PTENmutation

PTEN mutation refers to genetic alterations in the PTEN gene, a tumor suppressor located on chromosome 10q23.3. The PTEN gene encodes PTEN protein, a lipid phosphatase that dephosphorylates PIP3 to PIP2, thereby antagonizing the PI3K/AKT signaling pathway and inhibiting cell growth and survival. Loss or inactivation of PTEN reduces this brake, contributing to tumor development. PTEN mutations can be germline or somatic and occur across many tissue types.

Germline PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, and PTEN-related Proteus syndrome. Features often include macrocephaly, mucocutaneous lesions, gastrointestinal hamartomas, and developmental delay or autism spectrum features. Individuals with germline mutations have elevated lifetime cancer risks, notably breast, thyroid, and endometrial cancers, with risk estimates varying by cohort and age.

Somatic PTEN mutations are common in a wide range of cancers, including glioblastoma, endometrial, prostate, breast, and colorectal cancers. They typically lead to loss of function and hyperactivation of PI3K/AKT/mTOR signaling, promoting tumor growth and influencing prognosis. PTEN status can affect responses to targeted therapies; loss of PTEN may confer resistance or sensitivity to inhibitors in the PI3K/AKT/mTOR axis, and therapeutic strategies often explore these pathways.

Genetic testing and management: individuals with features of PHTS should be offered PTEN testing and lifelong surveillance. Surveillance commonly includes annual breast imaging (MRI) starting in early adulthood and periodic thyroid ultrasound, with consideration of endometrial cancer risk management and appropriate cancer screening based on age and guidelines. Molecular profiling of tumors for PTEN status informs treatment decisions in the clinical setting.