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. 2021 Apr;15(4):1024-1039.
doi: 10.1002/1878-0261.12813. Epub 2021 Feb 19.

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas

Lea A Moukarzel  1 , Lorenzo Ferrando  2   3 , Arnaud Da Cruz Paula  1 , David N Brown  2 , Felipe C Geyer  2 , Fresia Pareja  2 , Salvatore Piscuoglio  2   4 , Anastasios D Papanastasiou  2   5 , Nicola Fusco  2   6 , Caterina Marchiò  2   7 , Nadeem R Abu-Rustum  1 , Rajmohan Murali  2 , Edi Brogi  2 , Hannah Y Wen  2 , Larry Norton  8 , Robert A Soslow  2 , Anne Vincent-Salomon  9 , Jorge S Reis-Filho  2 , Britta Weigelt  2
Affiliations

The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas

Lea A Moukarzel et al. Mol Oncol. 2021 Apr.

Abstract

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole-exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial-to-mesenchymal transition (EMT)-related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD-related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.

Keywords: breast cancer; carcinosarcoma; homologous recombination DNA repair; metaplastic; uterine cancer; whole-exome sequencing.

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Conflict of interest statement

JS Reis‐Filho is a consultant of Paige.AI, REPARE Therapeutics and Goldman Sachs, a member of the Board of Directors of Grupo Oncoclinicas, a member of the scientific advisory board of Volition RX, Paige.AI, and REPARE Therapeutics, and an ad hoc member of the advisory boards of Roche Tissue Diagnostics, Novartis, Roche, Genentech, and InVicro, all outside the submitted work. NR Abu‐Rustum reports institutional grants from Stryker/Novadaq, Olympus, and GRAIL, outside the submitted work. The remaining authors have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Schematic representation of the metaplastic breast carcinomas and uterine carcinosarcomas included in this study. WES data of metaplastic breast cancers (MBCs; n = 35) from Ng et al. [2] and uterine carcinosarcomas (UCSs; n = 55, n = 2 hypermutated cases were excluded) from Cherniack et al./The Cancer Genome Atlas [19] were reanalyzed. In addition, the epithelial and mesenchymal components of 11 MBCs, of which 10 overlapped with those from Ng et al. [2], and of 6 UCSs were separately microdissected and subjected to WES.
Fig. 2
Fig. 2
Repertoire of somatic mutations in metaplastic breast carcinomas and uterine carcinosarcomas. (A) Total number of somatic mutations and nonsynonymous somatic mutations per Mb in metaplastic breast cancers (MBCs) reanalyzed from Ng et al. [2] and uterine carcinosarcomas (UCSs) reanalyzed from The Cancer Genome Atlas (TCGA) [19]. Mann–Whitney U‐test employed. (B) Nonsynonymous somatic mutations identified in WES data from MBCs reanalyzed from Ng et al. [2], left, and UCSs reanalyzed from TCGA [19], right. Cases are shown in columns and genes in rows. Mutation types, mutational signatures, LSTs, NtAIs, small deletion length, small insertion and deletion (indel) microhomology, and clinicopathologic factors are color‐coded according to the legend. . (C) Fraction of the genome altered in MBCs reanalyzed from Ng et al. [2] and UCSs reanalyzed from TCGA [19]. Mann–Whitney U‐test employed.
Fig. 3
Fig. 3
Metaplastic breast carcinomas and uterine carcinosarcomas harbor genetic alterations affecting similar signaling pathways. Frequency of activating (red) or loss‐of‐function (blue) somatic genetic alterations affecting genes in the canonical (A) p53, (B) PI3K/AKT/mTOR, (C) Wnt, and (D) Notch signaling pathways. The number of metaplastic breast cancers (MBCs, left) and uterine carcinosarcomas (UCSs, right) harboring a given somatic mutations or gene copy number alterations is depicted under the gene name. Pathways found to be significantly enriched (P < 0.01) in MCBs or UCSs and previously reported in Sanchez‐Vega et al. [46] are shown.
Fig. 4
Fig. 4
Genomic features of homologous recombination repair deficiency in metaplastic breast carcinomas and uterine carcinosarcomas. (A) Mutational signatures in metaplastic breast cancers (MBCs) from Ng et al. [2] and nonhypermutated uterine carcinosarcomas (UCSs) from TCGA [19] identified using DeconstructSigs [39]. Mutational signatures are color‐coded according to the legend and were only performed for samples ≥ 20 SNVs. (B) LST scores in MBCs from Ng et al. [2] and nonhypermutated UCSs from TCGA [19]. The gray line depicts the cutoff for LST high (≥ 15) [36]. (C) Small deletion length in MBCs from Ng et al. [2] and nonhypermutated UCSs from TCGA [19] according to Alexandrov et al. [40], which in HRD‐defective tumors has been found to be ≥ 5 nucleotides (gray line). (D) NtAI score in MBCs from Ng et al. [2] and nonhypermutated UCSs from TCGA [19] according to Morganella et al. [41]. Mann–Whitney U‐test was performed for comparisons in (B), (C), and (D). MBC, metaplastic breast cancer.
Fig. 5
Fig. 5
Clonal relatedness and decomposition of the epithelial and mesenchymal components of metaplastic breast carcinomas and uterine carcinosarcomas. (A) Clonality index of the epithelial and mesenchymal components of metaplastic breast cancers (MBCs, left) and of the epithelial and mesenchymal components of uterine carcinosarcomas (UCSs, right) subjected to WES based on somatic mutations. The histologic components are clonally related in all cases. (B) Cancer cell fractions (CCFs) of the somatic mutations identified in the epithelial and mesenchymal histologic components by WES in the metaplastic breast carcinoma MP15, (C) in the UCS CS4, and (D) UCS CS8. Mutations are grouped by their CCF as inferred by pyclone [44]. Cluster memberships are depicted below the heatmaps, and the corresponding phylogenetic trees are displayed. The length of the trunk and branches represent the number of shared and private somatic mutations identified in the different histologic components.
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References

    1. Weigelt B, Eberle C, Cowell CF, Ng CK & Reis‐Filho JS (2014) Metaplastic breast carcinoma: more than a special type. Nat Rev Cancer 14, 147–148. - PubMed
    1. Ng CKY, Piscuoglio S, Geyer FC, Burke KA, Pareja F, Eberle CA, Lim RS, Natrajan R, Riaz N, Mariani O et al. (2017) The landscape of somatic genetic alterations in metaplastic breast carcinomas. Clin Cancer Res 23, 3859–3870. - PMC - PubMed
    1. Cooper CL, Karim RZ, Selinger C, Carmalt H, Lee CS & O'Toole SA (2013) Molecular alterations in metaplastic breast carcinoma. J Clin Pathol 66, 522–528. - PubMed
    1. Piscuoglio S, Ng CKY, Geyer FC, Burke KA, Cowell CF, Martelotto LG, Natrajan R, Popova T, Maher CA, Lim RS et al. (2017) Genomic and transcriptomic heterogeneity in metaplastic carcinomas of the breast. NPJ Breast Cancer 3, 48. - PMC - PubMed
    1. Weigelt B, Ng CK, Shen R, Popova T, Schizas M, Natrajan R, Mariani O, Stern MH, Norton L, Vincent‐Salomon A et al. (2015) Metaplastic breast carcinomas display genomic and transcriptomic heterogeneity [corrected]. Mod Pathol 28, 340–351. - PMC - PubMed

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