PTEN-opathies: from biological insights to evidence-based precision medicine

J Clin Invest. 2019 Feb 1;129(2):452-464. doi: 10.1172/JCI121277. Epub 2019 Jan 7.

Abstract

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / pathology
  • Autism Spectrum Disorder / therapy
  • Evidence-Based Medicine*
  • Germ-Line Mutation*
  • Hamartoma Syndrome, Multiple* / genetics
  • Hamartoma Syndrome, Multiple* / metabolism
  • Hamartoma Syndrome, Multiple* / pathology
  • Hamartoma Syndrome, Multiple* / therapy
  • Humans
  • Neoplasms, Experimental* / genetics
  • Neoplasms, Experimental* / metabolism
  • Neoplasms, Experimental* / pathology
  • Neoplasms, Experimental* / therapy
  • PTEN Phosphohydrolase* / genetics
  • PTEN Phosphohydrolase* / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Precision Medicine*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • MTOR protein, human
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human