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Review
. 2020 Jun 28;11(7):719.
doi: 10.3390/genes11070719.

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

Nicola Fusco  1   2 , Elham Sajjadi  2 , Konstantinos Venetis  1   2   3 , Gabriella Gaudioso  4 , Gianluca Lopez  4 , Chiara Corti  4 , Elena Guerini Rocco  1   2 , Carmen Criscitiello  5 , Umberto Malapelle  6 , Marco Invernizzi  7
Affiliations
Review

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

Nicola Fusco et al. Genes (Basel). .

Abstract

Alterations in the tumor suppressor phosphatase and tensin homolog (PTEN) occur in a substantial proportion of solid tumors. These events drive tumorigenesis and tumor progression. Given its central role as a downregulator of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, PTEN is deeply involved in cell growth, proliferation, and survival. This gene is also implicated in the modulation of the DNA damage response and in tumor immune microenvironment modeling. Despite the actionability of PTEN alterations, their role as biomarkers remains controversial in clinical practice. To date, there is still a substantial lack of validated guidelines and/or recommendations for PTEN testing. Here, we provide an update on the current state of knowledge on biologic and genetic alterations of PTEN across the most frequent solid tumors, as well as on their actual and/or possible clinical applications. We focus on possible tailored schemes for cancer patients' clinical management, including risk assessment, diagnosis, prognostication, and treatment.

Keywords: PI3K/Akt; PTEN; biomarker; cancer; precision medicine; solid tumors; tumor immune microenvironment; tumor suppressor.

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Conflict of interest statement

N.F. has received honoraria for consulting/advisory role from Merck Sharp & Dohme (MSD) and Boehringer Ingelheim. E.G.R. has received honoraria for advisory role/speaker bureau from Thermo Fisher Scientific, Roche, Novartis, AstraZeneca. C.Cr. has received honoraria for consulting/advisory role/speaker bureau from Novartis, Eli-Lilly, Pfizer, Roche. U.M. reports personal fees from Boehringer Ingelheim, AstraZeneca, Roche, MSD, Amgen, Merck, and BMS for participation in a speaker bureau or for acting in an advisory role, outside the submitted work. M.I. has received consultation honoraria from Errekappa Euroterapici S.p.a. These companies had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, and/or in the decision to publish the results. All the other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of the open and closed conformations of phosphatase and tensin homolog (PTEN) based on its phosphorylation status. (A) Dephosphorylation leads to the open conformation that allows PTEN to associate with the membrane. The association of PTEN with the negatively charged membrane occurs through electrostatic interactions. (B) Binding of the C2 domain to phosphatidylserine leads to a conformational change and activation of the phosphatase C-tail domain.
Figure 2
Figure 2
PI3K/Akt/mTOR signaling and its interaction with PTEN. The PI3K pathway regulates diverse cellular processes, including protein synthesis, cell survival, proliferation, glucose metabolism, apoptosis, DNA repair, and genome stability. Akt-mediated phosphorylation inhibits the activity of the TSC1-TSC2 complex, also known as hamartin-tuberin. This is a critical step for the negative regulation of mTORC1, whose activity controls anabolic processes. Another important downregulation of Akt phosphorylation is towards BAD, while MDM2 activity is enhanced, promoting the degradation of the tumor-suppressor p53, which also plays a part in the P300-mediated cell apoptosis. Cell cycle regulation occurs by means of cyclins A and D stimulation and GSK3 inhibition. The latter event is also responsible for increased glucose metabolism. PTEN is intimately involved in the regulation of these mechanisms through its substrate PIP3. Of note, the activity of PTEN in the cell nucleus that leads to cell survival control is related to the upregulation of key mediators, such as RAD51, CDNPC, and P300. RTK, receptor tyrosine kinase; CKR, chemokine receptor; GPCR, G protein-coupled receptor; IRS-1, insulin receptor substrate 1; PI3K, phosphatidylinositol 3-kinase; JAK1, Janus kinase 1; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; TSC, tuberous sclerosis complex; mTORC1, mammalian target of rapamycin complex 1; MDM2, mouse double minute 2 homolog; BAD, BCL2 associated agonist of cell death; GSK3, glycogen synthase kinase-3; CDK2, cyclin-dependent kinase 2; CDNPC, centromere protein C.
Figure 3
Figure 3
Diagnostic algorithm for the evaluation of mismatch repair status in breast cancer using PTEN immunohistochemistry as a complementary test. In this proposed workflow, PTEN can be profiled before the execution of other tests in order to pre-screen patients for MMR proficiency. Tumors showing HER2 overexpression and/or amplification and those with a triple-negative phenotype should be considered mismatch repair proficient if PTEN expression is retained, with a positive predictive value of 95% and 100%, respectively. TNBC, triple-negative breast cancer; ER, estrogen receptor; MMR, mismatch repair; pMMR, mismatch repair proficient.
Figure 4
Figure 4
Role of PTEN in the regulation of the tumor immune microenvironment. PTEN in tumor cells may regulate the cancer cell secretome to prevent the secretion of immunosuppressive chemokines and, consequently, favoring the establishment of an immune-permissive tumor microenvironment, which would improve antitumor immune responses. PTEN may also prevent the formation of reactive stroma with pro-tumorigenic activity, whereas in stromal cells may suppress tumorigenesis through inhibition of a pro-oncogenic secretome that reprogrammes cancer cells. Cells in the tumor microenvironment may produce exosomes that contain PTEN-targeting microRNA (miRNA) to downregulate the expression of PTEN in cancer cells, thereby counteracting the tumor-suppressive effects of PTEN.
Figure 5
Figure 5
Oncoprint visualization of PTEN somatic molecular alterations overall mutational burden across PTEN-altered solid tumors. Types of alterations and tumors are color-coded on the basis of the legends on the bottom. Each column represents a sample and was sorted to appreciate the magnitude of alteration types. The bar plot on the top represents the mutation count, as reported on the green scale. The 19 main tumor types included in this analysis from cbioportal.org are melanoma, head and neck squamous cell carcinoma, non-small cell lung cancer (i.e., squamous cell and adenocarcinoma), mesothelioma, esophageal cancer, stomach cancer, colorectal cancer, cholangiocarcinoma, pancreatic cancer, liver cancer, renal cell carcinoma, bladder cancer, prostate adenocarcinoma, uterine cancer (i.e., endometrioid, serous, and carcinosarcoma), cervical cancer, ovarian cancer, and invasive breast cancer (samples n = 1068/7888; 13.5%). ADC, adenocarcinoma; SCC, squamous cell carcinoma.
Figure 6
Figure 6
RNA expression levels and copy-number alterations of PTEN across PTEN-altered solid tumors. Each column represents a tumor type from cbioportal.org datasets. Types of alterations are color-coded on the basis of the legend on the bottom. ADC, adenocarcinoma; SCC, squamous cell carcinoma.
Figure 7
Figure 7
Type of mutations, frequency, and affected PTEN domains across selected solid tumors. The 19 tumor types included in this analysis from cbioportal.org are melanoma, head and neck squamous cell carcinoma, non-small cell lung cancer (i.e., squamous cell and adenocarcinoma), mesothelioma, esophageal cancer, stomach cancer, colorectal cancer, cholangiocarcinoma, pancreatic cancer, liver cancer, bladder cancer, prostate adenocarcinoma, uterine cancer (i.e., endometrioid, serous, and carcinosarcoma), ovarian cancer, and invasive breast cancer. Green, missense; black, truncating; brown, inframe; purple, other types of genetic alteration.
Figure 8
Figure 8
Frequency of mutations targeting the highly recurrent mutated genes in PTEN-defective solid tumors. Each tumor type is color-coded on the basis of the legend on the bottom. ADC, adenocarcinoma; SCC, squamous cell carcinoma.
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