title: Tubular, lactating, and ductal adenomas are devoid of MED12 Exon2 mutations, and ductal adenomas show recurrent mutations in GNAS and the PI3K-AKT pathway.
abstract: Adenomas of the breast are rare benign tumors although single cases with malignant behavior have been reported. However, the genetic basis of these tumors is unknown. Employing targeted next generation sequencing of 50 cancer-related genes as well as Sanger sequencing, we profiled a cohort of 18 mammary adenomas comprising 9 ductal, 6 tubular, and 3 lactating adenoma. Missense mutations were detected in 8 of the 18 cases (44%). Specifically, five (56%) ductal adenomas and three (50%) tubular adenomas harbored mutated genes. No mutations were detected in lactating adenomas. Three of the nine ductal adenomas showed mutant AKT1 (p.E17K) with two of them harboring an additional GNAS mutation (p.R201C). One case had mutant PIK3CA (p.H1047R) and another case a mutation in GNAS (p.R201C). The three cases of mutated tubular adenomas showed mutations in either MET or FGFR3. Of note, we did not detect copy number changes and none of the cases including tubular adenomas had mutations in exon 2 of MED12. Our results suggest that ductal adenomas are related to papillomas of the breast and screening for mutations in exon 2 of MED12 might help to facilitate differential diagnosis between tubular adenoma and fibroadenoma in difficult cases. Lastly, our data exemplarily demonstrate that mutations in cancer-related genes per se do not indicate malignancy but occur in benign tumors. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Volckmar
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Leichsenring
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Christa
authors.initials: C
authors.lastname: Flechtenmacher
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.affiliation: Institute of Pathology University Hospital Halle, Halle, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Siebolts
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Kirchner
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bockmayr
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Ridinger
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Lorenz
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Tissue Bank of the National Center for Tumor Diseases (NCT), Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.affiliation: Institute of Pathology, Technical University Munich (TUM), Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Pathology University Hospital Halle, Halle, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|National Center of Tumor Diseases, Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002864:Chromogranins / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007774:Lactation / Q000235:genetics; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; C460107:MED12 protein, human; D056892:Mediator Complex; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs