Pancreatic cancer: molecular pathogenesis and new therapeutic targets

Wong, Hock Tsen; Lemoine, Nicholas R.

doi:10.1038/nrgastro.2009.89

Cited by 187 publications

(160 citation statements)

References 118 publications

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“…Oncogenic-mutated KRAS is expressed in up to 95% of PDAC cases and is involved in the initiation or early phase of pancreatic tumorigenesis [11,12]. 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).…”

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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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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“…Current targeted therapeutics have very limited effect on pancreatic cancer patients (9,(12)(13)(14). Past research has linked insulin and IGF signaling to the tumorigenesis and progression of pancreatic cancer (15,16).…”

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confidence: 99%

The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

Duan

Ying

Danzer

et al. 2014

Journal of Biological Chemistry

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Background: Prolylcarboxypeptidase (PRCP) and prolyl endopeptidase (PREP) regulate proliferation and survival of breast cancer cells. Results: PRCP and PREP regulate IRS-1 stability and PI3K/AKT activation in pancreatic cancer cells. Depletion/inhibition of PRCP/PREP suppresses rapamycin-induced activation of PI3K/AKT with consequent additive/synergistic cytotoxicity. Conclusion: PRCP and PREP regulate IRS-1 stability and PI3K/AKT activation in pancreatic cancer. Significance: Prolyl peptidases are potential therapeutic targets in pancreatic cancer.

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“…Recognized risk factors for the cancer include cigarette smoking, chronic and hereditary pancreatitis, history of diabetes and familial cancer syndromes. 2,3 This cancer is one of the most difficult conditions to treat, although it only accounts for 3% of all cancers; 5-year survival rate is about 5% in pancreatic cancer patients, and this figure remains largely unchanged over the past 3 decades. 3 Therefore, identification of new behavior risk factors as a prevention measure is crucial.…”

Section: Dear Editormentioning

confidence: 99%