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Single-nucleotide polymorphism array analysis reveals distinct chromosomal aberrations in breast cancer tumors according to the circulating tumor cells status

ABSTRACT: Recent technological advances have made it possible to detect circulating breast cancer cells as precursors of distant metastasis and as prognosis marker in nonmetastatic breast cancer patients. Association of circulating tumor cells (CTCs) with molecular alteration in the primary tumor is not widely explored. We reported differential profile of altered genome, copy number alteration and copy-neutral loss of heterogeneity in 14 primary tumors when comparing patients with CTCs+ versus CTCs- using single-nucleotide polymorphism array. The most prevalent copy number alteration in CTCs+ patients was at 8q and particularly at the cytoband 8q24 (MYC loci). As the role of MYC in the process of tumor cell invasion and migration is controversial, we further validated in a larger series of patients whether altered MYC (amplification or gained) in primary tumors was correlated with the presence of CTCs in peripheral blood (as a surrogate of micrometastais). No correlation between MYC alteration and presence of CTCs was observed, providing clinical support to the recent data that MYC suppresses cancer metastasis or at least suggesting that MYC alteration could be contributory but insufficient for the generation of CTCs. This molecular association needs to be further characterized in preclinical model and especially clinically.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43149 | GEO | 2014/11/19

SECONDARY ACCESSION(S): PRJNA184725

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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Single-nucleotide polymorphism array analysis reveals distinct chromosomal aberrations in breast cancer tumors according to the circulating tumor cells status

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