An Integrated Epigenomic and Genomic View on Phyllodes and Phyllodes-like Breast Tumors

Abstract

Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including “The Cancer Genome Atlas” (TCGA) and “Gene Expression Omnibus” (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions, and EGFR amplifications may inform therapeutic decision-making.

Gene Expression Profiling of Fibroepithelial Lesions of the Breast

“…A recent study revealed that borderline phyllodes tumor could be separated into either benign or malignant PTs using molecular assays (27). Interestingly, in our study, the hierarchical clustering heatmap show several borderline phyllodes cases clustered with the malignant PTs group, and some clustered closely with the benign phyllodes tumor group (supplement Fig.…”

Survey of recurrent diagnostic challenges in breast phyllodes tumours

“…Conversely, a mildly cellular PT that has well‐circumscribed margins, few mitoses, barely discernible atypia, and no stromal overgrowth, but a very focally infiltrative border, may on occasion render a degree of diagnostic hesitation. A recent study on methylation and copy number analysis of FELs found that the methylation profiles of PT and FA converge in a distinct cluster, while the copy number profiles of these FELs suggest that they may be separated into benign [flat copy number profiles/few copy number variants (CNVs)] and malignant (high CNVs) categories, the implication being that borderline PTs may separate into benign and malignant forms based on such analysis, thus potentially obviating the need for a discrete “borderline” grade 53 …”

“…A recent study on methylation and copy number analysis of FELs found that the methylation profiles of PT and FA converge in a distinct cluster, while the copy number profiles of these FELs suggest that they may be separated into benign [flat copy number profiles/few copy number variants (CNVs)] and malignant (high CNVs) categories, the implication being that borderline PTs may separate into benign and malignant forms based on such analysis, thus potentially obviating the need for a discrete "borderline" grade. 53 Johannes M€ uller, in 1838, conferred the appellation "cystosarcoma phyllodes" 54 (from the Greek: kystis [pouch, bladder], sarkoma [fleshy tumour] and phyllon [leaf]), accompanied by a "complete and comprehensive" description. 55 The term that now stands, "phyllodes tumour (Tumore Filloide)," was devised by Lomonaco in 1960.…”

Genetic and epigenetic analysis of hepatocellular adenomas with atypical morphological features

“…Top differentially methylated probes were determined by calculating standard deviations across the entire dataset comprising >18,000 cases obtained from public resources including TCGA and the Gene Expression Omnibus (GEO), as well as from in‐house reference collections ( n = 18 537, case Sentrix IDs and coordinates in Appendix S1). Filtered set of methylation beta values were compared by uniform manifold approximation projection (UMAP) for dimension reduction, as previously described 18,19 . Copy number plots were generated with conumee (in R, Vienna, Austria).…”

“…Filtered set of methylation beta values were compared by uniform manifold approximation projection (UMAP) for dimension reduction, as previously described. 18,19 Copy number plots were generated with conumee (in R, Vienna, Austria). All methylation data and annotations were curated in our public methylation analysis platform EpiDiP (www.epidip.org).…”