PMID- 26718977
OWN - NLM
STAT- MEDLINE
DCOM- 20160510
LR  - 20211203
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Linking)
VI  - 186
IP  - 1
DP  - 2016 Jan
TI  - Mutation Profiling of Usual Ductal Hyperplasia of the Breast Reveals Activating 
      Mutations Predominantly at Different Levels of the PI3K/AKT/mTOR Pathway.
PG  - 15-23
LID - S0002-9440(15)00566-0 [pii]
LID - 10.1016/j.ajpath.2015.09.004 [doi]
AB  - 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.
CI  - Copyright (c) 2016 American Society for Investigative Pathology. Published by 
      Elsevier Inc. All rights reserved.
FAU - Jahn, Stephan W
AU  - Jahn SW
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria. Electronic 
      address: stephan.jahn@medunigraz.at.
FAU - Kashofer, Karl
AU  - Kashofer K
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria.
FAU - Thuringer, Andrea
AU  - Thuringer A
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria.
FAU - Abete, Luca
AU  - Abete L
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria.
FAU - Winter, Elke
AU  - Winter E
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria.
FAU - Eidenhammer, Sylvia
AU  - Eidenhammer S
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria.
FAU - Viertler, Christian
AU  - Viertler C
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria.
FAU - Tavassoli, Fattaneh
AU  - Tavassoli F
AD  - Department of Pathology, Yale University School of Medicine, New Haven, 
      Connecticut.
FAU - Moinfar, Farid
AU  - Moinfar F
AD  - Institute of Pathology, Medical University of Graz, Graz, Austria; Department of 
      Pathology, Hospital of the Sisters of Charity, Linz, Austria.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Breast Diseases/*genetics/*pathology
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - DNA Mutational Analysis/methods
MH  - Female
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - Hyperplasia/genetics/pathology
MH  - Immunohistochemistry
MH  - Middle Aged
MH  - Phosphatidylinositol 3-Kinases/*genetics
MH  - Polymerase Chain Reaction
MH  - Precancerous Conditions/genetics/pathology
MH  - Proto-Oncogene Proteins c-akt/*genetics
MH  - TOR Serine-Threonine Kinases/*genetics
MH  - Young Adult
EDAT- 2016/01/01 06:00
MHDA- 2016/05/11 06:00
CRDT- 2016/01/01 06:00
PHST- 2015/04/25 00:00 [received]
PHST- 2015/08/29 00:00 [revised]
PHST- 2015/09/28 00:00 [accepted]
PHST- 2016/01/01 06:00 [entrez]
PHST- 2016/01/01 06:00 [pubmed]
PHST- 2016/05/11 06:00 [medline]
AID - S0002-9440(15)00566-0 [pii]
AID - 10.1016/j.ajpath.2015.09.004 [doi]
PST - ppublish
SO  - Am J Pathol. 2016 Jan;186(1):15-23. doi: 10.1016/j.ajpath.2015.09.004.