Loss of Heterozygosity of PTEN (Encoding Phosphate and Tensin Homolog) Associated with Elevated HER2 Expression Is an Adverse Prognostic Indicator in Gastric Cancer

Zaitsu, Yoko; Oki, Eiji; Ando, Koji; Ida, Satoshi; Kimura, Yasue; Saeki, Hiroshi; Morita, Masaru; Hirahashi, Minako; Oda, Yoshinao; Maehara, Yoshihiko

doi:10.1159/000368984

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…These findings are consistent with those of previous reports in gastric cancer (11-21.5 % with PTEN loss [17][18][19] and 2.5-15.9 % with PIK3CA mutations [18,[20][21][22]). More importantly, as many as 34.5 % of patients with HER2 overexpression who are thought to be candidates for trastuzumab therapy showed PTEN loss, whereas PIK3CA mutations were found in only 5.6 % of these patients.…”

Section: Discussionsupporting

confidence: 93%

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PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

et al. 2016

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Background Although trastuzumab improves the outcome of patients with human epidermal growth factor receptor 2 (HER2)-overexpressing gastric or gastroesophageal junction adenocarcinoma (collectively referred to as ''gastroesophageal adenocarcinoma''; GEA), no clinical response is observed in a substantial population of patients. A predictive biomarker of trastuzumab response is required. The aim of this study was to evaluate whether the hyperactivation of the downstream phosphatidylinositol 3-kinase pathway, due to phosphatase and tensin homolog (PTEN) loss or PIK3CA mutations, could provide trastuzumab resistance in GEA. Methods Expression of HER2 and PTEN, and PIK3CA gene mutations were screened in 264 surgically resected GEA specimens. The effects of PTEN knockdown on the response to trastuzumab on cell viability, HER2 downstream signaling, apoptosis, and cell cycle were evaluated in HER2-overexpressing NCI-N87 gastric adenocarcinoma and OE19 esophageal adenocarcinoma cell lines. Inhibition of xenograft tumor growth by trastuzumab was investigated in OE19 cells with or without PTEN knockdown. The PTEN expression and objective response were analyzed in 23 GEA patients who received trastuzumab-based therapy.Results PTEN loss was identified in 34.5 % of HER2-overexpressing GEA patients, whereas PIK3CA mutations were rare (5.6 %). Trastuzumab-mediated growth suppression, apoptosis, and G 1 cell cycle arrest were inhibited by PTEN knockdown through Akt activation in NCI-N87 and OE19 cells. PTEN knockdown impaired the antiproliferative effect of trastuzumab in OE19 xenograft models. A clinical response was observed in 50 % of PTEN-positive tumors (9 of 18) but in no tumors with PTEN loss (none of 5). Conclusions PTEN loss was frequently found in HER2-overexpressing tumors, and was associated with a poor response to trastuzumab-based therapy in patients with GEA.

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Section: Discussionsupporting

confidence: 93%

“…Zaitsu et al [19] showed that loss of heterozygosity of PTEN, which results in PTEN deficiency, was associated with HER2 overexpression. However, some reports have shown that loss of PTEN expression or deletion of the PTEN gene is rarely found (3.7-5.3 %) in HER2-overexpressing gastric cancer [23,24].…”

Section: Discussionmentioning

confidence: 99%

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

et al. 2016

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“…In addition, even in HER2-positive tumors, the antitumor activity of trastuzumab combined with chemotherapy is not always sufficient to extend the survival of gastric cancer patients. Among several markers that are reported to predict sensitivity to trastuzumab, loss of PTEN function is said to be one of the mechanisms of resistance to trastuzumab [42,43] . Taken together, these observations suggest that HER2-expressing cases might be sensitive to the anti-PD-L1 antibody, and PTEN loss may induce PD-1 expression, thus leading to the resistance to trastuzumab in patients with PTEN loss.…”

Section: Discussionmentioning

confidence: 99%

“…Details of the assessment method were previously reported [19,20] . In brief, two microsatellite markers, D10S1765 and D10S1173, were used and PCR amplifications performed as previously described [19] .…”

Section: Loss Of Heterozygosity Of Ptenmentioning

confidence: 99%

Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma

Oki¹,

Okano²,

Saeki³

et al. 2017

Oncology

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Objectives: Programmed death 1 (PD-1) is an immunoinhibitory receptor and has been identified as a new target for immunotherapy in cancer. Here we report the expression of PD-1 ligand 1 (PD-L1) in surgically resected gastric cancer. Materials and Methods: We examined formalin-fixed tumor samples from 144 gastric cancer patients with a primary diagnosis of gastric carcinoma. Immunohistochemistry was used to detect PD-L1. Human epidermal growth factor receptor 2 (HER2) expression and phosphatase and tensin homolog (PTEN) loss of heterozygosity were investigated in these patients. RNA interference was used to downregulate HER2 expression, and PD-L1 protein expression was assessed by flow cytometry using the gastric cancer cell line MKN45. Results: Overexpression of PD-L1 was significantly correlated with tumor invasion (p = 0.011) and associated with poor survival. The number of PD-L1-positive cases increased according to the HER2 score in clinical samples. siRNA-mediated downregulation of HER2 significantly decreased PD-L1 protein expression in MKN45 cells. Conclusions: PD-L1 expression was associated with poor survival of gastric cancer, and HER2 signaling affects the expression of PD-L1 in gastric cancer. In gastric cancer, PTEN and HER2 are potential candidate biomarkers for developing human antibodies that block PD-L1.

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“… + + * + + 119 100 Yoda 2015 Japan ? + + * + + 120 101 Zaitsu 2015 Japan + + + * + + 121 102 Lu 2015 China ? + + * ?…”

Section: Resultsunclassified

Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis

Tabibzadeh

Tameshkel

Moradi

et al. 2020

Sci Rep

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The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3–8%), 12% (95% CI: 8–18%), 17% (95% CI: 14–20%), and 20% (95% CI: 5–41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14–33%) and 20% (95% CI, 17–24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.

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Loss of Heterozygosity of PTEN (Encoding Phosphate and Tensin Homolog) Associated with Elevated HER2 Expression Is an Adverse Prognostic Indicator in Gastric Cancer

Cited by 7 publications

References 35 publications

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

PTEN loss is associated with a poor response to trastuzumab in HER2-overexpressing gastroesophageal adenocarcinoma

Protein Expression of Programmed Death 1 Ligand 1 and HER2 in Gastric Carcinoma

Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis

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