TERT promoter mutations are frequent and show association with MED12 mutations in phyllodes tumors of the breast

Abstract

Background:Phyllodes tumors are rare fibroepithelial neoplasms of the breast, which carry the potential risk of local recurrence and metastasis. Phyllodes tumors share several histological features with fibroadenomas, and no widely accepted markers for distinguishing these lesions have been identified.Methods:We analyzed molecular abnormalities related to telomere elongation in tumors, including TERT promoter mutations, as well as loss of expression of ATRX and DAXX, in a total of 104 phyllodes tumors and fibroadenomas.Results:Sequencing analyses showed that TERT promoter mutations were frequent in phyllodes tumors (30/46, 65%), but rare in fibroadenomas (4/58, 7%). Among phyllodes tumors, the mutations were more frequent in borderline tumors (13/15, 87%), but were also common in benign (9/18, 50%) and malignant tumors (8/13, 62%). Remarkably, all but one TERT promoter-mutated tumor also contained MED12 mutations, indicating that these mutations are strongly associated (P=8.4 × 10−6). Expression of ATRX and DAXX, as evaluated by immunohistochemistry, was retained in all tumors.Conclusions:Our observations suggest a critical role of TERT promoter mutations, in cooperation with MED12 mutations, in the development of phyllodes tumors. Because TERT promoter mutations are rare among fibroadenomas, their detection may be of potential use in discriminating between phyllodes tumors and fibroadenomas.

Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression

“…Our study differed from that of Yoshida et al in that the only TERT promoter mutation found in the 76 PTs analyzed here was the −124 C>T hotspot mutation, that the frequency of TERT promoter mutations in benign PTs in this study (7/40, 18%) was significantly lower than that reported by Yoshida et al (9/18, 50%, p = 0.02, Fisher's exact test) and that only 52% of the PTs harbouring TERT promoter mutations also displayed MED12 mutations in our study, as opposed to 97% of TERT mutant PTs reported by Yoshida et al ( p < 0.0001, Fisher's exact test). Most importantly, from a diagnostic perspective, the results of our study are fundamentally different from those of Yoshida et al with regard to the presence of TERT promoter mutations in fibroadenomas. Whilst four of the 58 (7%) fibroadenomas analyzed by Yoshida et al harboured the −124 C>T TERT promoter hotspot mutation, all of the 100 consecutive fibroadenomas analyzed here displayed wild‐type TERT .…”

“…harbouring TERT promoter mutations also displayed MED12 mutations in our study, as opposed to 97% of TERT mutant PTs reported by Yoshida et al [12] (p < 0.0001, Fisher's exact test). Most importantly, from a diagnostic perspective, the results of our study are fundamentally different from those of Yoshida et al [12] with regard to the presence of TERT promoter mutations in fibroadenomas.…”

“…Sanger sequencing analysis [12] revealed TERT promoter mutations, mostly −124 C>T but also −146 C>T and -124 C>A, in 50%, 87% and 62% of benign, borderline and malignant PTs, respectively, and, in all but one case, TERT promoter mutations were found in conjunction with MED12 mutations. In addition, 7% of the 58 fibroadenomas analyzed by Yoshida et al [12] harboured the TERT promoter −124 C>T hotspot mutation. In accord with Yoshida et al [12], our massively parallel sequencing and Sanger sequencing analyses revealed the presence of the TERT promoter −124 C>T hotspot mutation at similar frequencies in borderline and malignant PTs (8/14, 57% versus 50% in [12], and 12/22, 56% versus 62% in [12], respectively, p > 0.05, Fisher's exact tests).…”

“…In addition, 7% of the 58 fibroadenomas analyzed by Yoshida et al harboured the TERT promoter −124 C>T hotspot mutation. In accord with Yoshida et al , our massively parallel sequencing and Sanger sequencing analyses revealed the presence of the TERT promoter −124 C>T hotspot mutation at similar frequencies in borderline and malignant PTs (8/14, 57% versus 50% in , and 12/22, 56% versus 62% in , respectively, p > 0.05, Fisher's exact tests). Our study differed from that of Yoshida et al in that the only TERT promoter mutation found in the 76 PTs analyzed here was the −124 C>T hotspot mutation, that the frequency of TERT promoter mutations in benign PTs in this study (7/40, 18%) was significantly lower than that reported by Yoshida et al (9/18, 50%, p = 0.02, Fisher's exact test) and that only 52% of the PTs harbouring TERT promoter mutations also displayed MED12 mutations in our study, as opposed to 97% of TERT mutant PTs reported by Yoshida et al ( p < 0.0001, Fisher's exact test).…”

Phyllodes tumors with and without fibroadenoma-like areas display distinct genomic features and may evolve through distinct pathways

“…10,11 Finally, TERT promoter mutations and gene amplifications are absent or exceedingly rare in FAs, but recurrent in PTs, though significantly more frequent in borderline and malignant PTs than in benign PTs, suggesting that TERT genetic alterations might play a role in the progression from benign to malignant PTs. 8,10,12,13 …”