Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

Amato, Eliana; Molin, Marco Dal; Mafficini, Andrea; Yu, Jun; Malleo, Giuseppe; Rusev, Borislav; Fassan, Matteo; Antonello, Davide; Sadakari, Yoshihiko; Castelli, Paola; Zamboni, Giuseppe; Maitra, Anirban; Salvia, Roberto; Hruban, Ralph H.; Bassi, Claudio; Capelli, Paola; Lawlor, Rita T.; Goggins, Michael; Scarpa, Aldo

doi:10.1016/j.pan.2014.05.786

Cited by 61 publications

(108 citation statements)

References 28 publications

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“…10 Recent studies on the molecular carcinogenesis of pancreatic intraductal tubulopapillary neoplasms revealed that oncogenic pathways that are commonly altered in intraductal papillary mucinous neoplasms are rarely mutated in pancreatic intraductal tubulopapillary neoplasms, with the highest mutation prevalence in the PIK3CA gene (0-21.4%) and only rare mutations in KRAS (0-7.1%) and BRAF (0-7.1%). [13][14][15] In a recent study based on the targeted next-generation sequencing of 11 pancreatic intraductal tubulopapillary neoplasms, no mutations were identified in a panel of 300 key cancer-associated genes including KRAS, GNAS, and RNF3 genes. In fact, three cases (27%) did not reveal any mutations in the tested genes and only two specific genes were mutated in more than one case: MLL2 and MLL3, each identified in two cases.…”

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confidence: 99%

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

et al. 2015

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Intraductal tubulopapillary neoplasm is a well-established entity in the pancreas. A similar, if not identical, tumor occurs also in the biliary tract. We conducted a multicenter study of 20 such lesions, focusing on their clinicopathologic characteristics and molecular profile. Biliary intraductal tubulopapillary neoplasms were seen in patients in their 60s (mean 62 years). The tumors were intrahepatic 70%, extrahepatic 10%, and perihilar 20%; mean tumor size was 6.9 cm. Histologically, all intraductal tubulopapillary neoplasms showed, in addition to their typical tubular pattern, solid areas (70%) or abortive papillae (50%). Necrosis was common (85%), predominantly focal (40%), and with 'comedocarcinoma-like pattern' in 40%. Immunohistochemically, these neoplasms were characterized by the expression of MUC1 (80%) and MUC6 (30%) and by the absence of MUC2 and MUC5AC. Associated invasive carcinomas were present in 16 (80%), mainly conventional tubular adenocarcinoma (50%). The molecular alterations observed included CDKN2A/p16 (intraductal components 44%, invasive 33%) and TP53 (intraductal components 17%, invasive 9%). Mutations in KRAS (intraductal 6%, invasive 0%), PIK3CA (intraductal 6%, invasive 0%), and loss of SMAD4/DPC4 (intraductal 7%, invasive 0%) were rare. No alterations/mutations were identified in IDH1/2, BRAF, GNAS, EGFR, HER2, and β-catenin. Follow-up information was available for 17 patients (85%) with mean follow-up 44 months. Overall combined survival rates showed favorable prognosis: 1 year 100%, 3 years 90%, and 5 years 90%. In conclusion, despite the relatively high incidence of invasive carcinoma (80%), available follow-up suggests that biliary intraductal tubulopapillary neoplasms have an indolent behavior. Molecular analyses highlight the low prevalence of alterations of common oncogenic signaling pathways in intraductal tubulopapillary neoplasm. Further studies using whole-exome sequencing are required to discover yet unknown molecular changes and to understand the carcinogenesis of intraductal tubulopapillary neoplasms.

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confidence: 99%

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

et al. 2015

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Section: Gnas and Kras Mutations Are Frequent In Ipmnsmentioning

confidence: 96%

“…Mutations of both were found in 10 IPMNs (24%) and 1 (13%) with associated adenocarcinoma. Previous studies have found 25-51% of IPMNs harbor concurrent mutations in GNAS and KRAS [5,6,8].However, a mutation in either GNAS or KRAS was found in 34 IPMNs (83%) and 8 (89%) with associated adenocarcinoma. Importantly, mutations were absent in cystic PNETs, SCA, retention cysts, pseudocysts and the lymphoepithelial cyst.…”

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confidence: 91%

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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“…29 The advent of massive parallel sequencing, also known as next-generation sequencing (NGS) or deep sequencing where accurate detection of mutations in gene panels with limited DNA can be achieved, has demonstrated that both GNAS and KRAS mutations are found in 92% of all IPMNs. 30 Several studies have combined DNA quantity, KRAS mutations, and LOH and have shown variable sensitivities: 50% 31 vs 83%. 32 An additional study found that both KRAS and LOH was present in 50% of carcinoma or high grade dysplasia compared to 8% of premalignant IPMNs, indicating the progression of neoplasia may be correlated by increased number of genetic disturbances.…”

Section: Intraductal Papillary Mucinous Neoplasmmentioning

confidence: 99%

An appraisal of pancreatic cyst fluid molecular markers

Modi

Pavurala

Krishna

2017

Int J Gastrointest Interv

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Pancreatic malignancy is the third leading cause of cancer related death in the United States with limited viable screening options. By the end of this decade, cancers are poised to become the leading cause of death with pancreatic cancer projected to be the second leading cause of cancer related mortality. Pancreatic cystic lesions (PCLs) are found in approximately 5%-14% of patients due to the increased utilization of cross-sectional imaging, with approximately 8%-10% of pancreatic cancers originating as PCLs. Current screening guidelines have shown discrepancies between morphologic characteristics of PCLs and identifying advanced pancreatic disease. Molecular analysis has emerged as a novel technology to aid in adequate diagnosis and management decisions of PCLs. Mucinous cysts including intraductal papillary mucinous neoplasms (IPMNs) or mucinous cystic neoplasms have similar oncogenic mutations including KRAS, TP53, SMAD4, PIK3CA, PTEN, or CKDN2A, while GNAS and RNF43 mutations are specific only to IPMNs. Serous cystadenomas have been associated with a loss of tumor suppressor gene VHL, while solid-psuedopapillary neoplasms have an oncogenic mutation CTNNB1. A specific molecular marker to diagnose existing high-grade dysplasia or impending malignant transformation is yet to be identified. Moving forward it is important to advance technology in isolating and identifying high-risk molecular markers from cyst fluid while considering their increased utilization in the evaluation of PCLs.

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Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas.

Cited by 61 publications

References 28 publications

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

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

An appraisal of pancreatic cyst fluid molecular markers

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