MED12 mutations in breast phyllodes tumors: evidence of temporal tumoral heterogeneity and identification of associated critical signaling pathways.
Exome sequencing has recently identified highly recurrent MED12 somatic mutations in fibroadenomas (FAs) and phyllodes tumors (PTs). In the present study, based on a large series, we confirmed the presence of MED12 exon 1 and 2 mutations in 49% (41/83) of PTs, 70% (7/10) of FAs and 9.1% (1/11) of fibromatoses. We show that MED12 mutations are associated with benign behavior of phyllodes tumors, as they are detected less frequently in malignant PTs (27.6%) compared to benign (58.3%) and borderline (63.3%) PTs, respectively (p = 0.0036). Phyllodes tumors presented marked temporal heterogeneity of MED12 mutation status, as 50% (3/6) of primary and recurrent phyllodes tumor pairs with MED12 mutation presented different MED12 mutations between the primary and recurrent tumors. There was no correlation between MED12 status and genomic profiles obtained by array-CGH. MED12 mutations are associated with altered expressions of the genes involved in the WNT (PAX3, WNT3A, AXIN2), TGFB (TAGLN, TGFBR2, CTGF) and THRA (RXRA, THRA) signaling pathways.In conclusion, this study confirmed that MED12 plays a central oncogenic role in breast fibroepithelial tumorigenesis and identified a limited number of altered signaling pathways that maybe associated with MED12 mutations. MED12 exon 1 and 2 mutation status and some of the altered genes identified in this study could constitute useful diagnostic or prognostic markers, and form the basis for novel therapeutic strategies for PTs.
Service de Pathologie, Institut Curie, 75248 Paris Cedex 05, France.
Marick
M
Laé
Service de Pathologie, Institut Curie, 75248 Paris Cedex 05, France.|Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France.
Sophie
S
Gardrat
Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France.
Sophie
S
Rondeau
Service de Pathologie, Institut Curie, 75248 Paris Cedex 05, France.
Camille
C
Richardot
Service de Pathologie, Institut Curie, 75248 Paris Cedex 05, France.
Martial
M
Caly
Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France.
Walid
W
Chemlali
Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France.
Sophie
S
Vacher
Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France.
Jérôme
J
Couturier
Service de Pathologie, Institut Curie, 75248 Paris Cedex 05, France.
Odette
O
Mariani
Service de Pathologie, Institut Gustave Roussy, 94805, Villejuif Cedex, France.
Philippe
P
Terrier
Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France.
Ivan
I
Bièche
D000293:Adolescent; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002648:Child; D002869:Chromosome Aberrations; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D006801:Humans; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D003557:Phyllodes Tumor / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult
C460107:MED12 protein, human; D056892:Mediator Complex
MED12; phyllodes tumors