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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Jahn, SW; Kashofer, K; Thüringer, A; Abete, L; Winter, E; Eidenhammer, S; Viertler, C; Tavassoli, F; Moinfar, F.
Mutation Profiling of Usual Ductal Hyperplasia of the Breast Reveals Activating Mutations Predominantly at Different Levels of the PI3K/AKT/mTOR Pathway.
Am J Pathol. 2016; 186(1):15-23 Doi: 10.1016/j.ajpath.2015.09.004 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Jahn Stephan
Co-Autor*innen der Med Uni Graz
Abete Luca
Kashofer Karl
Moinfar Farid
Viertler Christian
Winter Elke

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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. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing)
Adult -
Aged -
Breast Diseases - genetics
Breast Diseases - pathology
Class I Phosphatidylinositol 3-Kinases -
DNA Mutational Analysis - methods
Female -
High-Throughput Nucleotide Sequencing -
Humans -
Hyperplasia - genetics
Hyperplasia - pathology
Immunohistochemistry -
Middle Aged -
Phosphatidylinositol 3-Kinases - genetics
Polymerase Chain Reaction -
Precancerous Conditions - genetics
Precancerous Conditions - pathology
Proto-Oncogene Proteins c-akt - genetics
TOR Serine-Threonine Kinases - genetics
Young Adult -

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