Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes
Ikram Ullah, … , Johan Hartman, Jonas Bergh
Ikram Ullah, … , Johan Hartman, Jonas Bergh
Published February 26, 2018
Citation Information: J Clin Invest. 2018;128(4):1355-1370. https://doi.org/10.1172/JCI96149.
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Research Article Genetics Oncology

Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes

Abstract

Metastatic breast cancers are still incurable. Characterizing the evolutionary landscape of these cancers, including the role of metastatic axillary lymph nodes (ALNs) in seeding distant organ metastasis, can provide a rational basis for effective treatments. Here, we have described the genomic analyses of the primary tumors and metastatic lesions from 99 samples obtained from 20 patients with breast cancer. Our evolutionary analyses revealed diverse spreading and seeding patterns that govern tumor progression. Although linear evolution to successive metastatic sites was common, parallel evolution from the primary tumor to multiple distant sites was also evident. Metastatic spreading was frequently coupled with polyclonal seeding, in which multiple metastatic subclones originated from the primary tumor and/or other distant metastases. Synchronous ALN metastasis, a well-established prognosticator of breast cancer, was not involved in seeding the distant metastasis, suggesting a hematogenous route for cancer dissemination. Clonal evolution coincided frequently with emerging driver alterations and evolving mutational processes, notably an increase in apolipoprotein B mRNA–editing enzyme, catalytic polypeptide-like–associated (APOBEC-associated) mutagenesis. Our data provide genomic evidence for a role of ALN metastasis in seeding distant organ metastasis and elucidate the evolving mutational landscape during cancer progression.

Authors

Ikram Ullah, Govindasamy-Muralidharan Karthik, Amjad Alkodsi, Una Kjällquist, Gustav Stålhammar, John Lövrot, Nelson-Fuentes Martinez, Jens Lagergren, Sampsa Hautaniemi, Johan Hartman, Jonas Bergh

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Figure 3

Phylogenetic and subclonal analysis supports a linear progression model in 4 patients.

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Phylogenetic and subclonal analysis supports a linear progression model ...
The ER, PR, and HER2 status, when available for primary tumors, is indicated above the tree. Subclonal information is represented by lines in the phylogenetic tree. The solid line represents a single subclone, while the multicolored, dotted line represents multiple subclones. Branch lengths are proportional to the number of substitutions, with the total number for each branch indicated in parentheses. Branches are annotated with known breast cancer gene alterations including somatic mutations (black), amplifications (red), and deletions (blue). Bootstrap support values, computed across 1,000 bootstrapped trees, are shown in the black circles. When subclonal analysis could not be performed for a sample due to low copy number resolution, the respective sample is colored dark gray. The time frames for metastatic relapses after the primary cancer diagnosis are indicated in months. Information on the inferred subclones and their cellular prevalence is provided in the cluster table and density plot, respectively, in Supplemental Figure 6, A, E, G, and Q for patients 1, 5, 8, and 19, respectively. (A) Patient 1 had 1 primary tumor, 2 regions of lung relapse (Lung1.R1 and Lung2.R1), and 2 regions of liver relapse (Liver1.R2 and Liver1.R2). (B) Patient 5 had 2 regions from the primary tumor (Primary1 and Primary2) and 2 bone relapses (Bone.R1 and Bone.R2). (C) Patient 8 had a primary tumor, an ALN metastasis, a skin local regional relapse (Local regional Skin.R1), and a bone metastasis (Bone.R2). (D) Patient 19 had 1 primary tumor (Primary), 1 brain relapse 3 (Brain.R3), and 2 blocks from brain relapse 5 (Brain1.R5 and Brain2.R5).