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Efficient identification of microRNAs for classification of tumor origin (I)

ABSTRACT: Carcinomas of unknown primary origin constitute 3-5% of all newly diagnosed metastatic cancers, of which the primary source is difficult to classify with current histological methods. Effective cancer treatment depends on early and accurate identification of the tumor, which is why patients with metastases of unknown origin have poor prognosis and short survival. Because microRNA expression is highly tissue specific, the microRNA profile of a metastasis may be used to identify its origin. As a first step to realize this goal, we evaluated the potential of microRNA profiling for identification of the primary tumor of known metastases. 208 formalin-fixed paraffin-embedded samples representing 15 different histologies were profiled on an LNA-enhanced microarray platform, which allows for highly sensitive and specific detection of microRNA. Based on these data, we developed and cross-validated a novel classification algorithm, LASSO (Least Absolute Shrinkage and Selection Operator), which had an overall accuracy of 85%. When the classifier was applied on an independent test set of 48 metastases, the primary site was correctly identified in 42 cases (88% accuracy). Our findings suggest that microRNA expression profiling on paraffin tissue can efficiently predict the primary origin of a tumor, and may provide pathologists with a molecular diagnostic tool that can improve their capability to correctly identify the origin of hitherto unidentifiable metastatic tumors, and eventually, enable tailored therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE50890 | GEO | 2013/12/01

SECONDARY ACCESSION(S): PRJNA219310

REPOSITORIES: GEO

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Efficient identification of microRNAs for classification of tumor origin (I)

Project description:Carcinomas of unknown primary origin constitute 3-5% of all newly diagnosed metastatic cancers, of which the primary source is difficult to classify with current histological methods. Effective cancer treatment depends on early and accurate identification of the tumor, which is why patients with metastases of unknown origin have poor prognosis and short survival. Because microRNA expression is highly tissue specific, the microRNA profile of a metastasis may be used to identify its origin. As a first step to realize this goal, we evaluated the potential of microRNA profiling for identification of the primary tumor of known metastases. 208 formalin-fixed paraffin-embedded samples representing 15 different histologies were profiled on an LNA-enhanced microarray platform, which allows for highly sensitive and specific detection of microRNA. Based on these data, we developed and cross-validated a novel classification algorithm, LASSO (Least Absolute Shrinkage and Selection Operator), which had an overall accuracy of 85%. When the classifier was applied on an independent test set of 48 metastases, the primary site was correctly identified in 42 cases (88% accuracy). Our findings suggest that microRNA expression profiling on paraffin tissue can efficiently predict the primary origin of a tumor, and may provide pathologists with a molecular diagnostic tool that can improve their capability to correctly identify the origin of hitherto unidentifiable metastatic tumors, and eventually, enable tailored therapy. 94 samples

2013-12-01 | E-GEOD-50890 | biostudies-arrayexpress

microRNA epxression patterns can discriminate between patients with oligometastatic and polymetastatic progression: tissues

Project description:Cancer staging and treatment frequently assume a binary division of tumors into localized or metastatic cancers. We proposed a state of metastatic disease defined by the number of metastases termed oligometastases. Patients with oligometastatic disease may be cured with localized methods of cancer treatment. We analyzed miRNA expression from paraffin blocks of primary or metastatic tumor samples derived from oligometastatic (≤ 5 metastases) patients treated with high dose localized radiotherapy. We report patterns of miRNA expression in the metastatic and primary tumor samples that identify patients who failed to progress to widespread polymetastases. We created a model of oligometastases of human tumors in immune compromised mice. The miRNA patterns of gene expression derived from patients accurately identified oligometastatic patterns in the mouse model as compared to animals that developed widespread metastases. MiRNA signatures may identify patients most likely to benefit from aggressive curative treatment of limited metastatic disease. Tissues: We collected samples from 5 patients with both primary and metastatic tumors available for analysis, 20 patients with primary tumors only, and 9 patients with metastatic tumors only. Eleven of these patients were analyzed retrospectively, while 23 patients were included prospectively from a previously reported radiotherapy protocol for oligometastatsis. Total RNA were derived from FFPE primary and metastatic tissue samples.

2010-11-25 | E-GEOD-25552 | biostudies-arrayexpress

Genomic Signatures of Metastasis in Prostate Cancer

Project description:Background: Metastases result in 90% of all cancer deaths. Prostate cancer primary tumors evolve to become metastatic through selective alterations, such as amplification and deletion of genomic DNA. Methods: Genomic DNA copy number alterations were used to develop a gene signature that measured the metastatic potential of a prostate cancer primary tumor. We studied the genomic landscape of these alterations in 294 primary tumors and 49 metastases from 5 independent cohorts. Receiver-operating characteristic cross-validation and Kaplan-Meier survival analysis were performed to assess the accuracy of our predictive model. The signature was measured in a panel of 337 cancer cell lines from 29 different tissue origins. Results: We identified 399 copy number alterations around genes that were over-represented in metastases and predictive of whether a primary tumor will metastasize. Cross-validation analysis resulted in a predictive accuracy of 80.5% and log rank analysis of the metastatic potential score was significantly related to the endpoint of metastasis-free survival (p=0.014). The metastatic signature was observed in cell lines originating from lung, breast, colon, thyroid, rectum, pancreas and melanoma. The signature was comprised in part of genes of known or putative metastatic role — 8 solute carrier genes, 6 Cadherin family genes and 5 potassium channel genes — that function in metabolism, cell-to-cell adhesion and escape from anoikis/apoptosis. Conclusions: Somatic Copy number alterations are an independent predictor of metastatic potential. The data indicate a prognostic utility for using primary tumor genomics to assist in clinical decision making and developing therapeutics for prostate and likely other cancers. genomic DNA from 29 prostate cancer tumors with matched normals run on Affymetrix 6.0 SNP arrays.

2013-12-01 | E-GEOD-27105 | biostudies-arrayexpress

Transcription profiling of oral cavity samples from human squamous cell carcinoma patients

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2007-08-25 | E-GEOD-2280 | biostudies-arrayexpress

Primary and secondary ovarian tumors

Project description:The distinction between primary and secondary ovarian tumors may be challenging for pathologists. We performed transcriptomic analysis in order to discriminate between primary ovarian tumors and ovarian metastases after primary breast cancer. We performed genomic analysis on tumor paired samples (breast/ovary) in order to know if genomic profiles could help for the discrimination of primary ovarian tumors and ovarian metastases after primary breast cancer.

2010-04-14 | GSE20565 | GEO

Differential Proteome Analysis of Human Neuroblastoma Xenograft Primary Tumors and Matched Spontaneous Distant Metastases

Project description:Metastasis formation is the major cause for cancer-related deaths and the underlying mechanisms remain poorly understood. In this study we describe spontaneous metastasis xenograft mouse models of human neuroblastoma used for unbiased identification of metastasis-related proteins by applying an infrared laser (IR) for sampling primary tumor and metastatic tissues, followed by mass spectrometric proteome analysis. IR aerosol samples were obtained from ovarian and liver metastases, which were indicated by bioluminescence imaging (BLI), and matched subcutaneous primary tumors. Corresponding histology proved the human origin of metastatic lesions. Ovarian metastases were commonly larger than liver metastases indicating differential outgrowth capacities. Among ~1,700 proteins identified at each of the three sites, 89 proteins were differentially regulated in ovarian metastases while 290 proteins were regulated in liver metastases. There was an overlap of 26 and 10 proteins up- and down-regulated at both metastatic sites, respectively, most of which were so far not related to metastasis such as LYPLA2, ACTL8, EIF4B, LGALS7, GFAP, and ELAVL4. Moreover, we established in vitro sublines from primary tumor and metastases and demonstrate differences in cellular protrusions, migratory/invasive potential and glycosylation. Summarized, this work identified several novel putative drivers of metastasis formation that are tempting candidates for future functional studies.

2018-09-24 | PXD009744 | Pride

Global gene expression profiling of human osteosarcomas of primary and metastatic origin reveals alterations in chemokine pattern

Project description:Global gene expression analysis was performed on a panel of 23 osteosarcoma samples of primary and metastatic origin using the Applied Biosystems Gene Expression Array System. When comparing the primary tumours with the metastases, we found a significantly increased expression of genes involved in immunological processes, e.g. coding for cytokines and chemokines, in the metastatic samples, suggesting that these signal molecules play an important role in promoting metastasis. In addition, a comparison of the gene expression in primary samples from patients with or without metastases demonstrated that patients who later developed metastases had high expression of the chemokine (C-X-C motif) receptor 4 (CXCR4), similar to the metastatic samples. Increased knowledge of mechanisms and interactions between specified molecular signalling pathways in osteosarcomas could lead to a more rational strategy for development of targeted therapy. Total RNA was isolated from tumor tissue of osteosarcoma patients. Gene expression patterns of metastatic versus primary samples were compared, as well as primary samples from patients who did or did not later develop metastases.

2012-01-01 | E-GEOD-32981 | biostudies-arrayexpress

Genomic Signatures of Metastasis in Prostate Cancer

2013-12-01 | GSE27105 | GEO

microRNA epxression patterns can discriminate between patients with oligometastatic and polymetastatic progression: cell lines

Project description:Cancer staging and treatment frequently assume a binary division of tumors into localized or metastatic cancers. We proposed a state of metastatic disease defined by the number of metastases termed oligometastases. Patients with oligometastatic disease may be cured with localized methods of cancer treatment. We analyzed miRNA expression from paraffin blocks of primary or metastatic tumor samples derived from oligometastatic (? 5 metastases) patients treated with high dose localized radiotherapy. We report patterns of miRNA expression in the metastatic and primary tumor samples that identify patients who failed to progress to widespread polymetastases. We created a model of oligometastases of human tumors in immune compromised mice. The miRNA patterns of gene expression derived from patients accurately identified oligometastatic patterns in the mouse model as compared to animals that developed widespread metastases. MiRNA signatures may identify patients most likely to benefit from aggressive curative treatment of limited metastatic disease. Injection of MDA-MB-435-GFP cancer cells into the mammary fat pad of female athymic mice to develop spontaneous macroscopic lung metastasis. Tail vein experimental lung colonization assay was performed to model the development of MDA-MB-435-GFP Oligo- or Poly-metastases in the lung in vivo. Cell lines: Total RNA were derived from MDA-MB-435-L1-GFP (Ol-like) or MDA-MB-435-L1Mic (Poly-like) cell lines.

2010-12-09 | E-GEOD-25967 | biostudies-arrayexpress

microRNA epxression patterns can discriminate between patients with oligometastatic and polymetastatic progression: cell lines

Project description:Cancer staging and treatment frequently assume a binary division of tumors into localized or metastatic cancers. We proposed a state of metastatic disease defined by the number of metastases termed oligometastases. Patients with oligometastatic disease may be cured with localized methods of cancer treatment. We analyzed miRNA expression from paraffin blocks of primary or metastatic tumor samples derived from oligometastatic (? 5 metastases) patients treated with high dose localized radiotherapy. We report patterns of miRNA expression in the metastatic and primary tumor samples that identify patients who failed to progress to widespread polymetastases. We created a model of oligometastases of human tumors in immune compromised mice. The miRNA patterns of gene expression derived from patients accurately identified oligometastatic patterns in the mouse model as compared to animals that developed widespread metastases. MiRNA signatures may identify patients most likely to benefit from aggressive curative treatment of limited metastatic disease. Injection of MDA-MB-435-GFP cancer cells into the mammary fat pad of female athymic mice to develop spontaneous macroscopic lung metastasis. Tail vein experimental lung colonization assay was performed to model the development of MDA-MB-435-GFP Oligo- or Poly-metastases in the lung in vivo.

2010-12-09 | GSE25967 | GEO

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