TARGETED AND WHOLE GENOME SEQUENCING ADVANCE DIAGNOSIS AND PROGRESSION MODELS OF BREAST FIBROEPITHELIAL LESIONS

Abstract

Differentiating cellular fibroadenomas (FAs) from benign phyllodes tumours (PTs) is clinically important but may be challenging due to subjective diagnostic criteria. Furthermore, there is growing evidence for MED12-dependent and MED12-independent progression pathways of fibroepithelial lesions, which require further investigation.

Targeted sequencing of n=628 fibroepithelial lesions using a 16-gene panel showed cellular FAs and benign PTs were differentially mutated in TERT (p<0.001), FLNA (p<0.001) and SETD2 (p<0.001). Histological review of 128 cases, identified by the panel to meet review criteria, led to re-classification of 6 (4.7%) cases. Whole-genome sequencing of another 7 fibroepithelial lesions demonstrated that PTs shared mutations in 12 distinct genes. MED12-wildtype PTs also showed higher mutational load, cancer driver mutation frequency and structural variant burden than MED12-mutant PTs, which may be integral in the former’s de novo development.

Targeted and whole-genome sequencing is therefore valuable in refining diagnostic assessment and understanding the biology of breast fibroepithelial lesions.