Frequent activating <i>GNAS</i> mutations in villous adenoma of the colorectum

Yamada, Masayoshi; Sekine, Shigeki; Ogawa, Reiko; Taniguchi, Hirokazu; Kushima, Ryoji; Tsuda, Hitoshi; Kanai, Yae

doi:10.1002/path.4012

Cited by 69 publications

(100 citation statements)

References 16 publications

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“…14,15,39 which may suggest a possible link at the molecular level to colorectal villous adenoma, where GNAS is commonly mutated (83%). 40 b-Catenin, a downstream target of the growthpromoting Wnt signalling pathway, was recently linked to progression of biliary intraductal papillary neoplasm of the bile duct associated with hepatolithiasis. 25 In our study, nuclear b-catenin accumulation was found only in four intraductal papillary neoplasms of the bile duct in non-invasive lesions.…”

Section: Discussionmentioning

confidence: 99%

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

Schlitter

Born

Bettstetter³

et al. 2014

Modern Pathology

132

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Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of the bile duct from 45 patients were graded and subtyped using mucin markers and CDX2. In addition, tumors were analyzed for common oncogenic pathways, and the findings were correlated with subtype and grade. Data were compared with those from 22 extra-and intrahepatic cholangiocarcinomas. Intraductal papillary neoplasms showed a development from preinvasive low-to highgrade intraepithelial neoplasia to invasive carcinoma. Molecular and immunohistochemical analysis revealed mutated KRAS, overexpression of TP53 and loss of p16 in low-grade intraepithelial neoplasia, whereas loss of SMAD4 was found in late phases of tumor development. Alterations of HER2, EGFR, b-catenin and GNAS were rare events. Among the subtypes, pancreato-biliary (36%) and intestinal (29%) were the most common, followed by gastric (18%) and oncocytic (13%) subtypes. Patients with intraductal papillary neoplasm of the bile duct showed a slightly better overall survival than patients with cholangiocarcinoma (hazard ratio (cholangiocarcinoma versus intraductal papillary neoplasm of the bile duct): 1.40; 95% confidence interval: 0.46-4.30; P ¼ 0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenomacarcinoma sequence that correlates with the stepwise activation of common oncogenic pathways. Further large trials are needed to investigate and verify the finding of a better prognosis of intraductal papillary neoplasms compared with conventional cholangiocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

Schlitter

Born

Bettstetter³

et al. 2014

Modern Pathology

132

131

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“…Somatic GNASactivating mutations cause McCune Albright syndrome, pituitary adenomas, endocrine tumors, and/or fibrous dysplasia of bone, primarily through increased cAMP levels, which in some cells can lead to proliferation [16,17]. Activating GNAS mutations have also been frequently observed in gastric and duodenal pyloric-gland adenomas [18], and colorectal villous adenomas and are often associated with KRAS mutations [19]. Interestingly, GNAS and KRAS mutations have been detected in 29 and 32% of intraductal papillary neoplasms of the bile duct respectively (especially those with intestinal differentiation) [20].…”

Section: Expert Commentary and Five-year Viewmentioning

confidence: 99%

Activating mutations ofGNASandKRASin cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas

Frampton

Stebbing

Gall

et al. 2015

Expert Review of Molecular Diagnostics

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Evaluation of: Singhi AD, Nikiforova MN, Fasanella KE, et al. Preoperative GNAS and KRAS testing in the diagnosis of pancreatic mucinous cysts. Clin. Cancer Res. 20(16), 4381-9 (2014).Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas have a risk of malignant transformation following an adenoma-carcinoma sequence. Surgical resection is often required, especially for main pancreatic duct IPMNs (MD-IPMNs). There is an urgent need for novel biomarkers to reliably differentiate IPMNs from more benign pancreatic cysts and therefore avoid unnecessary surgery. DNA sequencing has demonstrated that guanine nucleotide binding protein alpha stimulating (GNAS) activity polypeptide 1 mutations play a driving role in IPMN development. GNAS mutations have been shown to be highly specific for IPMNs, whereas oncogenic KRAS mutations have been associated with mucinous differentiation. The evaluated article by Singhi et al. helps to define the role of these mutations as biomarkers in preoperative endoscopic ultrasound fine-needle aspiration samples for detecting IPMNs. They found that the presence of a GNAS and/or a KRAS mutation was highly specific and sensitive for IPMNs. Cystic lesions of the pancreas can either be inflammatory or proliferative [1]. Differentiating between low-and high-risk pre-malignant tumors can be difficult and the consequences of missing the chance for a curative resection in patients who are suitable can be devastating. To prevent this, many centers recommend routine excision of all suspicious pancreatic cystic tumors (PCTs), potentially exposing patients with benign disease to the unjustifiable risks of major surgery. PCTs can be classified into non-mucinous tumors with negligible malignant potential, such as the serous cystadenomas (SCA), and those with significant malignant potential, such as intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). The mucinous cysts have the potential to give rise to in situ or invasive carcinoma, via an adenoma-carcinoma sequence. Thus, a correct pre-operative diagnosis and evaluation of a PCT is crucial for clinical decision-making.Endoscopic ultrasound fine-needle aspiration (EUS-FNA) has become an essential tool for cytopathologic confirmation of pancreatic lesions, and pre-operative planning. Recent meta-analysis has shown that pooled specificity for cytology is 93% (95% CI: 90-95) with a sensitivity of 54% (95% CI: 49-59) for a mucinous cyst [2]. Carcinoembryonic antigen (CEA) levels are raised in mucinous cyst fluid while low in non-mucinous lesions, and the optimum threshold of 192 ng/ml has high discriminatory accuracy [3]. Pooled specificity for CEA measurement is 88% (95% CI: 83-91), with a sensitivity of only 63% (95% CI: 59-67) for mucinous differentiation [ [4][5][6]. Of note, these experiments have revealed frequent activating mutations of GNAS and KRAS in IPMNs. Indeed, GNAS mutations appear to be a hallmark molecular alteration of IPMNs (prevalencẽ 66%) [6]. However, the ability and clinical usefulness of i...

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“…Immunohistochemistry was performed using anti-E-cadherin antibody (NCH-38; 1:100 dilution; DAKO, Glostrup, Denmark) as previously described [8]. The results showed loss of E-cadherin expression in SRCCs.…”

Section: Case Reportsmentioning

confidence: 99%

Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1

et al. 2013

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Hereditary diffuse gastric cancer (HDGC), characterized by susceptibility to gastric signet ring cell carcinomas (SRCCs) and caused by CDH1 germline mutations, is rare in the Japanese. We present here a Japanese family with HDGC identified by comparative genomic hybridization (CGH) analysis. A 55-year-old woman was treated with completion gastrectomy for multiple SRCCs, and pathological examination revealed approximately 200 foci of SRCC with loss of E-cadherin expression. Her 30-year-old son had surveillance endoscopy and was found to have multiple SRCCs. He underwent total gastrectomy, and 32 foci of SRCC with loss of E-cadherin expression were histologically found. Although no point mutations were detected in CDH1 by sequencing, CGH revealed a 275-kb deletion involving exons 7-16 of CDH1 in both patients. While only a few HDGCs have been reported in East Asia, patients with multiple SRCC may need to be offered appropriate genetic counseling and testing in this area.

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Frequent activating GNAS mutations in villous adenoma of the colorectum

Cited by 69 publications

References 16 publications

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways

Activating mutations ofGNASandKRASin cystic fluid can help detect intraductal papillary mucinous neoplasms of the pancreas

Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1

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