title: Mutation Profiling of Usual Ductal Hyperplasia of the Breast Reveals Activating Mutations Predominantly at Different Levels of the PI3K/AKT/mTOR Pathway.
abstract: Usual ductal hyperplasia (UDH) of the breast is generally regarded as a nonneoplastic proliferation, albeit loss of heterozygosity has long been reported in a part of these lesions. To gain deeper insights into the molecular drivers of these lesions, an extended mutation profiling was performed. The coding regions of 409 cancer-related genes were investigated by next-generation sequencing in 16 cases of UDH, nine unassociated with neoplasia (classic) and seven arising within papillomas. Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) activation was investigated by phosphorylated AKT, mTOR, and S6 immunohistochemistry. Of 16 lesions, 10 (63%) were mutated; 56% of classic lesions were unassociated with neoplasia, and 71% of lesions arose in papillomas. Fourteen missense mutations were detected: PIK3CA [6 (43%) of 14], AKT1 [2 (14%) of 14], as well as GNAS, MTOR, PIK3R1, LPHN3, LRP1B, and IGF2R [each 1 (7%) of 14]. Phosphorylated mTOR was seen in 83% and phosphorylated S6 in 86% of evaluable lesions (phospho-AKT staining was technically uninterpretable). In conclusion, UDH displays mutations of the phosphatidylinositol 3-kinase/AKT/mTOR axis at different levels, with PIK3R1, MTOR, and GNAS mutations not previously described. Specifically, oncogenic G-protein activation represents a yet unrecognized route to proliferation in UDH. On the basis of evidence of activating mutations, loss of heterozygosity, and a mass forming proliferation, we propose that UDH is most appropriately viewed as an early neoplastic intraductal proliferation.
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria. Electronic address: stephan.jahn@medunigraz.at.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Jahn
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kashofer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Thüringer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Luca
authors.initials: L
authors.lastname: Abete
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Elke
authors.initials: E
authors.lastname: Winter
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Eidenhammer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Viertler
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Fattaneh
authors.initials: F
authors.lastname: Tavassoli
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria; Department of Pathology, Hospital of the Sisters of Charity, Linz, Austria.
authors.forename: Farid
authors.initials: F
authors.lastname: Moinfar
mesh_terms: D000328:Adult; D000368:Aged; D001941:Breast Diseases / Q000235:genetics* / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D055815:Young Adult
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human