GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type

Nomura, Ryosuke; Saito, Tsuyoshi; Mitomi, Hiroyuki; Hidaka, Yuko; Lee, Se-yong; Watanabe, Sumio; Yao, Takashi

doi:10.1016/j.humpath.2014.08.016

Cited by 69 publications

(97 citation statements)

References 23 publications

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“…Patients with GAFG were predominantly male, and GAFG was typically located in the upper third portion of the stomach in accordance with previous reports [1,5,8]. Patients with GAFG were significantly younger than those with CGA.…”

Section: Discussionsupporting

confidence: 90%

“…These comprised 13 samples that were examined in our previous study [8] and 14 newly collected ones. In accordance with a previous description [1], GAFGs were defined as tumors consisting of irregular anastomosing glands or cords of columnar cells mimicking fundic gland cells (mainly chief cells) with mild nuclear atypia and submucosal involvement (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical staining for β-catenin was assessed as described previously [5,8]. The percentage of cells exhibiting β-catenin nuclear staining (labeling index [LI]) was evaluated in areas showing the highest immunoreactivity by counting the number of positive cells among at least 500 tumor cells.…”

Section: Methodsmentioning

confidence: 99%

“…Sections were lightly stained with hematoxylin, and tumor areas were separated by a modified microdissection approach, with the tissue being directly observed under a light microscope. The resulting DNA samples were subjected to polymerase chain reaction, followed by direct sequencing, as previously described [5,8]. The sequences of the primers used, as well as the corresponding exons (codons), annealing temperatures, and product sizes are listed in online supplementary Table 1 (see www.karger.com/doi/10.1159/000478999).…”

Section: Methodsmentioning

confidence: 99%

“…PPP2R1A (the gene encoding PP2A protein) is a Wnt/β-catenin signal-associated gene that is also mutated in this type of tumor without submucosal involvement [6]. In addition, mutations within guanine nucleotide-binding protein, alpha stimulating complex ( GNAS ), have been shown to occur in a small subset of GAFGs exhibiting nuclear β-catenin accumulation, implying that this mutation may act as an alternative mechanism of Wnt/β-catenin signaling activation [7,8]. …”

Section: Introductionmentioning

confidence: 99%

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Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Tajima

Murakami²,

Saito³

et al. 2017

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Background/Aims: Gastric adenocarcinoma of fundic gland type (GAFG), which is a rare variant of gastric cancer, is reportedly associated with both Wnt/β-catenin signaling activation and guanine nucleotide binding protein, alpha stimulating complex (GNAS) mutations. This study aimed to elucidate potential roles of the Sonic hedgehog (Shh) signaling pathway in GAFG. Methods: We performed immunostaining for β-catenin and Shh signal-associated proteins, including Patched (Ptch), Smoothened (Smo), and Glioma-associated oncogene-1 (Gli1), and the direct sequencing of GNAS/BRAF/KRAS in 27 GAFGs, and compared them with 30 conventional gastric adenocarcinomas (CGAs). Results: GAFGs exhibited significantly lower immunoreactivity scores for Ptch, Smo, and Gli1 than CGAs. Moreover, while the Ptch score was significantly lower in the GAFG tumor areas than in the non-neoplastic areas adjacent to GAFG, the score was significantly higher in the CGA tumor areas than in the non-neoplastic areas. Similar trends were observed in the scores for Smo and Gli1. β-Catenin expression and GNAS mutations were found in 22 (81%) and 8 (30%) of the 27 GAFGs respectively. Gli1 expression was significantly associated with mutations in GNAS. Conclusion: GAFG and CGA exhibited distinct Ptch, Smo, and Gli1 expression patterns. Downregulation of the Shh signaling pathway, as well as activation of the Wnt/β-catenin signaling pathway, may therefore be associated with tumorigenesis in GAFG.

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Section: Discussionsupporting

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Tajima

Murakami²,

Saito³

et al. 2017

Digestion

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Spectrum of Somatic Cancer Gene Variations Among Adults With Appendiceal Cancer by Age

et al. 2020

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Key Points Question What are the differences in somatic cancer gene variations in appendiceal cancer among adults based on age at disease onset? Findings In this cohort study of 385 patients diagnosed with appendiceal cancer with targeted clinical-grade sequencing data from the American Association for Cancer Project Genomics Evidence Neoplasia Information Exchange, patients who were diagnosed at age younger than 50 years harbored unique somatic variant patterns in PIK3CA , GNAS , SMAD3 , and TSC2 compared with those diagnosed at age 50 years and older. Meaning These findings suggest that appendiceal cancer diagnosed among young individuals harbors a distinct spectrum of somatic variations, which may yield clinical actionability in the development of targeted therapeutic modalities for young patients with appendiceal cancer.

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G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

2020

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G protein‐coupled receptors (GPCRs) and heterotrimeric G proteins play central roles in a diverse array of cellular processes. As such, dysregulation of GPCRs and their coupled heterotrimeric G proteins can dramatically alter the signalling landscape and functional state of a cell. Consistent with their fundamental physiological functions, GPCRs and their effector heterotrimeric G proteins are implicated in some of the most prevalent human diseases, including a complex disease such as cancer that causes significant morbidity and mortality worldwide. GPCR/G protein‐mediated signalling impacts oncogenesis at multiple levels by regulating tumour angiogenesis, immune evasion, metastasis, and drug resistance. Here, we summarize the growing body of research on GPCRs and their effector heterotrimeric G proteins as drivers of cancer initiation and progression, and as emerging antitumoural therapeutic targets.

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GNAS mutation as an alternative mechanism of activation of the Wnt/β-catenin signaling pathway in gastric adenocarcinoma of the fundic gland type

Cited by 69 publications

References 23 publications

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Distinct Involvement of the Sonic Hedgehog Signaling Pathway in Gastric Adenocarcinoma of Fundic Gland Type and Conventional Gastric Adenocarcinoma

Spectrum of Somatic Cancer Gene Variations Among Adults With Appendiceal Cancer by Age

G Protein‐Coupled receptors and heterotrimeric G proteins as cancer drivers

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