Project description:PURPOSE: Bone marrow (BM) is a common homing organ for early disseminated tumor cells (DTC) and their presence can predict the subsequent occurrence of overt metastasis and survival in lung cancer. It is still unclear whether the shedding of DTC from the primary tumor is a random process or a selective release driven by a specific genomic pattern. EXPERIMENTAL DESIGN: DTCs were identified in BM from lung cancer patients by an immunocytochemical cytokeratin assay. Genomic aberrations and expression profiles of the respective primary tumors were assessed by microarrays and FISH analyses. The most significant results were validated on an independent set of primary lung tumors and brain metastases. RESULTS: Combination of DNA copy number profiles (array CGH) with gene expression profiles identified five chromosomal regions differentiating BM-negative from BM-positive patients (4q12-q32, 10p12-p11, 10q21-q22, 17q21 and 20q11-q13). Copy number changes of 4q12-q32 were the most prominent finding, containing the highest number of differentially expressed genes irrespective of chromosomal size (p=0.018). FISH analyses on further primary lung tumor samples confirmed the association between loss of 4q and the BM-positive status. In BM-positive patients 4q was frequently lost (37% vs. 7%), whereas gains could be commonly found among BM-negative patients (7% vs. 17%). The same loss was also found to be common in brain metastases from both small and non-small-cell lung cancer patients (39%). CONCLUSIONS: Thus, our data indicates for the first time that early hematogeneous dissemination of tumor cells might be driven by a specific pattern of genomic changes.
Project description:Recent insights into the role of the VHL tumor suppressor gene in hereditary and sporadic clear cell carcinoma of the kidney (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of 3 genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors, and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into 2 groups: one group with genomic profiles highly dissimilar to the majority of ccRCC, and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL. Keywords: comparative genomic hybridization 90 clear cell renal cell carcinomas and 21 renal cancer cell lines were subject to 250K SNP analysis.
Project description:Recent insights into the role of the VHL tumor suppressor gene in hereditary and sporadic clear cell carcinoma of the kidney (ccRCC) have led to new treatments for patients with metastatic ccRCC, although virtually all patients eventually succumb to the disease. We performed an integrated, genome-wide analysis of copy-number changes and gene expression profiles in 90 tumors, including both sporadic and VHL disease-associated tumors, in hopes of identifying new therapeutic targets in ccRCC. We identified 14 regions of nonrandom copy-number change, including 7 regions of amplification (1q, 2q, 5q, 7q, 8q, 12p, and 20q) and 7 regions of deletion (1p, 3p, 4q, 6q, 8p, 9p, and 14q). An analysis aimed at identifying the relevant genes revealed VHL as one of 3 genes in the 3p deletion peak, CDKN2A and CDKN2B as the only genes in the 9p deletion peak, and MYC as the only gene in the 8q amplification peak. An integrated analysis to identify genes in amplification peaks that are consistently overexpressed among amplified samples confirmed MYC as a potential target of 8q amplification and identified candidate oncogenes in the other regions. A comparison of genomic profiles revealed that VHL disease-associated tumors are similar to a subgroup of sporadic tumors, and thus more homogeneous overall. Sporadic tumors without evidence of biallelic VHL inactivation fell into 2 groups: one group with genomic profiles highly dissimilar to the majority of ccRCC, and a second group with genomic profiles that are much more similar to tumors with biallelic inactivation of VHL. Keywords: comparative genomic hybridization
Project description:Lung cancer is the leading cause of cancer mortality and early detection is the key to improve survival. However, there are no reliable blood-based tests currently available for early-stage lung cancer diagnosis. Here, we performed single-cell RNA sequencing of early-stage lung cancer and found lipid metabolism was broadly dysregulated in different cell types and glycerophospholipid metabolism is the most significantly altered lipid metabolism-related pathway. Untargeted lipidomics were detected in an exploratory cohort of 311 participants. Through support vector machine algorithm-based and mass spectrum-based feature selection, we have identified nine lipids as the most important detection features and developed a LC-MS-based targeted assay utilizing multiple reaction monitoring. This target assay achieved 100.00% specificity on an independent validation cohort. In a hospital-based lung cancer screening cohort of 1036 participants examined by low dose CT and a prospective clinical cohort containing 109 participants, this assay reached over 90.00% sensitivity and 92.00% specificity. Accordingly, matrix-assisted laser desorption/ionization-mass spectrometry imaging assay confirmed the selected lipids were differentially expressed in early-stage lung cancer tissues in situ. Thus, this method, designated as Lung Cancer Artificial Intelligence Detector (LCAID), may be used for early detection of lung cancer or large-scale screening of high-risk populations in cancer prevention.
Project description:Non small cell lung cancer is the leading cause of cancer related mortality in the western world. RNA expression profiles have been demonstrated to be associated with a specific clinical course of the disease. We used microarray analysis to capture the whole transcriptome of a series of lung cancer cell lines to extract RNA profiles associated with specific genomic lesions Keywords: steady state Lung cancer cell lines were exponentially grown and harvested during this phase of exponential growth
Project description:Non small cell lung cancer is the leading cause of cancer related mortality in the western world. RNA expression profiles have been demonstrated to be associated with a specific clinical course of the disease. We used microarray analysis to capture the whole transcriptome of a series of lung cancer cell lines to extract RNA profiles associated with specific genomic lesions Keywords: steady state