PMID- 33822054
OWN - NLM
STAT- MEDLINE
DCOM- 20220407
LR  - 20220407
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 30
IP  - 14
DP  - 2021 Jun 26
TI  - mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in 
      patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion.
PG  - 1273-1282
LID - 10.1093/hmg/ddab094 [doi]
AB  - Ultra-rare genetic disorders can provide proof of concept for efficacy of 
      targeted therapeutics and reveal pathogenic mechanisms relevant to more common 
      conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in 
      chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: 
      phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone 
      morphogenetic protein receptor type IA (BMPR1A). Loss of PTEN and BMPR1A results 
      in a much more severe phenotype than deletion of either gene alone, with 
      infantile onset pan-enteric polyposis and a high mortality rate. No effective 
      pharmacological therapy exists. A multi-center cohort analysis was performed to 
      characterize phenotype and investigate the therapeutic effect of mammalian target 
      of rapamycin (mTOR) inhibition (adverse events, disease progression, time to 
      colectomy and mortality) in patients with JPI. Among 25 JPI patients identified 
      (mean age of onset 13 months), seven received mTOR inhibitors (everolimus, n = 2; 
      or sirolimus, n = 5). Treatment with an mTOR inhibitor reduced the risk of 
      colectomy (hazard ratio = 0.27, 95% confidence interval = 0.07-0.954, P = 0.042) 
      and resulted in significant improvements in the serum albumin level (mean 
      increase = 16.3 g/l, P = 0.0003) and hemoglobin (mean increase = 2.68 g/dl, 
      P = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an 
      accumulated follow-up time of 29.8 patient years. No serious adverse events were 
      reported. Early therapy with mTOR inhibitors offers effective, pathway-specific 
      and personalized treatment for patients with JPI. Inhibition of the 
      phosphoinositol-3-kinase-AKT-mTOR pathway mitigates the detrimental synergistic 
      effects of combined PTEN-BMPR1A deletion. This is the first effective 
      pharmacological treatment identified for a hamartomatous polyposis syndrome.
CI  - (c) The Author(s) 2021. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Taylor, Henry
AU  - Taylor H
AD  - Department of Surgery and Cancer, Imperial College London, London SW7 2BX, UK.
FAU - Yerlioglu, Dilay
AU  - Yerlioglu D
AD  - Faculty of Medicine, Istanbul University, Istanbul, Fatih 34093, Turkey.
FAU - Phen, Claudia
AU  - Phen C
AD  - Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of 
      Texas Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Ballauff, Antje
AU  - Ballauff A
AD  - Zentrum fur Kinder- und Jugendmedizin Gastroenterology, HELIOS Klinikum Krefeld, 
      Krefeld, Nordrhein-Westfalen 47805, Germany.
FAU - Nedelkopoulou, Natalia
AU  - Nedelkopoulou N
AD  - Pediatric Gastroenterology, Sheffield Children's Hospital NHS Foundation Trust, 
      Sheffield, Yorkshire S10 2TH, UK.
FAU - Spier, Isabel
AU  - Spier I
AD  - Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, 
      Nordrhein-Westfalen 53012, Germany.
AD  - National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, 
      Nordrhein-Westfalen 53126, Germany.
FAU - Loverdos, Ines
AU  - Loverdos I
AD  - Pediatric Gastroenterology Hepatology and Nutrition Unit, Parc Tauli Hospital 
      Universitari, Institut d'Investigacio i Innovacio Parc Tauli I3PT, Universitat 
      Autonoma de Barcelona, Sabadell, Catalonia comunidad 08208, Spain.
FAU - Busoni, Veronica B
AU  - Busoni VB
AD  - Pediatric Gastroenterology, Hepatology and Liver-Intestine Transplantation 
      Division, Hospital Italiano de Buenos Aires, Ciudad Autonoma de Buenos Aires, 
      Argentina.
FAU - Heise, Jurgen
AU  - Heise J
AD  - Zentrum fur Kinder- und Jugendmedizin Gastroenterology, HELIOS Klinikum Krefeld, 
      Krefeld, Nordrhein-Westfalen 47805, Germany.
FAU - Dale, Peter
AU  - Dale P
AD  - Royal Gwent Hospital, Newport NP20 2UB, UK.
FAU - de Meij, Tim
AU  - de Meij T
AD  - VU University Medical Center, Amsterdam 1081, The Netherlands.
FAU - Sweet, Kevin
AU  - Sweet K
AD  - Division of Human Genetics, Ohio State University Wexner Medical Center, 
      Columbus, OH 43210, USA.
FAU - Cohen, Marta C
AU  - Cohen MC
AD  - Histopathology Department, Sheffield Children's Hospital NHS Foundation Trust, 
      Sheffield, Yorkshire S10 2TH, UK.
FAU - Fox, Victor L
AU  - Fox VL
AD  - Division of Gastroenterology, Hepatology and Nutrition, Boston Children's 
      Hospital, Boston, MA 02115, USA.
FAU - Mas, Emmanuel
AU  - Mas E
AD  - Unite de Gastroenterologie, Hepatologie, Nutrition, Diabetologie et Maladies 
      Hereditaires du Metabolisme, Hopital des Enfants, CHU de Toulouse, and IRSD, 
      Universite de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, Occitanie 31300, 
      France.
FAU - Aretz, Stefan
AU  - Aretz S
AD  - Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, 
      Nordrhein-Westfalen 53012, Germany.
AD  - National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, 
      Nordrhein-Westfalen 53126, Germany.
FAU - Eng, Charis
AU  - Eng C
AD  - Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer 
      Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
AD  - Department of Genetics and Genome Sciences, and CASE Comprehensive Cancer Center, 
      Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
FAU - Buderus, Stephan
AU  - Buderus S
AD  - GFO-Kliniken Bonn, St. Marien-Hospital, Bonn, Nordrhein-Westfalen 53115, Germany.
FAU - Thomson, Mike
AU  - Thomson M
AD  - Pediatric Gastroenterology, Sheffield Children's Hospital NHS Foundation Trust, 
      Sheffield, Yorkshire S10 2TH, UK.
FAU - Rojas, Isabel
AU  - Rojas I
AD  - Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of 
      Texas Southwestern Medical Center, Dallas, TX 75390, USA.
FAU - Uhlig, Holm H
AU  - Uhlig HH
AD  - Translational Gastroenterology Unit, University of Oxford, Oxford, Oxfordshire 
      OX3 9DU, UK.
AD  - Department of Pediatrics, University of Oxford, Oxford, Oxfordshire OX3 9DU, UK.
AD  - Biomedical Research Centre, University of Oxford, Oxford, Oxfordshire OX4 2PG, 
      UK.
LA  - eng
GR  - NIHR Oxford Biomedical Research Centre/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (MTOR Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.30 (BMPR1A protein, human)
RN  - EC 2.7.11.30 (Bone Morphogenetic Protein Receptors, Type I)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - Juvenile polyposis syndrome
SB  - IM
MH  - Bone Morphogenetic Protein Receptors, Type I
MH  - Colectomy
MH  - Gastrointestinal Hemorrhage
MH  - Humans
MH  - Intestinal Polyposis/congenital
MH  - *MTOR Inhibitors
MH  - *Neoplastic Syndromes, Hereditary/genetics/pathology/surgery
MH  - PTEN Phosphohydrolase/genetics
MH  - TOR Serine-Threonine Kinases/genetics
PMC - PMC8804886
EDAT- 2021/04/07 06:00
MHDA- 2022/04/08 06:00
PMCR- 2021/04/02
CRDT- 2021/04/06 12:34
PHST- 2021/01/13 00:00 [received]
PHST- 2021/03/28 00:00 [revised]
PHST- 2021/03/30 00:00 [accepted]
PHST- 2021/04/07 06:00 [pubmed]
PHST- 2022/04/08 06:00 [medline]
PHST- 2021/04/06 12:34 [entrez]
PHST- 2021/04/02 00:00 [pmc-release]
AID - 6209145 [pii]
AID - ddab094 [pii]
AID - 10.1093/hmg/ddab094 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2021 Jun 26;30(14):1273-1282. doi: 10.1093/hmg/ddab094.