Frequent lack of <i>GNAS</i> mutations in colorectal adenocarcinoma associated with <i>GNAS</i>‐mutated villous adenoma

Sekine, Shigeki; Ogawa, Reiko; Oshiro, Taihei; Kanemitsu, Yukihide; Taniguchi, Hirokazu; Kushima, Ryoji; Kanai, Yae

doi:10.1002/gcc.22147

Cited by 15 publications

(23 citation statements)

References 18 publications

(31 reference statements)

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“…The recent study by Sekine et al might indicate that the mutation is relevant for tumor initiation but dispensable for malignant www.fhc.viamedica.pl tumor progression. It confirms our observation of the potential coincidence with a KRAS mutation [27]. Another recent study of 428 colon adenocarcinoma reported a rather low GNAS1 mutation rate of 2.3% and also a coincidence with KRAS mutations.…”

Section: Discussionsupporting

confidence: 92%

“…In fact, a very recent Japanese study of 12 villous adenomas in association with colon adenocarcinoma confirmed the high incidence since GNAS1 mutations were detected in 9 cases (75%). Interestingly, the GNAS1 mutations were shared in only 3 of the 12 adenocarcinomas (25%) of which 11 also harbored KRAS mutations [27]. It should be mentioned, however, that this study came from the same group that initially reported GNAS1 mutation in villous adenoma.…”

Section: Discussionmentioning

confidence: 76%

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GNAS1 mutation analysis in gastrointestinal tumors

Walther

Chen³

et al. 2014

Folia Histochem Cytobiol.

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GNAS1 codes for a part of the a-stimulatory subunit (Gsa) of the G protein. Mutation of GNAS1 has been frequently found in myxoid soft tissues, however, in gastrointestinal tumors, little is known about the mutation status of GNAS1. The aim of the study was to analyze the occurrence of GNAS1 mutations in different gastrointestinal, gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and colorectal tumors. Mutation status of GNAS1 exon 8 was analyzed in one hundred thirty-five formalin-fixed, paraffin-embedded (FFPE) gastrointestinal tumor samples including 45 tubular-villous adenomas, 11 tubular adenomas, 6 villous adenomas, 10 hyperplastic gastric polyps, 31 GEP-NETs and 32 colorectal adenocarcinomas by using polymerase chain reaction (PCR) and direct sequencing. Five GNAS1 mutations were found in 2 tubular-villous adenomas, 2 villous adenomas and 1 colorectal adenocarcinoma. No mutations were detected in the tubular adenomas, the hyperplastic gastric polyps or GEP-NETs. GNAS1 mutation is not a frequent molecular event in GEP-NETs or hyperplastic gastric polyps. The study confirms the presence of GNAS1 mutations in colon tumors with villous differentiation. (Folia Histochemica et Cytobiologica 2014, Vol. 52, No. 2, 90-95)

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 76%

GNAS1 mutation analysis in gastrointestinal tumors

Walther

Chen³

et al. 2014

Folia Histochem Cytobiol.

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“…Mucinous colon/appendix cancers display phenotypic and genotypic characteristics that are predictive of responses to dual MEK‐PI3K inhibition. Mucinous colon cancers are more likely to occur in younger female patients; particularly the right colon; follow the serrated pathway for carcinogenesis; and are more likely to have RAS, RAF, and GNAS mutations . Similarly, mucinous appendix cancers are almost always KRAS mutant, and low‐grade histology almost uniformly demonstrates GNAS mutations .…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we tested the efficacy of dual MEK‐PI3K drug therapy against mucinous colon/appendix cancers since these tumors demonstrate unique phenotypic and genotypic features that are likely to be predictive of sensitivity to this combination therapy. Genotypically, these tumors frequently demonstrate KRAS mutations, resulting in downstream activation of MAPK and PI3K signaling pathways . Phenotypically, mucinous tumors demonstrate high basal endoplasmic reticulum stress (ERS), and associated signaling pathways known as the upregulated protein response (UPR), likely due to high mucin 2 (MUC2) protein turnover .…”

Section: Introductionmentioning

confidence: 99%

Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors

et al. 2020

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Molecular‐targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK‐PI3K drug therapy against KRAS mutated mucin 2 (MUC2)‐secreting LS174T cells and patient‐derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co‐therapy. Co‐treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)‐induced synergistic cytotoxicity and intrinsic mitochondrial‐mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)‐associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock‐down assays demonstrated that mitochondrial‐mediated apoptosis in LS174T cells was not ERS‐dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post‐translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient‐derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK‐PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co‐treatment based on their unique phenotypic and genotypic characteristics.

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“…These associated genes were a component of the associated gene network in adenocarcinoma. Finally, the last component of the associated gene network in adenocarcinoma was identified using the relevant literature (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). The four aforementioned components were then summarized as the associated gene network in adenocarcinoma.…”

Section: Materials Collection and Data Processingmentioning

confidence: 99%

Construction and analysis of three networks of genes and microRNAs in adenocarcinoma

et al. 2015

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Abstract. Adenocarcinoma is one of the most serious diseases that threaten human health. Numerous studies have investigated adenocarcinoma and have obtained a considerable amount of data regarding genes and microRNA (miRNA) in adenocarcinoma. However, studies have only focused on one or a small number of genes and miRNAs, and the data is stored in a scattered form, making it challenging to summarize and assess the associations between the genes and miRNAs. In the present study, three networks of genes and miRNAs in adenocarcinoma were focused on. This enabled the construction of networks of elements involved in adenocarcinoma and the analysis of these networks, rather than only discussing one gene. Transcription factors (TFs), miRNAs, and target and host genes of miRNAs in adenocarcinoma, and the regulatory associations between these elements were identified in the present study. These elements and associations were then used to construct three networks, which consisted of the differentially-expressed, associated and global networks. The similarities and differences between the three networks were compared and analyzed. In total, 3 notable TFs, consisting of TP53, phosphatase and tensin homolog and SMAD4, were identified in adenocarcinoma. These TFs were able to regulate the differentially-expressed genes and the majority of the differentially-expressed miRNAs. Certain important regulatory associations were also found in adenocarcinoma, in addition to self-regulating associations between TFs and miRNAs. The upstream and downstream elements of the differentially-expressed genes and miRNAs were recorded, which revealed the regulatory associations between genes and miRNAs. The present study clearly revealed components of the pathogenesis of adenocarcinoma and the regulatory associations between the elements in adenocarcinoma. The present study may aid the investigation of gene therapy in adenocarcinoma and provides a theoretical basis for studies of gene therapy methods as a treatment for adenocarcinoma.

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Frequent lack of GNAS mutations in colorectal adenocarcinoma associated with GNAS‐mutated villous adenoma

Cited by 15 publications

References 18 publications

GNAS1 mutation analysis in gastrointestinal tumors

GNAS1 mutation analysis in gastrointestinal tumors

Rational application of targeted therapeutics in mucinous colon/appendix cancers with positive predictive factors

Construction and analysis of three networks of genes and microRNAs in adenocarcinoma

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