Research Papers:

Sequencing of cancer cell subpopulations identifies micrometastases in a bladder cancer patient

Kris Prado, Kelvin X. Zhang, Matteo Pellegrini and Arnold I. Chin _

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Oncotarget. 2017; 8:45619-45625. https://doi.org/10.18632/oncotarget.17312

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Kris Prado1,*, Kelvin X. Zhang2,*, Matteo Pellegrini3,4,5 and Arnold I. Chin1,4,5

1Department of Urology, UCLA, Los Angeles, CA 90095, USA

2Merck Sharp & Dohme Co., Computational Genomics and Informatics, Boston, MA 02210, USA

3Department of Molecular, Cell, and Developmental Biology, UCLA, Los Angeles, CA 90095, USA

4Broad Stem Cell Research Center, UCLA, Los Angeles, CA 90095, USA

5Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA 90095, USA

*Co-first authors

Correspondence to:

Arnold I. Chin, email: [email protected]

Keywords: bladder cancer, next-generation sequencing, micrometastases, cancer initiating cells, pathologic staging

Abbreviations: CSC = cancer stem cells, GSEA = gene set enrichment analysis, PCA = principle component analysis, SNV = single nucleotide variations

Received: January 25, 2017    Accepted: April 06, 2017    Published: April 21, 2017


Purpose: Pathologic staging of bladder cancer patients remains a challenge. Standard-of-care histology exhibits limited sensitivity in detection of micrometastases, which can increase risk of cancer progression and delay potential adjuvant therapies. Here, we sought to develop a proof of concept novel molecular approach to improve detection of cancer micrometastasis.

Experimental Design: We combined fluorescence activated cell sorting and next-generation sequencing and performed whole-exome sequencing of total cancer cells and cancer cell subpopulations in multiple tumor specimens and regional lymph nodes in a single patient with muscle-invasive urothelial carcinoma of the bladder following radical cystectomy.

Results: Mean allele frequency analysis demonstrated a significant correlation between primary tumor cancer cells and cancer cells isolated from the lymph nodes, confirming lymph node disease despite negative pathologic staging. RNA-sequencing revealed intratumoral heterogeneity as well as enrichment for immune system and lipid metabolism gene sets in the micrometastatic cancer cell subpopulations.

Conclusions: Our analysis illustrates how next-generation sequencing of cancer cell subpopulations may be utilized to enrich for cancer cell markers and enhance detection of bladder cancer micrometastases to improve pathologic staging and provide insight into cancer cell biology.

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