Mutation profiling of key cancer genes in primary breast cancers and their distant metastases

Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease, with higher incidence of brain metastases than ER-positive/HER2-negative cancers. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2-positive (n=9) and ER-, progesterone receptor (PR-), HER2-negative (n=8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes. A large subset of non-synonymous somatic mutations (45%) and gene copy number alterations (55%) were shared between the primary tumors and paired metastases. However, mutations restricted to either a given primary tumor or its metastasis, the acquisition of loss of heterozygosity of the wild-type allele and clonal shifts of genes affected by somatic mutations such as TP53 and RB1 were observed in the progression from primary tumors to metastases. No metastasis location-specific alterations were identified, but synchronous metastases showed higher concordance with the paired primary tumor than metachronous metastases. Novel potentially targetable alterations were found in the metastases relative to their matched primary tumors. These data indicate that repertoires of somatic genetic alterations in ER-negative metastatic breast cancers may differ from those of their primary tumors, even by the presence of driver and targetable somatic genetic alterations.

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