The genetic landscape of metaplastic breast cancers and uterine carcinosarcomas.

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

doi:10.1002/1878-0261.12813

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 bonafide 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.

Highlights

Metaplastic breast carcinoma (MBC) is a rare histologic form of breast cancer, usually of triplenegative phenotype, accounting for 0.2%-5% of breast cancers [1]
TP53 mutations were common in both tumor types, they were significantly more frequently found in uterine carcinosarcoma (UCS) than in MBCs (93% vs 69%; P=0.004, Fisher’s exact test)
We demonstrate that MBCs and UCSs harbor recurrent genetic alterations affecting TP53, PIK3CA and PTEN, consistent with prior studies [2,5,14,17,19], and that these tumors display overall similar patterns of gene copy number alterations

Summary

Introduction

Metaplastic breast carcinoma (MBC) is a rare histologic form of breast cancer, usually of triplenegative phenotype, accounting for 0.2%-5% of breast cancers [1]. We and others have previously shown that the histologic heterogeneity of MBCs is paralleled by heterogeneity at the genomic and transcriptomic levels [2,3,4,5,6], and provided evidence that the histologically distinct components of each MBC are almost uniformly clonally related [7,8,9,10,11] Given their clonal nature, it has been postulated that in MBCs with mesenchymal elements, epithelial to mesenchymal transition (EMT) may play a role in the development of the metaplastic components [12,13,14]. MBCs are characterized by recurrent mutations affecting TP53 and genes related to the PI3K/AKT/mTOR, MAPK, Wnt and Notch signaling pathways [2,4,8,16,17]

Methods

Results

Discussion

Conclusion