Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, andTERTpromoter hotspot mutations andTERTgene amplification as likely drivers of progression

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Phyllodes tumours (PTs) are breast fibroepithelial lesions that are graded based on histological criteria as benign, borderline or malignant. PTs may recur locally. Borderline PTs and malignant PTs may metastasize to distant sites. Breast fibroepithelial lesions, including PTs and fibroadenomas, are characterized by recurrentMED12exon 2 somatic mutations. We sought to define the repertoire of somatic genetic alterations in PTs and whether these may assist in the differential diagnosis of these lesions. We collected 100 fibroadenomas, 40 benign PTs, 14 borderline PTs and 22 malignant PTs; six, six and 13 benign, borderline and malignant PTs, respectively, and their matched normal tissue, were subjected to targeted massively parallel sequencing (MPS) using the MSK-IMPACT sequencing assay. RecurrentMED12mutations were found in 56% of PTs; in addition, mutations affecting cancer genes (egTP53,RB1,SETD2andEGFR) were exclusively detected in borderline and malignant PTs. We found a novel recurrent clonal hotspot mutation in theTERTpromoter (−124 C>T) in 52% andTERTgene amplification in 4% of PTs. Laser capture microdissection revealed that these mutations were restricted to the mesenchymal component of PTs. Sequencing analysis of the entire cohort revealed that the frequency ofTERTalterations increased from benign (18%) to borderline (57%) and to malignant PTs (68%;p <0.01), andTERTalterations were associated with increased levels ofTERTmRNA (p <0.001). NoTERTalterations were observed in fibroadenomas. An analysis ofTERTpromoter sequencing and gene amplification distinguished PTs from fibroadenomas with a sensitivity and a positive predictive value of 100% (CI 95.38–100%) and 100% (CI 85.86–100%), respectively, and a sensitivity and a negative predictive value of 39% (CI 28.65–51.36%) and 68% (CI 60.21–75.78%), respectively. Our results suggest thatTERTalterations may drive the progression of PTs, and may assist in the differential diagnosis between PTs and fibroadenomas. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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