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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 6

Genome regions associated with lymph node metastasis in breast cancers identified by whole-genome association analysis of detailed copy ratios.

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Genome regions associated with lymph node metastasis in breast cancers i...
(A) Differences in the average logR (outer circle) across the whole genome between primary ER+ breast cancers of patients with N0 (265 samples) and N2–N3 (106 samples) lymph node metastasis status (data from TCGA). P value of each gene (inner circle) was calculated for the logRs between the 2 groups (Wilcoxon’s rank sum test); red bars denote genes with P < 0.02. (B) Comparison of copy ratios of AURKA (chr20q), CDKN2A (chr9p), MYC (chr8q), MDM2 (chr12q), SMAD2 (chr18q), and SMC3 (chr10q) in the TCGA ER+ breast cancers grouped according to patient lymph node status (N0, N1, and N2–N3,). Significance of difference between N0 and N2–N3 groups was tested by Wilcoxon’s rank sum test. Each point represents the copy ratio of 1 sample. (C) Comparison of copy ratios of MCL1, MYC, and BCL2L1 in 170 Danish primary ER+ breast cancers grouped according to the number of positive lymph nodes of the patient (of n = 0, 0 < n < 3, and n ≥ 3) and recurrence status (recurrence [Recur] vs. without recurrence [Free]). Significance of difference between n = 0 and n ≥ 3 groups and between recurrence and without recurrence groups was tested by Wilcoxon’s rank sum test. Each point represents the copy ratio of 1 sample. Error bars in B and C represent the values of median and upper and lower quartiles.

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

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