BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas

Schönleben, Frank; Qiu, Wanglong; Bruckman, Karl C.; Ciau, Nancy; Li, Xiaojun; Lauerman, Margaret H.; Frucht, Harold; Chabot, John A.; Allendorf, John D.; Remotti, Helen; Su, Gloria H.

doi:10.1016/j.canlet.2006.09.007

Cited by 105 publications

(87 citation statements)

References 39 publications

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“…[18][19][20][21][22] Consistent with previous studies, the prevalence of KRAS mutations in IPMNs was 67%. In contrast, only 14% of MCNs harbored a KRAS mutation.…”

Section: Discussionsupporting

confidence: 89%

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

et al. 2013

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With improvements in abdominal imaging, detection of incidental pancreatic cysts are becoming increasingly common. Analysis of pancreatic cyst fluid from fine-needle aspiration is particularly important in identifying intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which have significant implications in clinical intervention and follow-up. Previous controlled studies have shown that KRAS mutations in cyst fluid are highly specific for mucinous differentiation in pancreatic cysts; however, this has not been examined in the clinical setting. Over a 6-year study period, 618 pancreatic cyst fluids obtained by fine-needle aspiration at the time of endoscopic ultrasound were tested for KRAS mutations as part of routine evaluation for a cystic neoplasm. Of the 618 specimens, 603 (98%) from 546 patients were satisfactory for molecular analysis. Patients ranged in age from 17 to 90 years (mean, 63.9 years) and were predominantly female (68%). Pancreatic cysts were relatively evenly distributed throughout the pancreas and ranged in size from 0.6 to 11.0 cm (mean, 2.3 cm). Mutations in KRAS were detected in 232 of 603 (38%) aspirates. Although sufficient for molecular analysis, 320 of 603 (53%) specimens were either less than optimal (38%) or unsatisfactory (15%) for cytopathologic diagnosis. Surgical follow-up information was available for 142 (26%) patients and consisted of 53 KRAS-mutated and 89 KRAS-wild-type cysts. Overall, KRAS mutations had a specificity of 100%, but a sensitivity of 54% for mucinous differentiation. When stratified by cyst type, KRAS had a sensitivity of 67% and 14% for IPMNs and MCNs, respectively. In summary, KRAS mutations were highly specific for mucinous differentiation, but were inadequate in identifying MCNs. Future molecular studies and the combination of other fluid markers are required to improve the detection and classification of pancreatic mucinous neoplasms by endoscopic ultrasound fine-needle aspiration.

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“…[18][19][20][21][22] Consistent with previous studies, the prevalence of KRAS mutations in IPMNs was 67%. In contrast, only 14% of MCNs harbored a KRAS mutation.…”

Section: Discussionsupporting

confidence: 89%

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

et al. 2013

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“…However, targeting the B-Raf kinase isoform appears to be most effective when activating mutations are present in cancer cells, such as the reported V600E Raftype mutation in thyroid cancer and melanoma (27,37). In our study, we investigated the effects of a small-molecule inhibitor to Raf and VEGFR2 on pancreatic cancer cells, although the Raf signaling cascade in this cancer entity is predominantly activated via KRAS (10), an oncogene known to be mutated in >90% of pancreatic adenocarcinomas (38,39). Indeed, we found that inhibition of Raf led to a potent reduction in MEK, Erk, and STAT3 activation in cancer cells, suggesting that the Raf pathway represents a valid molecular target in this cancer entity.…”

Section: Discussionmentioning

confidence: 99%

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Lang¹,

Schachtschneider²,

Moser³

et al. 2008

Molecular Cancer Therapeutics

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The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growthinhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer.

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“…Indeed, frequent mutations of KRAS have been previously detected in the pancreatic juice, tissues and EUSFNAs of patients with PDAC and IPMN (SUPPLEMENTARY TABLE 1 [supplementary material can be found online at www.informahealthcare.com/suppl/10.1586/14737159.2015.1002771_Suppl). Interestingly, the frequency of mutated KRAS remains consistent as IPMN progresses (i.e., from adenoma to carcinoma) [13]. However, KRAS mutations have been shown to have high specificity, but low sensitivity for mucinous differentiation (100-96% and 54-45%, respectively) [14,15].…”

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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BRAF and KRAS gene mutations in intraductal papillary mucinous neoplasm/carcinoma (IPMN/IPMC) of the pancreas

Cited by 105 publications

References 39 publications

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

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

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