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

Abstract

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...

Next generation sequencing of the cellular and liquid fraction of pancreatic cyst fluid supports discrimination of IPMN from pseudocysts and reveals cases with multiple mutated driver clones: First findings from the prospective ZYSTEUS biomarker study

“…Some studies indicate that the detection of GNAS rather than KRAS mutations may be a predictor of IPMN development toward mucinous cystadenocarcinoma . Clinical follow‐up data of the prospective ZYSTEUS study are still very preliminary thus preventing any meaningful conclusions.…”

“…Some studies indicate that the detection of GNAS rather than KRAS mutations may be a predictor of IPMN development toward mucinous cystadenocarcinoma. 16,25,[36][37][38][39] Clinical follow-up data of the prospective ZYSTEUS study are still very preliminary thus preventing any meaningful conclusions. Until now, we observed GNAS mutations in both multifocal branch duct IPMNs with and without worrisome features and main duct IPMN.…”

Glycopatterns and Glycoproteins Changes in MCN and SCN: A Prospective Cohort Study

“…According to the evidence, carcinoembryonic antigen (CEA) >192ng/L in cyst fluids could be reports on potential malignant PCNs. Mostly, gene mutations of KRAS at codon 12,13 are hallmark genetic alterations of pancreatic ductal adenocarcinoma (PDAC), and GNAS codon 201 mutations are hallmark genetic alterations of IPMNs [13, 14].…”

A prospective study of endoscopic ultrasonography features, cyst fluid carcinoembryonic antigen, and fluid cytology for the differentiation of small pancreatic cystic neoplasms

“…DNA analyses of pancreatic cystic fluid, including K-ras, GNAS gene mutation analysis, tumor suppressor genes, and loss of heterozygosity, can be used for the identification of benign and malignant lesions. [ 29 ] Therefore, in the long-term follow-up of pancreatic cysts, focal monitoring of fluid, including changes in certain molecules (BRAF, CDKN2A, CTNNB1 GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL) is very important. [ 30 ] Pancreatic mucins are highly glycosylated high-molecular-weight glycoproteins and can be used in the determination of the malignant potential of precancerous or malignant lesions.…”