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Ralph H Hruban

Publications and source records attributed to Ralph H Hruban.

At least 55 records · Page 3Linked to original sources
PubMed2005

Age- and disease-related methylation of multiple genes in nonneoplastic duodenum and in duodenal juice.

PURPOSE: Methylation of CpG islands contributes to gene silencing during cancer development, and although some methylation alterations are promising diagnostic markers of cancer, some CpG islands are also methylated in normal tissues. We have previously observed that some normally unmethylated CpG islands that undergo methylation in pancreatic cancers are normally methylated in the adjacent duodenum. Because duodenal methylation patterns are an important consideration when sampling pancreatic tissues for pancreatic cancer methylation alterations, we determined the DNA methylation patterns of 24 genes in the normal duodenum of patients with pancreatic disease and related these patterns to demographic factors. EXPERIMENTAL DESIGN: The nonneoplastic duodenal mucosa of 158 patients with pancreatic carcinoma and 41 patients with chronic pancreatitis was analyzed using methylation-specific PCR and combined bisulfite restriction analysis. Secretin-stimulated pancreatic/duodenal juice from 15 individuals undergoing endoscopic investigation for upper gastrointestinal disease was also analyzed. RESULTS: Low-level methylation was detectable by methylation-specific PCR in the nonneoplastic duodenum of many patients with pancreatic cancer and chronic pancreatitis as well as in the pancreaticoduodenal secretions of patients without pancreaticobiliary disease. For many genes, the prevalence of methylation increased with age and was more prevalent in patients with pancreatic cancer than in age-matched patients with chronic pancreatitis. Our results indicate that strategies to detect pancreatic cancer using aberrantly methylated genes should rely on analysis of pure pancreatic juice rather than on pancreatic juice collected within the duodenal lumen. Patients who develop pancreatic cancer may have a greater propensity to methylate CpG islands than age-matched controls.

Adult↗
PubMed2005

23Na MRI combined with contrast-enhanced 1H MRI provides in vivo characterization of infarct healing.

Although (23)Na MRI has been shown to delineate acute myocardial infarction (MI), the time course of in vivo (23)Na MRI during infarct healing remains unknown. In this study (23)Na MRI was combined with contrast-enhanced (CE) (1)H MRI to noninvasively characterize infarct healing in vivo. Serial in vivo 3D (23)Na MRI and (1)H MRI were performed for up to 9 weeks postinfarction in 10 dogs. Radioactive microspheres were used to measure myocardial perfusion, and Hematoxylin-Eosin (H&E) and Masson's trichrome (MT) staining were used to assess interstitial cell infiltrate and collagen content. In vivo (23)Na MRI accurately delineated infarct size up to day 5 postinfarction in comparison with (1)H MRI (8.9% +/- 8.1% vs. 8.6% +/- 7.9% on day 1 postinfarction, P = NS; and 6.3% +/- 6.2% vs. 6.2% +/- 6.2% on days 4/5 postinfarction, P = NS). The in vivo (23)Na MRI signal intensity, expressed as the signal intensity ratio of infarcted tissue vs. noninfarcted tissue (MI/R) peaked on day 1 of infarction (2.04 +/- 0.23) but decreased significantly to 1.27 at 9 weeks postinfarction (P < 0.05) due to granulation tissue infiltrate and collagen deposition. To confirm the MI/R decrease during scar formation ex vivo, we performed (23)Na MRI in 12 rats on day 3 post-MI (N = 5) and after 6 weeks (N = 7). H&E and Picrosirius Red staining confirmed granulation tissue infiltrate on day 3 and scar formation after 6 weeks. MI/R decreased significantly from 1.91 +/- 0.45 on day 3 post-MI to 1.3 +/- 0.09 after 6 weeks. Thus, in vivo (23)Na MRI accurately delineates infarct size up to day 5 postinfarction. In vivo (23)Na MRI signal intensity decreases during infarct healing as a result of the underlying infarct healing process.

Analysis of Variance↗
PubMed2005

Treatment of familial pancreatic cancer and its precursors.

Approximately 10% of pancreatic cancers are believed to have a familial basis. The familial aggregation of pancreatic cancers provides a unique opportunity to prevent the development of pancreatic cancer, to identify and treat precancerous lesions of the pancreas, and to advance our understanding of the genetic basis for the development of all forms of pancreatic cancer. After appropriate genetic counseling, individuals with a strong family history of pancreatic cancer can now be tested for inherited genetic alterations that are known to increase the risk of pancreatic cancer. These include germline BRCA2, STK11/LKB1, p16/CDKN2A and PRSS1 gene mutations. Individuals with one of these inherited genetic alterations and individuals with a strong family history of pancreatic cancer can be counseled on smoking cessation and possible dietary modifications. Selected individuals, even if they are asymptomatic, can be screened using a combination of endoscopic ultrasound and multidetector computed tomography. Patients found to have a mass lesion in the pancreas would then be candidates for surgical resection. The resection of noninvasive precancers will cure these lesions before they have the opportunity to spread and metastasize. Even with the best early detection efforts, some patients will still be diagnosed with an invasive cancer. Surgical resection of invasive pancreatic cancer is proven to be safe and can provide long-term survival in patients with small, node-negative, and margin-negative cancers. Chemotherapy and radiation therapy are effective in some patients with invasive pancreatic cancer, but these therapies do not usually result in long-term cures. Individuals with a family history of pancreatic cancer may also choose to join a research study such as the National Familial Pancreas Tumor Registry.

Journal Article↗
PubMed2005

Intestinal and oncocytic variants of pancreatic intraepithelial neoplasia. A morphological and immunohistochemical study.

We report 2 previously undescribed morphological variants of pancreatic intraepithelial neoplasia (PanIN). The first variant with an intestinal phenotype was associated with mucinous carcinomas that occurred in the tail of the pancreas of 2 men (60 and 65 years old). The carcinomas lacked the characteristic ovarian-like stroma of mucinous cystic neoplasms observed in female patients and did not show a papillary architecture. Whether they represent mucinous cystadenocarcinomas or mucinous carcinomas that arose from the flat variant of intraductal papillary mucinous neoplasms could not be determined with certainty. Microscopically, the intestinal type of PanIN was composed of pseudostratified columnar cells similar to those of colonic adenomas and showing variable degrees of dysplasia. A significant increase in the MIB-1 labeling index correlated with the severity of dysplasia. In contrast to conventional PanIN, the intestinal variant expressed MUC-2 and was MUC-1 negative. The second type of PanIN had an oncocytic phenotype, coexpressed MUC-2 and MUC-1 mucins, and was associated with intraductal oncocytic papillary carcinomas that showed a similar immunohistochemical mucin profile. Both intestinal and oncocytic types of PanIN expressed DPC4 and lacked p53 reactivity. The anatomical separation of the PanINs from the carcinomas and the gradual progression of cytological and architectural abnormalities in both variants of PanIN argue against ductal spread (cancerization of the ducts). The intestinal and oncocytic variants of PanIN broaden the morphological spectrum of this intraductal lesion. Although their significance is unknown, the possibility that these PanIN variants represent cancer precursors should be considered.

Adenocarcinoma, Mucinous↗
PubMed2005

Genome-wide aberrations in pancreatic adenocarcinoma.

Chromosomal instability, manifesting as copy number alterations (CNAs), is characteristic of pancreatic adenocarcinoma. We used bacterial artificial chromosome (BAC) array-based comparative genomic hybridization (aCGH) to examine the pancreatic adenocarcinoma genome for submicroscopic amplifications and deletions. Profiles of 33 samples (17 first-passage xenografts and 16 cell lines) identified numerous chromosomal regions with CNAs, including losses at 1p36.33 approximately p34.3, 1p13.3 approximately p13.2, 3p26, 3p25.2 approximately p22.3, 3p22.1 approximately p14.1, 4q28.3, 4q31, 4q35.1, 5q14.3, 6p, 6q, 8p23.3 approximately p12, 9p, 9q22.32 approximately q31.1, 13q33.2, 15q11.2, 16p13.3, 17p, 18q11.21 approximately q23 , 19p13.3 approximately p13.12, 19q13.2, 21p, 21q, and 22p, 22q and gains at 7p21.1 approximately p11.2, 7q31.32, 7q33, 8q11.1 approximately q24, 11p13, 14q22.2, 20p12.2, and 20q11.23 approximately q13.33. Novel regions containing CNAs were identified and refined by combining the increased resolution of our BAC CGH array with a statistical algorithm developed for assigning significance values to altered BACs across samples. A subset of array-based CNAs was validated using polymerase chain reaction-based techniques, immunohistochemistry and fluorescence in situ hybridization. BAC aCGH proved to be a powerful genome-wide strategy to identify molecular alterations in pancreatic cancer and to distinguish differences between cell line and xenograft aberration profiles. These findings should greatly facilitate further research in understanding the pathogenesis of this lethal disease, and could lead to the identification of novel therapeutic targets and biomarkers for early detection.

Adenocarcinoma↗
PubMed2005

Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.

To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease. The primary carcinomas and metastases demonstrate a high degree of genomic instability manifested by nonreciprocal translocations without obvious telomere erosion-hallmarks of human carcinomas not typically observed in mice. No mutations were discovered in other cardinal tumor suppressor gene pathways, which, together with previous results, suggests that there are distinct genetic pathways to PDA with different biological behaviors. These findings have clear implications for understanding mechanisms of disease pathogenesis, and for the development of detection and targeted treatment strategies.

Animals↗
PubMed2005

A new mouse model of pancreatic cancer: PTEN gets its Akt together.

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a negative regulator of the oncogenic PI3-K/Akt signaling pathway. Loss-of-function mutations of PTEN are seen in several human solid cancers. A murine model of conditional Pten inactivation in the pancreas is described that leads to acquisition of a profound metaplastic ductal phenotype accompanied by loss of differentiated acinar units. Evidence is presented for a centroacinar cell origin of the metaplastic "neoductules." These mice also develop invasive pancreatic adenocarcinomas at a low frequency, and provide a unique in vivo platform for exploring the role of PI3-K/Akt signaling in pancreatic neoplasia.

Animals↗
PubMed2005

Hypercalcemia and pancreatic endocrine neoplasia with elevated PTH-rP: report of two new cases and subject review.

Humoral hypercalcemia of malignancy is widely associated with tumor production of parathyroid hormone related protein (PTH-rP). This peptide functions in endocrine, autocrine and paracrine mechanisms in a manner similar to PTH; increasing renal uptake of calcium, decreasing retention of phosphorous, and stimulating adenylate cyclase and phospholipase C. Although PTH-rP production has been well documented in neoplasms of the exocrine pancreas, we present here two cases of endocrine pancreatic neoplasms elaborating PTH-rP. We then review the literature of previous cases and delve into the pathophysiology of this peptide.

Adult↗
PubMed2005

Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival.

The study objective was to update the survival analysis at the 5-year mark of patients undergoing standard versus radical (extended) pancreaticoduodenectomy (PD) for periampullary adenocarcinoma (cancers of the pancreas, ampulla, common bile duct, and duodenum). A prospective randomized trial was performed (April 1996 through June 2001) comparing survival after pylorus-preserving PD resection (standard) to survival after PD with distal gastrectomy and retroperitoneal lymphadenectomy (radical). An interim report (Ann Surg 1999;229:613) and report after closing the trial (Ann Surg 2002;236:355) showed no differences in survival between the standard and radical groups. Two hundred ninety-nine patients were randomized to either the standard or radical group. Five patients were excluded from final analysis because final pathology failed to reveal adenocarcinoma. The 5-year survival of the two groups was evaluated. The median live patient follow-up is now 64 months (5.33 years). For all periampullary cancer patients, those undergoing standard resection had 1- and 5-year survival rates of 78% and 25%, respectively, compared with 76% and 31% (P = 0.57) for those patients in the radical group. For pancreatic adenocarcinoma patients, the 1- and 5-year survival rates in the standard group were 75% and 13%, respectively, compared with 73% and 29% in the radical group (P = 0.13). The increased morbidity rate, longer operative time, and similar survival for radical PD led us to conclude that pylorus-preserving PD without retroperitoneal lymphadenectomy should be the procedure of choice for most patients with resectable periampullary adenocarcinoma. While there is an intriguing trend toward improved survival in patients with pancreatic adenocarcinoma in the radical group, this trend may be largely accounted for by the higher incidence of microscopically margin positive resections in the standard resection group (21%) compared with a 5% incidence in the radical group (P = 0.002).

Adenocarcinoma↗
PubMed2005

Pectus excavatum in a 112-year autopsy series: anatomic findings and the effect on survival.

BACKGROUND/PURPOSE: The purpose of this study was to determine the frequency of pectus excavatum and associated conditions in a large autopsy series. It also sought to determine whether there were different survival patterns for pectus excavatum patients than for patients without pectus excavatum. METHODS: A computer-assisted search of autopsy files maintained by Johns Hopkins University was conducted, dating from 1889 to 2001. Each patient's Autopsy Pathology Information System report was reviewed for diagnosis and comorbid conditions. To determine whether there were differences in survival patterns, we tested whether pectus excavatum patients survived longer than controls, using a standard epidemiological method. Each patient in the autopsy series was compared with the 2 patients entered in the autopsy database chronologically immediately before and the 2 patients immediately after the case. A Kaplan-Meier survival analysis was conducted. RESULTS: Pectus excavatum was identified at autopsy in 62 of 50,496 cases. Of these 62 patients, 17 were 65 years or older and appeared to have died of causes unrelated to pectus excavatum, the oldest being 91 years. Twenty-one were between the ages of 14 and 65 years and were found to have coexisting conditions or syndromes. Six were between the ages of 1 and 4 years. One of the 6 died in 1947 because of complications from pectus repair. No autopsied patient with pectus excavatum died between the ages of 5 and 14 years. Eighteen were infants younger than 1 year, and all 18 died because of conditions unrelated to pectus excavatum. There were no reported cases of pectus excavatum before 1947, and the severity of deformity could not be determined from the autopsy data. Survival analysis indicated that pectus excavatum patients had a different survival than the controls. Pectus excavatum patients tended to die earlier (P = .0001). However, pectus excavatum patients who survived past the age of 56 years tended to survive longer than their matched controls (P = .0001). CONCLUSION: Although there were no histological abnormalities noted in the cartilage of the pectus excavatum patient's conditions, pectus excavatum was associated with several connective tissue abnormalities. Analysis is consistent with the theory that this condition can impact survival.

Adolescent↗
PubMed2005

Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma.

The non-neoplastic pancreatic parenchyma adjacent to infiltrating ductal adenocarcinoma demonstrates inflammation, fibrosis, acinar cell loss and small duct-like metaplasia of acinar cells. Similar morphologic changes are also observed in the setting of chronic pancreatitis. In addition, peritumoral acini have been shown to have alterations in gene expression even in the absence of morphological changes. To better understand the pancreatic acinar responses to infiltrating pancreatic ductal adenocarcinoma, we characterized gene expression patterns of pancreatic acinar tissue adjacent to infiltrating pancreatic ductal adenocarcinomas and compared them to gene expression patterns of acinar tissue affected by chronic pancreatitis as well as to those of normal pancreatic acini. Fresh-frozen pancreatic acinar tissue was microdissected from nine patients (three with pancreatic cancer, three with chronic pancreatitis, three with normal pancreata) using laser capture microdissection, and extracted RNA from each microdissection was subjected to two rounds of linear amplification and hybridized to oligonucleotide microarrays. Gene expression patterns were confirmed using quantitative RT-PCR and/or immunohistochemistry. A total of 20 genes was found to be overexpressed in peritumoral acinar tissue compared to normal acinar tissue and to acini affected by chronic pancreatitis. These 20 genes included pancreatitis-associated protein (HIP/PAP), a gene known to be overexpressed in acini adjacent to infiltrating pancreatic cancer, and the gene cartilage glycoprotein-39 (HC gp-39 or TKL-40). Serum HC gp-39 protein levels were significantly higher in patients with pancreatic cancer and in those with chronic pancreatitis than in controls without pancreatic disease. There was no significant difference in the levels of serum HC gp-39 in patients with pancreatic cancer and those with chronic pancreatitis. Our results demonstrate some of the molecular alterations in acinar cells that occur in response to adjacent infiltrating pancreatic ductal adenocarcinoma and reveal that such alterations can provide a rich source of markers of pancreatic cancer.

Adipokines↗
PubMed2005

Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways.

Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood. In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms. We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors. Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (<5%). Expression of topoisomerase II alpha is not seen in solid pseudopapillary tumors and undifferentiated carcinomas with osteoclastic-like giant cells but is focally seen in pancreatoblastomas (50%) and acinar cell carcinomas (85%). Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%). CK19, a marker of pancreatic ductal adenocarcinomas, is not expressed in pancreatic nonductal neoplasms. Expression of gamma-synuclein as well as stromal markers (fascin, hsp47 and fibronectin) is frequently seen in both. Our findings indicate pancreatic nonductal neoplasms have distinctive patterns of protein expression relative to pancreatic ductal adenocarcinomas and suggest that pancreatic nonductal neoplasms have different genetic pathways from the more common pancreatic ductal adenocarcinomas.

14-3-3 Proteins↗
PubMed2005

Concordant loss of MTAP and p16/CDKN2A expression in pancreatic intraepithelial neoplasia: evidence of homozygous deletion in a noninvasive precursor lesion.

The p16INK4A/CDKN2A (p16) gene on chromosome 9p21 is inactivated in >90% of invasive pancreatic cancers. In 40% of pancreatic cancers the p16 gene is inactivated by homozygous deletion, in 40% by an intragenic mutation coupled with loss of the second allele, and in 10-15% by hypermethylation of the p16 gene promoter. Immunohistochemical labeling for the p16 gene product parallels gene status, but does not provide information of the mechanism of p16 gene inactivation. The methylthioadenosine phosphorylase gene (MTAP) gene also resides on chromosome 9p21, approximately 100 kb telomeric to the p16 gene. The MTAP gene is frequently contained within p16 homozygous deletions, producing concordant loss of both p16 and MTAP gene expression. Concordant loss of both p16 and MTAP protein expression can therefore be used as a surrogate marker for p16 homozygous deletion. Here we immunolabeled a series of pancreatic intraepithelial neoplasia (PanIN) lesions of various histologic grades for the p16 and MTAP gene products using a high-throughput PanIN tissue microarray (TMA) format. We demonstrate concordant loss of p16 and MTAP protein expression in 6/73 (8%) PanINs, including five high-grade lesions and one low-grade lesion. Immunolabeling for both p16 and MTAP protein expression provides a tool to evaluate tissues with intact morphology for p16 gene homozygous deletions. The concordant loss of expression of both genes in PanIN lesions demonstrates that homozygous deletions of the p16 tumor suppressor gene can occur in noninvasive precursor lesions.

Cyclin-Dependent Kinase Inhibitor p16↗
PubMed2005

Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: interobserver agreement.

OBJECTIVES: The goal of this study was to evaluate the consistency of distinction between pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary-mucinous neoplasms (IPMN) and the hypothesis that guidelines for their distinction might be inadequate. METHODS: A group of 93 pancreas specimens from surgical resections or autopsies that contained lesions consistent with histopathological diagnoses of PanIN-1A, PanIN-1B, PanIN-2, or IPMN (adenoma or borderline) was collected. The classification of these neoplasms by 6 pathologists, 2 from Europe, 2 from Japan, and 2 from the United States, was compared. The pathologists initially used guidelines current in their practice and then reviewed 47 of the 93 specimens a second time using new consensus definitions and guidelines for PanIN and IPMN that were developed in 2003. RESULTS: The initial comparison showed frequent disagreement regarding both category and grade of the lesions. Agreement was greater for category than grade. In the second review, agreement among the 6 reviewers improved, remaining higher for category, although disagreements persisted for both category and grade. CONCLUSIONS: We conclude that the new definitions of PanIN and IPMN improve the consistency in classifying these lesions, but additional work is needed to further improve the reproducibility of their classification.

Adenocarcinoma, Mucinous↗
PubMed2005

Precursors to invasive pancreatic cancer.

Pancreatic cancer, once invasive, is almost uniformly fatal. In order to alleviate the dismal prognosis associated with this disease, it is imperative that pancreatic cancer be recognized and treated prior to invasion. Understanding the morphology and biology of precursor lesions of invasive pancreatic cancer has therefore become an issue of paramount importance. In the last decade, significant progress has been in the recognition and appropriate classification of these precursor lesions, and the current review will focus on our state-of-the-art knowledge on this topic. Mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic intraepithelial neoplasia (PanIN) encompass the three known morphologically distinct precursors to invasive pancreatic cancer. In addition to discussion of the "classic" precursor entities, this review will also address some of the recent diagnostic controversies for these lesions, in particular features that distinguish IPMNs from PanIN lesions. Finally, the potential clinical impact of recognizing these precursor lesions in the context of early detection of pancreatic cancer will be discussed.

Adenocarcinoma, Mucinous↗
PubMed2005

Identification and analysis of precursors to invasive pancreatic cancer.

Histologically distinct noninvasive precursor lesions have been recognized in the pancreas for close to a century. The recent development of a consistent reproducible nomenclature and classification system for these lesions has been a major advance in the study of these noninvasive precursors. The "pancreatic intraepithelial neoplasia" or PanIN system was developed at a National Cancer Institutes sponsored think tank in Park City, Utah. Numerous studies have now demonstrated that genetic alterations in cancer-associated genes are more common in higher grade PanIN lesions then they are in lower grade PanIN lesions, and that higher grade PanIN lesions have many of the same genetic alterations that are found in invasive ductal adenocarcinomas of the pancreas. Thus, just as there is a progression in the colorectal of adenomas to invasive adenocarcinoma, so too is there a progression in the pancreas of histologically low-grade PanIN, to high-grade PanIN to invasive ductal adenocarcinoma.

Epithelial Cells↗
PubMed2004

MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course.

MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis.

Adenocarcinoma↗
PubMed2004

Differentially expressed genes in pancreatic ductal adenocarcinomas identified through serial analysis of gene expression.

Serial analysis of gene expression (SAGE) is a powerful tool for the discovery of novel tumor markers. The publicly available online SAGE libraries of normal and neoplastic tissues (http://www.ncbi.nlm.nih.gov/SAGE/) have recently been expanded; in addition, a more complete annotation of the human genome and better biocomputational techniques have substantially improved the assignment of differentially expressed SAGE "tags" to human genes. These improvements have provided us with an opportunity to re-evaluate global gene expression in pancreatic cancer using existing SAGE libraries. SAGE libraries generated from six pancreatic cancers were compared to SAGE libraries generated from 11 non-neoplastic tissues. Compared to normal tissue libraries, we identified 453 SAGE tags as differentially expressed in pancreatic cancer, including 395 that mapped to known genes and 58 "uncharacterized" tags. Of the 395 SAGE tags assigned to known genes, 223 were overexpressed in pancreatic cancer, and 172 were underexpressed. In order to map the 58 uncharacterized differentially expressed SAGE tags to genes, we used a newly developed resource called TAGmapper (http://tagmapper.ibioinformatics.org), to identify 16 additional differentially expressed genes. The differential expression of seven genes, involved in multiple cellular processes such as signal transduction (MIC-1), differentiation (DMBT1 and Neugrin), immune response (CD74), inflammation (CXCL2), cell cycle (CEB1) and enzymatic activity (Kallikrein 6), was confirmed by either immunohistochemical labeling of tissue microarrays (Kallikrein 6, CD74 and DMBT1) or by RT-PCR (CEB1, Neugrin, MIC1 and CXCL2). Of note, Neugrin was one of the genes whose previously uncharacterized SAGE tag was correctly assigned using TAGmapper, validating the utility of this program. Novel differentially expressed genes in a cancer type can be identified by revisiting updated and expanded SAGE databases. TAGmapper should prove to be a powerful tool for the discovery of novel tumor markers through assignment of uncharacterized SAGE tags.

Adenocarcinoma↗