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Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE13191 | GEO | 2009/10/05

SECONDARY ACCESSION(S): PRJNA109481

REPOSITORIES: GEO

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Project description:The aim of this study was to establish a single-cell array comparative genomic hybridization (SCaCGH) method providing in-depth genomic analysis of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs). The robustness and resolution limits of the method were estimated with different cell amounts of the breast cancer cell line SKBR3 using 44k and 244k arrays. Subsequent adjustments of the method were conducted analyzing the copy number profiles of 28 CTCs in combination with four hematopoietic cell (HC) controls from eight metastatic patients and of 24 DTCs, three probable HCs, and five HC controls from seven breast cancer patients and one healthy donor. The frequency of the major genomic gains and losses of the analyzed DTC revealed similarities to primary breast tumor samples with some evident differences. Three of the patients had available profiles for DTC and the corresponding primary tumor. In 2/3 of the examined DTCs, equivalent genomic changes and common aberration breakpoints were disclosed, both to each other and to the corresponding primary tumors. Interestingly, similar copy number changes were found in DTCs taken at time of diagnosis or in DTCs collected at 3-years relapse-free follow up. Residual immunomorphological characterized tumor cells showed balanced profiles with only minor aberrations. Three cells with unclear morphological identification showed either balanced profiles (n=2) or aberrations comparable to the primary tumor and DTC (n=1). SCaCGH may be a powerful tool for molecular characterisation of immunostained and morphological identified CTCs and DTCs to explore the malignant potential, therapeutic targets and tumor heterogeneity of single tumor cells. 24 DTCs, 3 probable HCs, and 5 HCs from 7 early-stage breast cancer patients, 28 CTCs and 4 HCs from 8 metastatic breast cancer patients, and 1 healthy donor were analysed. Comparison with the primary tumor was done in 3 patients. The reference for the patients was DNA from multiple anonymous female donors. This submission does not include the SKBR3 data obtained from the 44k array.

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Genomic Profiles Associated with Early Micrometastasis in Lung Cancer: Relevance of 4q Deletion

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