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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 4

Comparison of mutations and CNVs in the Chinese sample set of 54 primary breast cancers between patients with and without lymph node metastasis revealed MCL1 is more frequently altered in primary cancers of patients with lymph node metastases.

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Comparison of mutations and CNVs in the Chinese sample set of 54 primary...
(A) Heatmaps of CNVs of primary tumors from a Chinese sample set of 54 breast cancer patients with (upper panel) and without (lower panel) lymph node metastasis. Gain and loss are displayed by red and blue, respectively. (B) Mutational spectrum of 54 primary breast cancers with (left panel) and without (right panel) lymph node metastasis. The left panel (yellow bar plot) shows P values (Fisher’s exact test) for aberrant samples in the 2 subgroups for each gene. The middle panel (bar plot) shows the proportion of aberrant samples in each subgroup.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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