Abstract
A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. The genetic concordance between different steps of malignant progression is mostly unexplored as very few studies have included cancer samples separated by both space and time. We applied whole exome sequencing and targeted deep sequencing to 26 successive samples from six patients with metastatic estrogen receptor (ER)-positive breast cancer. Our data provide support for both linear and parallel progression towards metastasis. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence. This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis.
Highlights
A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively
We analyzed a set of six breast cancers with matched premalignant, synchronous axillary lymph node metastases and/or asynchronous distant metastases (Table 1, Supplementary Table S1). aDM from four of the patients were biopsied with a relapse time between 1.82–4.05 years
We are to the best of our knowledge, the first to report a detailed description of the mutational evolution through successive steps of breast cancer progression with establishment of the clonal origin of metastases, revealing complex patterns of metastatic spread
Summary
A main controversy in cancer research is whether metastatic abilities are present in the most advanced clone of the primary tumor or result from independently acquired aberrations in early disseminated cancer cells as suggested by the linear and the parallel progression models, respectively. We report for the first time evidence of metastasis-to-metastasis seeding in breast cancer. Our results point to three distinct routes of metastasis emergence This may have profound clinical implications and provides substantial novel molecular insights into the timing and mutational evolution of breast cancer metastasis. Two studies of single breast cancer patients have provided support for a linear progression model, where metastases emerge from late occurring advanced clonal subpopulations[8,9]. We provide evidence of three distinct routes of breast cancer progression and find diverse patterns of progression among and even within patients
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