Toward Systems Pathology for PTEN Diagnostics

Abstract

Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline PTEN mutation. Furthermore, outside of the familial setting, somatic variants of PTEN occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a PTEN mutation. Detection of a germline PTEN mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a PTEN mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.

Figure 1.

PTEN structure and germline mutation spectrum in PTEN hamartoma tumor syndrome (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 carboxy-terminal tail including a PDZ-binding domain. The active site is included within amino acid residues 123 and 130. (B) PTEN consists of nine 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 panels reproduced from Yehia et al. 2019, with permission, from the American Society for Clinical Investigation © 2019.)

Figure 2.

A systems pathology approach for the treatment of patients with PTEN-related disease. (A) Proposed integration of molecular and clinical data for patients with PTEN hamartoma tumor syndrome (PHTS). (B) A proposed systems pathology approach to patients presenting with sporadic tumors harboring aberrant PTEN. (AI) artificial intelligence.