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 PTEN 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 PTEN mutations, of which 19 (55.9%) showed PTEN protein loss. The most common PTEN variants associated with protein loss were p.R130 (n = 4) followed by p.R335, p.L265fs, and deletions (n = 2). All the ten nonsense mutations identified in the samples resulted in PTEN inactivation. In the remaining 288 GC cases with wild-type PTEN, protein loss was found in 35 cases (12.2%). Thus, PTEN mutations were significantly associated with PTEN protein loss (p = 5.232 × 10−10), high MSI (p = 3.936 × 10−8), and EBV-positivity (p = 0.0071). In conclusion, our results demonstrate that loss-of-function mutations in PTEN are a frequent genetic mechanism of PTEN inactivation in GC.
Highlights
Mechanisms of DNA damage repair are crucial to preserve the genomic integrity of the cell.In normal cells, DNA damage triggers the activation of DNA damage response (DDR) pathways to repair the damage, and these depend on the type of DNA damage
Somatic phosphatase and tensin homolog (PTEN) mutation, a frequent event in endometrial cancer, is associated with microsatellite instability (MSI) status ranging from 25% to 83% [4], and PTEN inactivation is thought to be an early step in the development and progression of endometrial cancer [5]
Of the 322 gastric cancer (GC) cases with next generation sequencing (NGS) data included in this study, 38 showed pathogenic PTEN alterations confirmed by COSMIC [19], Polyphen [20], and SIFT [21]
Summary
DNA damage triggers the activation of DNA damage response (DDR) pathways to repair the damage, and these depend on the type of DNA damage. The phosphatase and tensin homolog (PTEN), a well-known tumor suppressor gene, is involved in double-strand break repair, and nucleotide excision repair, and regulates the DDR pathways by interacting with Chk and p53 [1,2]. Cancers 2020, 12, 1724; doi:10.3390/cancers12071724 www.mdpi.com/journal/cancers (PI3K)/Akt pathway and control of cell adhesion, migration, and tumor invasion, by downregulating the activity of focal adhesion kinases (FAKs) [3]. Somatic PTEN mutation, a frequent event in endometrial cancer, is associated with microsatellite instability (MSI) status ranging from 25% to 83% [4], and PTEN inactivation is thought to be an early step in the development and progression of endometrial cancer [5]. In gastric cancers (GCs), the frequency of PTEN mutation is relatively low (7–11%)
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