TERT promoter mutations are frequent and show association with MED12 mutations in phyllodes tumors of the breast.
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.
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Masayuki
M
Yoshida
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Reiko
R
Ogawa
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Hiroshi
H
Yoshida
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Akiko
A
Maeshima
Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Yae
Y
Kanai
Breast Surgery Division, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Takayuki
T
Kinoshita
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.|Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Nobuyoshi
N
Hiraoka
Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 104-0045, Japan.|Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Shigeki
S
Sekine
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000235:genetics; D005260:Female; D018226:Fibroadenoma / Q000235:genetics; D006801:Humans; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D003557:Phyllodes Tumor / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D000075924:X-linked Nuclear Protein; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C460107:MED12 protein, human; D056892:Mediator Complex; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C509186:TERT protein, human; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein