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

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 BRCA2mutated breast cancer. While longitudinal WES-cfDNA recapitulated clonal and subclonal mutations and copy number profiles detected in LR, emergence of plasmaexclusive 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 platinumbased 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. Conception and design: RAT, JAS, MRO, RCC Development of methodology: RAT, RKH, MV, ABMC, KP, LP, DG, LM Acquisition of data (acquired and managed patients, provided facilities, etc.): KK, AT, SA, CR, MRO Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): RKH, RAT, MV, DFG, BT, LM, JAS