Project description:Biopsies (lymph nodes, ascites or hydrothorax) from 60 patients with cancer of unknown primary origin were analyzed. Results provide insight into the molecular pathogenesis of CUP.
Project description:Biopsies (lymph nodes, ascites or hydrothorax) from 60 patients with cancer of unknown primary origin were analyzed. Results provide insight into the molecular pathogenesis of CUP.
Project description:Biopsies (lymph nodes, ascites or hydrothorax) from 60 patients with cancer of unknown primary origin were analyzed. Results provide insight into the molecular pathogenesis of CUP. 60 samples; 1 array per sample
Project description:Employing genome wide transcriptome analysis,Linear Discriminant Analysis (LDA) and Quadratic Discriminant Analysis (QDA), we created a successful classification model to identify the putative origin of a CUP. Using the classifications of the CUPs enable the comparison of transcriptome profiles from CUPs to the equivalent normal metastasis across the different carcinoma types. Gene Set Enrichment Analysis (GSEA) and Pathway analysis were used to reveal the common biological features characterizing CUPs. The classifier was build using 2208 samples of normal tissue, known primary tumors, metastasis of known origin and tested on 60 CUP samples. 130 of these samples were collected and analyzed as part of the project and submitted to ArrayExpress. The analyses show that CUPs are distinct from metastases of known origin. CUPs exhibit inconsistent expression of conventional cancer biomarkers and QDA derived outlier scores show that CUPs are more distantly related to their primary tumor class than corresponding metastases of known origin. Gene set enrichment analysis showed that CUPs display increased expression of genes involved in DNA damage repair and by employing signatures of chromosome instability (CIN), we found that CUPs are chromosome unstable compared to metastases of known origin.
Project description:Carcinomas of unknown primary (CUP) are characterized by early metastatic dissemination in the absence of a detectable primary tumor. This disease accounts for about 3% of all malignant tumors. Most CUPs are poorly responsive to chemotherapy and have a rapid fatal evolution. The biological mechanisms supporting metastatic growth in various sites combined with regression or absence of growth in the primary site are still poorly understood. The aim of this project was to investigate characteristics of gene expression profile specific of CUPs with special attention to genes overexpressed or silenced in CUPs but not in classical secondary metastases. Three series of experiments were performed in 2006 and 2007. In all experiments, the mRNA used as a reference was obtained from diploid untransformed human fibroblasts (MRC5). The CUP samples were 2 xenografted CUP tumors (Capi1 and Capi3) and 4 CUP biopsies including a squamous carcinoma (Aud) and 3 adenocarcinomas (Gal, Pro, Gag). Samples representative of secondary metastases were xenografted tumors derived from metastases of nasopharyngeal carcinoma (C17), lung adenocarcinoma (IC14) and pancreatic adenocarcinoma (xenografted Capan 1 cell line) and one biopsy from a breast carcinoma (Vuc).
Project description:Cancers of Unknown Primary (CUPs), featuring metastatic dissemination in the absence of a primary tumor, are a biological enigma and a fatal disease. We propose that CUPs are a distinct, yet unrecognized, pathological entity originating from stem-like cells endowed with distinguished properties. These cells can be isolated in vitro (agnospheres) and propagated in vivo by serial transplantation, displaying a high tumor-initiating cell frequency. After subcutaneous engraftment, agnospheres recapitulated the CUP phenotype, by spontaneously and quickly disseminating, and forming widespread established metastases. Regardless of different genetic backgrounds, agnospheres invariably displayed cell-autonomous proliferation and self-renewal, mostly relying on unrestrained activation of the MAP kinase/MYC axis, which confers sensitivity to MEK inhibitors in vitro and in vivo. Such sensitivity is associated with a transcriptomic signature predicting that more than 70% of CUP patients could be eligible to MEK inhibition. These data shed light on CUP biology and unveil an opportunity for therapeutic intervention.
Project description:Carcinomas of unknown primary (CUP) are characterized by early metastatic dissemination in the absence of a detectable primary tumor. This disease accounts for about 3% of all malignant tumors. Most CUPs are poorly responsive to chemotherapy and have a rapid fatal evolution. The biological mechanisms supporting metastatic growth in various sites combined with regression or absence of growth in the primary site are still poorly understood. The aim of this project was to investigate structural genome alterations specifically detected by CGH-array in CUP but not in classical secondary metastases. The design of the project was as follows : 5 samples representative of CUPs were compared to 3 samples representative of classical secondary metastases. The CUP samples were : a) 3 fresh biopsies containing more than 60 % malignant cells on tissue sections adjacent to the tumor fragment used for DNA extraction (Gal., Pro., Gag.); b) 2 fragment derived from 2 xenografted CUP tumor lines, Capi 1 and Capi 3 respectively. The samples derived from classical secondary metastases were : a) one fresh biopsy fragment derived from the secondary metastasis of a rectal adenocarcinoma (Vuc.); b) fragments of a tumor resulting from a xenograft of Capan 1, an in vitro cell line derived from a pancreatic adenocarcinoma secondary metastasis; 3) fragments of a xenografted tumor derived from a lung adenocarcinoma metastasis called IC14 (NSCLC).