Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia

Rivera, Jaime A.; Rall, Christopher; Graeme‐Cook, Fiona; Castillo, Carlos Fernández‐del; Shu, Pei; Lakey, Nathan; Tepper, Robert I.; Rattner, David W.; Warshaw, Andrew L.; Rustgi, Anil K.

doi:10.1016/s0039-6060(97)90181-1

Cited by 77 publications

(32 citation statements)

References 23 publications

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“…The detection of K-ras mutations in nonneoplastic ducts was not surprising, because these are known to occur in the setting of benign conditions such as chronic pancreatitis. 35 Our results suggest that neoplastic transformation is ongoing at the periphery of MCN, particularly in association with malignant MCN. The presence of K-ras mutations in grossly normal pancreatic tissue supports formal pancreatic resection for the treatment of MCN and raises the question of incomplete resection when simple enucleation is performed.…”

Section: Discussionmentioning

confidence: 58%

Sequential Accumulation of K-ras Mutations and p53 Overexpression in the Progression of Pancreatic Mucinous Cystic Neoplasms to Malignancy

Jimenez¹,

Warshaw²,

Z’graggen³

et al. 1999

Annals of Surgery

166

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ObjectivePancreatic mucinous cystic neoplasms (MCNs) provide a spectrum of neoplastic changes ranging from benign to malignant. The authors have correlated K-ras mutations and p53 overexpression with the evolution of these tumors. MethodsAreas of mild, moderate, or severe dysplasia were microdissected from paraffin-embedded tissue sections of 28 different MCNs (10 benign, 9 borderline, 9 malignant). Nonneoplastic pancreatic ducts were also microdissected from tissues adjacent to the tumors. Ten serous cystadenomas served as negative controls. K-ras codon 12 mutations were identified by a mutant-enriched nested polymerase chain reaction-restriction fragment length polymorphism assay and confirmed by sequencing. p53 overexpression was demonstrated by immunohistochemistry. ResultsK-ras mutations were detected in 20% of benign, 33% of borderline, and 89% of malignant MCNs. Histologically, mutations were found in 26% (7/27) of MCN epithelia with mild dysplasia, 38% (5/13) of MCN epithelia with moderate dysplasia, and 89% (8/9) of MCN epithelia with severe dysplasia or carcinoma. Ten percent (4/39) of nonneoplastic pancreatic ducts at the margins of MCN harbored mutations, all associated with borderline or malignant tumors. Overexpression of p53 occurred in none of the benign or borderline MCNs but in 44% (4/9) of the malignant tumors (p ϭ 0.006 benign/borderline vs. malignant). p53 immunoreactivity was concentrated in areas of severe dysplasia/carcinoma or invasion, where K-ras mutation had been detected. ConclusionThese findings demonstrate a sequential accumulation of genetic changes in the carcinogenesis of MCN. K-ras mutations appear early and increase in proportion with increasing dysplasia. Overexpression of p53 is a late finding observed only in carcinomas, and in combination with mutated K-ras genes. The presence of K-ras mutations in nonneoplastic ducts supports formal pancreatic resection over enucleation for treatment. Mucinous cystic neoplasms may be a useful model to study the evolution of pancreatic ductal adenocarcinomas, in which precursor lesions remain unknown.Since the landmark paper of Compagno and Oertel, 1 cystic neoplasms of the pancreas have been increasingly reported in the medical literature.2-4 Pancreatic cystic neoplasms are relatively uncommon, accounting for 4% to 6% of exocrine pancreatic tumors. Although there is a wide variety of cystic neoplasms, the majority (Ͼ90%) are accounted for by mucinous cystic neoplasms (MCNs) and serous cystadenomas. 5 Other tumors with a cystic appearance, such as intraductal papillary mucinous tumors (IPMTs), are now identified as separate pathologic entities.

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Section: Discussionmentioning

confidence: 58%

Sequential Accumulation of K-ras Mutations and p53 Overexpression in the Progression of Pancreatic Mucinous Cystic Neoplasms to Malignancy

Jimenez¹,

Warshaw²,

Z’graggen³

et al. 1999

Annals of Surgery

166

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“…Furthermore, DOC-2 mRNA and protein are present in chronic pancreatitis-like lesions adjacent to the cancer mass and are particularly strong in the hyperplastic multiple layer epithelium, in comparison with single-layer epithelium. Because chronic pancreatitis-like lesions frequently harbor K-ras mutations (Mangray and King, 1998;Rivera et al, 1997), it seems that the upregulation of DOC-2 might occur already as an early event in the pathogenesis of pancreatic cancer. This hypothesis is supported by our observation that there were no differences in DOC-2 mRNA expression between early and advanced tumor stages.…”

Section: Discussionmentioning

confidence: 99%

DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Huang

Friess

Kleeff

et al. 2001

Laboratory Investigation

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SUMMARY:DOC-2/hDab2 (DOC-2) has tumor suppressive functions in ovarian cancer and choriocarcinoma. In these tumors, it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. Pancreatic cancer exhibits a high frequency of K-ras gene mutations; however, it is not known whether DOC-2 expression is altered in these tumors. Therefore, we investigated DOC-2 expression in 22 pancreatic adenocarcinomas and in 6 pancreatic cancer cell lines. Findings in human tumors were compared with normal controls and correlated with clinicopathological data. Additionally, the influence of K-ras on DOC-2 transcription was investigated. Northern blot and Western blot analyses both demonstrated an increase of DOC-2 mRNA and protein levels in primary pancreatic cancers in comparison with normal controls. In situ hybridization showed DOC-2 mRNA expression in the majority of cancer cells of primary tumors, as well as in chronic pancreatitis-like lesions surrounding the cancer mass. Immunohistochemistry mirrored the in situ hybridization findings. In contrast, levels of expression of DOC-2 in lymph node metastases were markedly decreased in comparison with levels in primary tumors. In addition, in 5 metastatic pancreatic cancer cell lines, DOC-2 mRNA and protein levels were low, whereas quantitative RT-PCR demonstrated relatively higher levels in a nonmetastatic pancreatic cancer cell line. In conclusion, DOC-2 is overexpressed in primary pancreatic adenocarcinoma but down-regulated in metastatic disease, suggesting a tumor suppressor function of DOC-2 in the late steps of pancreatic carcinogenesis. (Lab Invest 2001, 81:863-873).P ancreatic adenocarcinomas are the fourth or fifth leading cause of cancer-related death in developed countries, with an average 5-year survival rate of less than 0.5% (Gudjonsson, 1995). The poor prognosis of pancreatic cancer manifests itself by low resection rates, nonresponsiveness to adjuvant or palliative therapy, and a high incidence of recurrence and early metastasis formation following potentially curative resection.It is known that various genetic and epigenetic alterations are involved in the pathogenesis of pancreatic cancer, including overexpression of mitogenic growth factors and growth factor receptors (Friess et al, 1993;Korc et al, 1992), as well as mutations of the K-ras proto-oncogene and p53 and Smad4 tumor suppressor genes (Friess et al, 1998). A better understanding of the underlying molecular mechanisms, including those related to metastasis in this malignancy, will hopefully contribute to improvement of early diagnosis and effective therapy in the future. DOC-2/hDab2(DOC-2) is a candidate tumor suppressor gene that was first isolated by differential RNA display techniques (Liang and Pardee, 1992;Mok et al, 1994). In 1995, Albertsen and coworkers (Albertsen et al, 1996) reported the complete gene sequence of the 3.2-kb DOC-2 transcript and its localization at chromosome 5p13. It was shown that DOC-2 is the human homolog of mouse Dab2, which was cloned f...

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“…Indeed, CP patients have an overall 16-fold higher risk of developing PDAC compared to unaffected individuals (Rivera et al, 1997). Histologically, there are many features such as fibrosis, desmoplasia and immune cell infiltration that are observed in both PDAC and CP (Bai et al, 2011;Ino et al, 2013).…”

Section: Increased Nrf2 Activity In Pancreatic Carcinogenesismentioning

confidence: 99%

Keap1–Nrf2 signalling in pancreatic cancer

Hayes

Skouras

Haugk

et al. 2015

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tTranscription factor NF-E2 p45-related factor 2 (Nrf2, also called Nfe2l2), a master regulator of redox homeostasis, and its dominant negative regulator, Kelch-like ECH-associated protein 1 (Keap1), together tightly control the expression of numerous detoxifying and antioxidant genes. Nrf2 and the 'antioxidant response element' (ARE)-driven genes it controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Upregulation of Nrf2 is, at least in part, K-Ras oncogene-driven and contributes to pancreatic cancer proliferation and chemoresistance. In this review, we aim to provide an overview of Keap1-Nrf2 signalling as it relates to pancreatic cancer, discussing the effects of inhibiting Nrf2 or Nrf2/ARE effector proteins to increase chemosensitivity.

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Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia

Cited by 77 publications

References 23 publications

Sequential Accumulation of K-ras Mutations and p53 Overexpression in the Progression of Pancreatic Mucinous Cystic Neoplasms to Malignancy

Sequential Accumulation of K-ras Mutations and p53 Overexpression in the Progression of Pancreatic Mucinous Cystic Neoplasms to Malignancy

DOC-2/hDab2 Expression Is Up-Regulated in Primary Pancreatic Cancer but Reduced in Metastasis

Keap1–Nrf2 signalling in pancreatic cancer

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