PTEN Protein Loss and Loss-of-Function Mutations in Gastric Cancers: The Relationship with Microsatellite Instability, EBV, HER2, and PD-L1 Expression

Abstract

Inactivation of phosphatase and tensin homolog (PTEN) is caused by multiple mechanisms, and loss of PTEN activity is related to the progression of various cancers. In gastric cancer (GC), the relationship between the loss of PTEN protein expression and various genetic alterations remains unclear. The effects of microsatellite instability (MSI), Epstein-Barr virus (EBV), HER2 overexpression, and PD-L1 expression on <i>PTEN</i> mutation have not been fully explored. We performed comprehensive cancer panel tests with a cohort of 322 tumor samples from patients with advanced GC. Immunohistochemistry for PTEN protein was performed in all cases, and the loss of protein expression was defined as a complete absence of nuclear staining. In total, 34 cases (10.6%) had pathogenic <i>PTEN</i> mutations, of which 19 (55.9%) showed PTEN protein loss. The most common <i>PTEN</i> variants associated with protein loss were p.R130 (<i>n</i> = 4) followed by p.R335, p.L265fs, and deletions (<i>n</i> = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type <i>PTEN</i>, protein loss was found in 35 cases (12.2%). Thus, <i>PTEN</i> mutations were significantly associated with PTEN protein loss (<i>p</i> = 5.232 × 10^-10), high MSI (<i>p</i> = 3.936 × 10^-8), and EBV-positivity (<i>p</i> = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in <i>PTEN</i> are a frequent genetic mechanism of PTEN inactivation in GC.