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J Clin Invest. 2018 Jun 1;128(6):2310-2324. doi: 10.1172/JCI97449. Epub 2018 Apr 23.

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer.

Bao L1,2,3,4, Qian Z2, Lyng MB1,3, Wang L5, Yu Y2, Wang T5, Zhang X2, Yang H2,3, Brünner N3,4, Wang J2,3, Ditzel HJ1,3,6,7.

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Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
BGI-Shenzhen, Shenzhen, China.
Sino-Danish Breast Cancer Research Center, and.
Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Oncology, and.
Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense, Denmark.


Single cancer cell-sequencing studies currently use randomly selected cells, limiting correlations among genomic aberrations, morphology, and spatial localization. We laser-captured microdissected single cells from morphologically distinct areas of primary breast cancer and corresponding lymph node metastasis and performed whole-exome or deep-target sequencing of more than 100 such cells. Two major subclones coexisted in different areas of the primary tumor, and the lymph node metastasis originated from a minor subclone in the invasive front of the primary tumor, with additional copy number changes, including chr8q gain, but no additional point mutations in driver genes. Lack of metastasis-specific driver events led us to assess whether other clonal and subclonal genomic aberrations preexisting in primary tumors contribute to lymph node metastasis. Gene mutations and copy number variations analyzed in 5 breast cancer tissue sample sets revealed that copy number variations in several genomic regions, including areas within chr1p, chr8q, chr9p, chr12q, and chr20q, harboring several metastasis-associated genes, were consistently associated with lymph node metastasis. Moreover, clonal expansion was observed in an area of morphologically normal breast epithelia, likely driven by a driver mutation and a subsequent amplification in chr1q. Our study illuminates the molecular evolution of breast cancer and genomic aberrations contributing to metastases.


Breast cancer; Genetic variation; Genetics; Molecular genetics; Oncology

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