Figure 5

Sequencing analysis of HER2-positive and HER2-negative components of HER2 heterogeneous breast cancers identified founder genetic events and intra-tumor mutational heterogeneity. (A) Clonal frequencies of mutations identified in HER2-positive and HER2-negative components of HER2 heterogeneous breast cancers T6, T11 and T12, which were subjected to whole exome sequencing and orthogonal validation by amplicon sequencing (Ion Torrent) or targeted capture massively parallel sequencing (Illumina). Clonal mutation frequencies were estimated from the mutant allelic fractions adjusted according to tumor cellularity, tumor ploidy and local copy number states using ABSOLUTE [47]. Indel, insertion and deletion; SNV, single nucleotide variant. (B) Diagram illustrating the cancer cell fraction, as defined by ABSOLUTE, of mutations identified in cases T6, T11 and T12. Note the presence of subclonal mutations in the HER2-negative components of all cases, and in the HER2-positive components of cases T6 and T12. (C) Allelic fractions of mutations identified in HER2-positive and HER2-negative components of HER2 heterogeneous breast cancers obtained through targeted massively parallel sequencing analysis using a panel of 273 genes comprising genes frequently mutated in breast cancer and DNA repair-related genes. Indel, insertion and deletion; SNV, single nucleotide variant.