Longitudinal whole-exome sequencing of cell-free DNA unravels the metastatic evolutionary dynamics of BRCA2 mutated breast cancer

Hastings, R. K.; Openshaw, M. R.; Vazquez, M.; Moreno, A. B.; Fernandez-Garcia, D.; Martinson, L. J.; Toghill, B.; Kulbicki, K. J.; Primrose, L.; Guttery, D.; Page, K.; Richards, C.; Thomas, A.; Tabernero, J.; Coombes, R. C.; Ahmed, S.; Toledo, R.; Shaw, J. A.

doi:10.1101/2020.01.10.901330

bioRxiv · 10.1101/2020.01.10.901330

Longitudinal whole-exome sequencing of cell-free DNA unravels the metastatic evolutionary dynamics of BRCA2 mutated breast cancer

Hastings, R. K.·Openshaw, M. R.·Vazquez, M.·Moreno, A. B.·Fernandez-Garcia, D.·Martinson, L. J.·Toghill, B.·Kulbicki, K. J.·Primrose, L.·Guttery, D.·Page, K.·Richards, C.·Thomas, A.·Tabernero, J.·Coombes, R. C.·Ahmed, S.·Toledo, R.·Shaw, J. A.

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Abstract

Little is known about the metastatic evolutionary dynamics of BRCA2-mutated cancers. Here, we applied whole-exome sequencing (WES) of primary tumor (PT), local relapse (LR) and eight serial plasma cfDNA samples collected from disease progression to depict the 12 years evolutionary trajectory of a metastatic BRCA2-mutated breast cancer. While longitudinal WES-cfDNA recapitulated clonal and subclonal mutations and copy number profiles detected in LR, emergence of plasma-exclusive mutations in TSC2 and HDAC9 cancer-related genes and loss of HLA loci as an immune escape mechanism were also detected. Lastly, mutation signature 3, associated with homologous recombination deficiency and response to platinum-based therapy raised profoundly from 19% in PT to 60% in late stage disease. In conclusion, we show for the first time that longitudinal WES-cfDNA enables the evolutionary trajectory of advanced cancer to be uncovered and that increment of MS3 and loss of HLA are key players in this BRCA2-mutated breast metastasis.

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Hastings, R. K., Openshaw, M. R., Vazquez, M., Moreno, A. B., Fernandez-Garcia, D., Martinson, L. J., Toghill, B., Kulbicki, K. J., Primrose, L., Guttery, D., Page, K., Richards, C., Thomas, A., Tabernero, J., Coombes, R. C., Ahmed, S., Toledo, R., Shaw, J. A.. 2020-01-10. Longitudinal whole-exome sequencing of cell-free DNA unravels the metastatic evolutionary dynamics of BRCA2 mutated breast cancer. https://doi.org/10.1101/2020.01.10.901330

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