Dataset Information

EGAD00000000045

ABSTRACT: Genomic sequencing and transcriptome shotgun sequencing of a metastatic tumour and its recurrence after drug therapy in a single patient

PROVIDER: EGAD00000000045 | EGA |

REPOSITORIES: EGA

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Publications

Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.

Jones Steven Jm SJ Laskin Janessa J Li Yvonne Y YY Griffith Obi L OL An Jianghong J Bilenky Mikhail M Butterfield Yaron S YS Cezard Timothee T Chuah Eric E Corbett Richard R Fejes Anthony P AP Griffith Malachi M Yee John J Martin Montgomery M Mayo Michael M Melnyk Nataliya N Morin Ryan D RD Pugh Trevor J TJ Severson Tesa T Shah Sohrab P SP Sutcliffe Margaret M Tam Angela A Terry Jefferson J Thiessen Nina N Thomson Thomas T Varhol Richard R Zeng Thomas T Zhao Yongjun Y Moore Richard A RA Huntsman David G DG Birol Inanc I Hirst Martin M Holt Robert A RA Marra Marco A MA

Genome biology 20100809 8

<h4>Background</h4>Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment.<h4>Results</h4>In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four gen ...[more]

PMID: 20696054

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Project description:Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2- primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2- circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2+ and HER2- circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance. Seventy-four single candidate CTCs from two representative ER+/HER2- patients (BRx-42 and BRx-82) and 14 triple negative patients were isolated via micromanipulation and subjected to single-cell RNA-sequencing. Thirteen candidate CTCs expressed PTPRC at a level higher than 10 reads-per-million, so were deemed potential White Blood Cells and therefore dropped from further consideration. Expression profiles of CTCs expressing ERBB2 at a level greater than 10 RPM were compared with those expressing ERBB2 at a level less than 10 RPM.

Dataset Information

EGAD00000000045

Publications

Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors.

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