Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms

Nishikawa, Gen; Sekine, Shigeki; Ogawa, Reiko; Matsubara, Akiko; Mori, Tohru; Taniguchi, Hirokazu; Kushima, Ryoji; Hiraoka, Nobuyoshi; Tsuta, Koji; Tsuda, Hitoshi; Kanai, Yae

doi:10.1038/bjc.2013.47

Cited by 142 publications

(174 citation statements)

References 26 publications

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“…In that study, 89% of the mutations were in codon 12 and 11% in codon 13. In 2013, Nishikawa and colleagues identified GNAS mutations as common in LAMNs and suggested that mutant GNAS might play a direct role in mucin production (16 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

Li¹,

Mody²,

Abreu³

et al. 2014

Clinical Chemistry

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BACKGROUND Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. METHODS Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extracted DNA and multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. RESULTS A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1 (v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. CONCLUSIONS Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

Li¹,

Mody²,

Abreu³

et al. 2014

Clinical Chemistry

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“…GNAS has been shown to elevate intracellular cAMP levels by stimulating adenylyl cyclase,17 which provokes cellular proliferation through the protein kinase A‐ERK signal pathway 18. Previous studies have detected these mutations in glandular neoplasms in the pancreas, colon, stomach, duodenum, and appendix16, 19, 20, 21, 22, 23, 24 Matsubara et al also identified GNAS gene mutations in 42% of LEGH 25. However, the relation among GNAS mutations, clinical courses and histological types of LEGH remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Usefulness of a management protocol for patients with cervical multicystic lesions: A retrospective analysis of 94 cases and the significance of GNAS mutation

Ando

Miyamoto

Kashima

et al. 2016

J of Obstet and Gynaecol

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AimThe proper preoperative diagnosis and management of cervical proliferative disorders presenting with multiple cysts, including minimal deviation adenocarcinoma (MDA), lobular endocervical glandular hyperplasia (LEGH), and nabothian cyst (NC), have not been fully established. We previously proposed a management protocol comprising a diagnostic approach using cytology, magnetic resonance imaging, and gastric‐type mucin and subsequent treatment. We herein evaluate the usefulness of this protocol and implications of GNAS mutations in LEGH.MethodsThe clinical courses of 94 patients with cervical multicystic lesions who visited our hospital between June 1995 and September 2014 were retrospectively analyzed. GNAS mutations were investigated in 10 LEGH, five LEGH with atypia, and two MDA cases.ResultsOf the 94 patients, the conditions of 10, 59, and 25 were clinically diagnosed as suspicious of MDA or carcinoma (S/O MDA‐Ca), suspicious of LEGH (S/O LEGH), and NC, respectively. Ten patients each with S/O MDA‐Ca and S/O LEGH underwent hysterectomy, and the correct ratio for diagnosis was 90% (18/20). Of the 42 S/O LEGH cases followed‐up for more than 12 months, three showed an increase in tumor size. After hysterectomy, two were LEGH with atypia while one was NC. The GNAS mutation was detected in two cases of LEGH with atypia, one of which showed an increase in tumor size during follow‐up.ConclusionThe management protocol we propose herein will be useful. An increase in tumor size is important to detect potentially malignant LEGH. GNAS mutations may be involved in the tumorigenesis of potentially malignant LEGH.

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“…Because of the widespread occurrence of G-protein-coupled receptors mutations the gene could in principle be involved in a large number of different tumor types. And indeed, it was shown that GNAS1 mutation could be found in different neoplasia throughout the whole body ranging from pituitary gland tumors [12] over www.fhc.viamedica.pl pancreatic intraductal papillary mucinous neoplasm (IPMN) [13,14], low-grade appendiceal mucinous neoplasia [15], villous adenomas of the colorectum [16] to colorectal carcinoma [17]. However, the mutation status of GNAS1 in gastrointestinal cancer has not yet been well investigated.…”

Section: Introductionmentioning

confidence: 99%

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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Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms

Cited by 142 publications

References 26 publications

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

Molecular Profiling of Appendiceal Epithelial Tumors Using Massively Parallel Sequencing to Identify Somatic Mutations

Usefulness of a management protocol for patients with cervical multicystic lesions: A retrospective analysis of 94 cases and the significance of GNAS mutation

GNAS1 mutation analysis in gastrointestinal tumors

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