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1 SUPPLEMENTARY FIGURE AND TABLE LEGENDS Supplementary Fig. S1. Estrogen receptor (ER) and progesterone receptor (PR) status of MTC18 and HER2 status of MTC23 and representative Sanger sequencing traces for validated mutations. (a) Representative micrograph of a hematoxylin and eosin-stained slide of case MTC18 with (b) 1% of cells weakly expressing ER and (c) 20% of cells weakly expressing PR. (d) Representative micrograph of case MTC23 (e) lacking HER2 expression by immunohistochemistry but (f) harboring HER2 gene amplification by fluorescence in situ hybridization. (g) Genome plot of MTC23 showing HER2 gene amplification. In the genome plot, smoothed Log2 ratios (y-axis) were plotted according to their genomic positions (x-axis). The red arrow points at the HER2 gene locus. (h) Representative Sanger sequencing traces for validated mutations. Original magnification of micrographs and immunohistochemical staining 200x. Scale bar: 500 m. Supplementary Fig. S2. Repertoire of somatic non-synonymous mutations of metaplastic breast cancers (MBCs) and triple-negative invasive ductal carcinomas of no special type (IDC-NSTs). Clinico-pathologic and immunohistochemical features, and non-synonymous somatic mutations somatic mutations identified in (a) 35 MBCs subjected to whole-exome sequencing, and in 69 triplenegative IDC-NSTs from TCGA breast cancer study (9) and in (b) 16, ten and nine chondroid, spindle and squamous MBCs, respectively, subjected to whole-exome sequencing. The effects of the mutations are colored-coded according to the legend, with hotspots colored in red. Mutations of indeterminate pathogenicity and likely passenger mutations are indicated by hatched boxes. The presence of multiple non-synonymous mutations in the same gene is represented by an asterisk. For MBCs, the presence of loss of heterozygosity of the wild-type allele of a mutated gene is represented by a diagonal bar, and mutations found to be clonal by ABSOLUTE (24) are indicated by a black box. Only recurrently mutated genes are presented (i.e. genes affected by nonsynonymous somatic mutations in ≥2 MBCs). Gene names highlighted in purple were (a) 2 significantly more frequently altered in MBCs or (b) differentially altered in the given subtype of MBC. Percentages to the right of the mutation heatmaps indicate the percentage of cases affected by non-synonymous somatic mutations in a given gene. Bar charts (top) indicate the number of nonsynonymous and synonymous somatic single nucleotide variants (SNVs), and the number of somatic insertions and deletions (indels) for each sample. The dominant mutational signatures (35, 36) were assigned using deconstructSigs (37). Large-scale transitions (LST)-high and LST-low status was determined in accordance with Popova et al (39). TCGA, The Cancer Genome Atlas. Supplementary Fig. S3. Patterns of copy number alterations in metaplastic breast cancers (MBCs) and triple-negative invasive ductal carcinomas of no special type (IDC-NSTs) and unsupervised clustering of metaplastic breast cancers (MBCs) and triple-negative IDC-NSTs based on copy number alterations and somatic mutations. Frequency plot and multi-Fisher's exact test comparisons of copy number gains and losses in (a) MBCs and triple-negative IDC-NSTs and in (b) MBCs of triple-negative phenotype and triplenegative IDC-NSTs, and frequency plot and multi-Fisher's exact test comparisons of high-level gains/ amplifications and deletions in (c) MBCs and triple-negative IDC-NSTs and in (d) MBCs of triple-negative phenotype and triple-negative IDC-NSTs. In each panel (a-d), the frequency of gains/ high-level gains/ amplifications (purple bars) or losses/ deletions (orange bars) for each gene is plotted on the y-axis, according to their genomic position on the x-axis. Inverse Log10 values of the Fisher’s exact test p-values are plotted according to genomic location (x-axis). Hierarchical clustering of (e) copy number alterations of MBCs and triple-negative IDC-NSTs using categorical states (i.e. gains, losses, amplifications and homozygous deletions) using Euclidean distance metric and the Wards algorithm, and of (f) somatic non-synonymous mutations and (g) somatic likely pathogenic mutations in genes found in at least one of the cancer gene lists (29-31) or were more frequently mutated in MBCs than triple-negative IDC-NSTs using an asymmetric binary distance metric and complete-linkage hierarchical clustering. Sample types, types of copy number alterations and the presence of somatic mutation in a given gene are color-coded according to the color key. 3 Supplementary Fig. S4. Mutational signatures and genetic alterations affecting genes in the homologous recombination DNA repair pathway in metaplastic breast cancers (MBCs) and triple-negative invasive carcinomas of no special type (IDC-NSTs). (a) In bar graphs illustrating the mutational signatures, the mutations were grouped by the sequence context (i.e. AxA, AxC, AxG, AxT, CxA, CxC, CxG… TxT, where x is the mutated base), with the different colors indicating the mutation type (i.e. C>A, C>G, C>T, T>A, T>C and T>G). The height of colored bars represents the fraction of mutations attributed in each of the 96 sub-bins. (b) Genetic alterations that would result in the bi-allelic inactivation (i.e. two mutations in the same gene, one mutation associated with loss of heterozygosity or homozygous deletion) of genes known to be involved in homologous recombination DNA repair (see Supplementary Table S6) are color-coded by their effect according to the legend. Genes mutated in at least one MBC or triple-negative IDCNST are included and are ordered from top to bottom in decreasing order of mutational frequency in MBCs. The presence of loss of heterozygosity of the wild-type allele of a mutated gene is represented by a diagonal bar. Percentages to the right indicate the percentage of cases affected by non-synonymous somatic mutations in a given gene. TCGA, The Cancer Genome Atlas. Supplementary Table S1: Clinico-pathologic features and sequencing statistics of the 35 metaplastic breast cancers included in the study. Supplementary Table S2: List of somatic mutations identified in the cohort of 35 metaplastic breast cancers and list of primers used for validation with Sanger sequencing of selected mutations. Supplementary Table S3: Comparison of the mutational frequencies in metaplastic breast cancers, metaplastic breast cancers of triple-negative phenotype and triple-negative invasive ductal carcinomas of no special type. Genes with non-synonymous mutations in >5% of samples from either group of each comparison are included. 4 Supplementary Table S4: Significantly mutated genes analysis of metaplastic breast cancers (n=35) using MutSigCV and the algorithm proposed by Youn and Simon. Supplementary Table S5: Comparison of the mutational frequencies between metaplastic breast cancers with different morphologic features. Genes recurrently mutated in any of the groups in each comparison are included. Supplementary Table S6: Comparative analysis of the mutational frequencies of genes affecting selected functional pathways in metaplastic breast cancers and triple-negative invasive ductal carcinomas of no special type and correlations of mutational status with clinicopathologic parameters. p<0.05 are highlighted in bold. *: Fisher's exact test. **: Mann-Whitney U-test.