Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma

• DOI: 10.1002/path.6250
• Publication Date: 2024-02-01T15:00:14Z
• Authors: Braydon Meyer; Clare Stirzaker; Sonny Ramkomuth; Kate Harvey; Belinda Chan; Cheok Soon Lee; Rooshdiya Karim; Niantao Deng; Kelly A Avery‐Kiejda; Rodney J Scott; Sunil Lakhani; Stephen Fox; Elizabeth Robbins; Joo‐Shik Shin; Jane Beith; Anthony Gill; Loretta Sioson; Charles Chan; Mrudula Krishnaswamy; Caroline Cooper; Sanjay Warrier; Cindy Mak; John EJ Rasko; Charles G Bailey; Alexander Swarbrick; Susan J Clark; Sandra O'Toole; Ruth Pidsley
• Keywords: Phyllodes tumor; Metaplastic Carcinoma; Breast carcinoma

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that classified as benign, borderline, or malignant. As little is known about molecular underpinnings PTs, current diagnosis relies on histological examination. However, accurate classification often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed other tumour types with shared features, such fibroadenoma and metaplastic cancers. DNA methylation a recognised hallmark many cancers, we hypothesised could provide novel biomarkers stratification in whilst also allowing insight into aetiology this otherwise understudied tumour. We generated whole-genome data using Illumina EPIC microarray PT cohort (n = 33) curated published datasets including potentially histopathologically similar (total n 817 samples). Analyses revealed have unique methylome compared to normal tissue (metaplastic cancer, sarcomas), PT-specific changes enriched gene sets involved KRAS signalling epithelial-mesenchymal transition. Next, identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) specifically delineated non-malignant The top DMR both validation cohorts was hypermethylation at HSD17B8 CpG island promoter. Matched single-cell expression showed had minimal fibroblast (putative tumour) cells. Finally, created classifier distinguish cancer samples, where likely misdiagnosis two TCGA samples. In conclusion, alterations associated histopathology hold potential improve our understanding aetiology, diagnostics, risk stratification. © 2024 Authors. Journal Pathology by John Wiley & Sons Ltd behalf Pathological Society Great Britain Ireland.