MED12 mutations in breast phyllodes tumors: evidence of temporal tumoral heterogeneity and identification of associated critical signaling pathways
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Marick Laé1, Sophie Gardrat1,2, Sophie Rondeau2, Camille Richardot1, Martial Caly1, Walid Chemlali2, Sophie Vacher2, Jérôme Couturier2, Odette Mariani1, Philippe Terrier3, Ivan Bièche2
1Service de Pathologie, Institut Curie, 75248 Paris Cedex 05, France
2Service de Génétique, Unité de pharmacogénomique, Institut Curie, 75248 Paris Cedex 05, France
3Service de Pathologie, Institut Gustave Roussy, 94805, Villejuif Cedex, France
Marick Laé, email: firstname.lastname@example.org
Keywords: MED12, phyllodes tumors
Received: April 15, 2016 Accepted: October 13, 2016 Published: October 31, 2016
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.
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