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

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.

Figure 1. Cytoplasmic and nuclear PTEN signaling.

In the cytoplasm, PTEN canonically functions to regulate the PI3K/AKT/mTOR signaling pathway. Under growth factor stimulation, PI3K is activated and catalyzes the phosphorylation of PIP2 to PIP3. PIP3 recruits PDK1 to the plasma membrane, which then contributes to the activation of AKT. AKT regulates a myriad of downstream cellular processes such as cell growth, proliferation, and decreased apoptosis. The lipid phosphatase activity of PTEN counteracts PI3K by dephosphorylating PIP3 to PIP2, thereby dampening AKT activation. In the nucleus, PTEN plays a vital role in maintaining genomic stability, chromosomal architecture, cell cycle control, and the regulation of ribosome biogenesis within nucleoli.

Figure 2. The classic PTEN pathway and associated PTEN-opathies.

The PTEN-opathies encompass a spectrum of disorders with mutations within genes encoding proteins belonging to the PTEN pathway. PIK3CA-related overgrowth spectrum (PROS) includes distinct clinical entities with phenotypic overlap among the different syndromes. These overgrowth disorders are typically associated with postzygotic somatic mosaic PIK3CA mutations in affected tissues and are characterized by segmental overgrowth affecting the body (e.g., CLOVES syndrome, fibroadipose hyperplasia) or the brain (e.g., megalencephaly–capillary malformation syndrome [MCAP], hemimegalencephaly). PIK3CA encodes the catalytic p110α subunit protein of PI3K. Similarly to PTEN dysfunction, PIK3CA activation results in phosphorylation and activation of AKT, ultimately resulting in overgrowth-promoting downstream effects within the PI3K/AKT/mTOR signaling pathway downstream of PTEN. Expectedly, these syndromes show clinical phenotypic overlap with PHTS, including megalencephaly, vascular malformations, overgrowth, and neurocognitive deficits.

Figure 3. PTEN structure and germline mutation spectrum in PHTS.

(A) PTEN germline mutation spectrum from 431 PHTS patients. PTEN is canonically a 403–amino acid protein. Different types of mutations are depicted in the lollipop plot overlaying the PTEN protein structure. The frequency of mutations correlates with the heights of the vertical lines representing each lollipop. PTEN comprises a PIP2-binding domain (PBD), a phosphatase domain, a C2 domain, and a C-terminal tail including a PDZ-binding domain. The active site is included within amino acid residues 123 and 130. (B) PTEN consists of 9 exons that encode the 403–amino acid protein. The exons are overlaid to match the protein domains in A. Intronic regions are not represented. The colored bars represent large deletions (abbreviated as del) and duplications (abbreviated as dup) annotated by affected exon numbers and the number of affected patients in parentheses. Figure adapted with permission from ref. .