages the search for biomarkers of this resistance. Methods: From twenty-three formalin-fixed paraffin-embedded (FFPE) biopsies performed before NRCT with 5-FU of locally advanced non-metastatic CRC patients, we extracted and analysed the tumor proteome of these patients. From clinical data, we were able to classify the twenty-two patients in our cohort into three treatment response groups: non-responders (NR), partial responders (PR) and total responders (TR), and to compare the proteomes of these different groups. Results: We have highlighted 384 differentially expressed proteins between NR and PR, 248 between NR and TR and 417 between PR and TR. Among these proteins, we have identified many differentially expressed proteins identified as having a role in cancer (IFIT1, FASTKD2, PIP4K2B, ARID1B, SLC25A33: overexpressed in TR; CALD1, CPA3, B3GALT5, CD177, RIPK1: overexpressed in NR). We have also identified that DPYD, the main degradation enzyme of 5-FU, was overexpressed in NR, as well as several ribosomal and mitochondrial proteins also overexpressed in NR. Conclusions: From these retrospective study, we implemented a protein extraction protocol from FFPE biopsy to highlight protein differences between different response groups to RCTN with 5-FU in patients with locally advanced non-metastatic CRC. These results will pave the way for a larger cohort for better sensitivity and specificity of the signature to guide decisions in the choice of treatment.

Project description:Prostate cancer (PCa) is the second most prevalent malignancy in Western countries and the fifth leading cause of cancer-related death in men. The risk factors for PCa include obesity, age, and family history. Visceral fat has been linked to PCa risk, which has prompted researchers to investigate the influence of body composition and fat distribution on PCa prognosis. This study investigated the correlation between the composition of pelvic adipose tissue (PAT) and PCa aggressiveness to understand the role played by this tissue in PCa progression. Moreover, we prepared a periprostatic adipose tissue (PPAT)-conditioned medium (CM) to determine the influence of the PPAT secretome on the pathophysiology of PCa. This study included 60 patients with localized PCa who received robot-assisted radical prostatectomy. Medical records were collected, and magnetic resonance imaging scans were analyzed, and body compositions were calculated to identify the correlations between adipose tissue volume and clinical PCa aggressiveness. CM was prepared using PPAT and perivesical adipose tissue (PVAT) collected from 25 patients during surgery, and its influence was investigated using the PCa cell lines C4-2 and LNCaP and the prostate epithelial cell line PZ-HPV-7. Cell proliferation assays and RNA sequencing were performed. The initial prostate-specific antigen level was significantly correlated with pelvic and perirectal adipose tissue volumes. PPAT volume was significantly higher in patients with extracapsular tumor extension. PCa cells proliferated was significantly slower when cultured in PPAT-CM compared with when cultured in control- and PVAT-CM. RNA sequencing revealed that immune responses and the cell death and apoptosis pathways were enriched in PPAT-CM-cultured cells. The cytokines or other secreted factors in PPAT-CM induced PCa cell apoptosis. This in vitro study revealed that the PPAT secretome inhibits PCa cells proliferation by activating immune responses and promoting cancer cell apoptosis. This mechanism may act as a first-line defense during the early stages of PCa.

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The expression profile of 5-fluorouracil pathway genes in colorectal carcinoma

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