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Coexisting genomic aberrations associated with lymph node metastasis in breast cancer
Li Bao, … , Jun Wang, Henrik J. Ditzel
Li Bao, … , Jun Wang, Henrik J. Ditzel
Published March 15, 2018
Citation Information: J Clin Invest. 2018;128(6):2310-2324. https://doi.org/10.1172/JCI97449.
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Research Article Genetics Oncology

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer

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Abstract

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.

Authors

Li Bao, Zhaoyang Qian, Maria B. Lyng, Ling Wang, Yuan Yu, Ting Wang, Xiuqing Zhang, Huanming Yang, Nils Brünner, Jun Wang, Henrik J. Ditzel

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Figure 1

Subclone distribution within different tissues of the analyzed breast cancer patient.

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Subclone distribution within different tissues of the analyzed breast ca...
(A) Schematic representation of the tissues analyzed by WES of single cells and cell pools and the distribution of the different subclones within these areas. MT, metastasis. (B) Axillary lymph node containing large MT stained for estrogen receptor. (C) Magnification of an area of the lymph node exhibiting normal architecture and morphology, but also containing disseminated single cancer cells. (D) H&E-stained section of the BN-T including normal breast ducts. (E) Magnification of an area of D showing normal breast epithelia. (F) H&E-stained section of the primary tumor biopsy provides a spatial overview of the 3 solid growth tumor areas selected for LCM in addition to the InvF. (G and H) Solid growth area 2 (PT2). (I and J) Border of solid growth area 1 (PT1) including the InvF. H and J are stained for Ki-67, while G and I are stained for ER. Original magnification: ×12.5 (D, E, F); ×100 (B, C, K, L, M, N); ×50 (G, H, I, J). Section containing area of DCIS stained with H&E (K), and for ER (L), CK14 (M), and Ki-67 (N). (M) The intact myoepithelial layer is visualized by staining for CK14.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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