Chromosome abnormalities in pancreatic adenocarcinoma

Adenocarcinoma of the pancreas is the fifth most common cause of cancer deaths in the United States, yet few cytogenetic studies of this tumor have been reported. We analyzed 26 primary tumors to identify which chromosome abnormalities occur most frequently in this neoplasm. One carcinoma was well differentiated and mucin producing, 18 were moderately well differentiated, and seven were poorly differentiated. Only normal karyotypes were obtained from nine carcinomas. The remaining 17 carcinomas frequently had normal metaphase cells in addition to simple to highly complex karyotypes. The modal chromosome number in 20 carcinomas was diploid or near-diploid; four carcinomas had both a major near-diploid and near-triploid or near-tetraploid component, and two were near-tetraploid. Numerical abnormalities included loss of whole copies of chromosomes 6, 17, and 18, and gains of chromosome 20. Structural abnormalities were frequent, with 1p, 2p, 3p, 4q, 6q, 7q, 1 1q, and 17p recurrently involved. Results of this study were combined with karyotypes of 19 other primary adenocarcinomas of the pancreas reported in the literature. The combined data involving 1 17 breakpoints suggest that careful analysis of chromosome 20, proximal 1 q. 6q, proximal 8p. and proximal 17p could be productive in defining genes involved in adenocarcinoma of the pancreas. Genes Chrom Cancer 9:93-100 (1994).© 1994 Wiley-Liss, Inc.     

Early pancreatic duct adenocarcinoma

A 68-year-old Japanese woman presented with complaints of appetite and weight loss. Early pancreatic duct adenocarcinoma was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP), which revealed partial obstruction of the main pancreatic duct. Pancreatoduodenectomy with lymph node dissection was performed. Macroscopically, no pancreatic tumor was detected. Histologically, the pancreatic lesion showed continuous changes consisting of duct epithelial cell hyperplasia, carcinoma in situ, and invasive carcinoma. Immunohistochemical stains for carcinoembryonic antigen and CA19-9 were positive in cancer cells.     

Chromosome abnormalities in a pancreatic adenocarcinoma

Short-term cultures initiated from a pancreatic adenocarcinoma were cytogenetically investigated. The composite karyotype was 74-76,XX,+X,+2,+3,+del(3)(p21),+5,+5,+der(7) t(1;7)(q21;p22),+der(7),del(8)(p21),+del(8)(p21),+der(8)t(8;?)(q24; +),+9,+9,+10,+10,+11,+11,+12,+13,+14,+der(14)t(14; +)(p11;?),+der(16)t(15;16)(q11;p13),+der(16),+der(17)t(17;?) (p11;?),+der(17),+18,+20,+20,-21,-21,+22,+22,+1-3mar. A comparison with the few previously cytogenetically characterized cases of this tumor type reveals no consistent abnormalities.     

胰腺导管腺癌中胰腺星形细胞的研究进展

胰腺星形细胞(pancreatic stellate cells,PSC)是胰腺导管腺癌(pancreatic ductal adenocarcinoma,PDAC)肿瘤微环境中最重要的成分,在PDAC发生发展中具有非常关键的作用.目前大量研究关注于PSC与胰腺癌细胞(pancreatic cancer cells,PCC)之间的相互作用及PSC在PDAC微环境中发挥的作用.PSC在许多情况下发生活化,如乙醇、氧化应激和高血糖等.PDAC早期即可出现PSC的活化,PCC可以诱导刺激PSC发生活化,活化的PSC可以产生大量胶原纤维,形成适宜PCC生长的间质微环境,促进PCC的增殖,减少化疗药物对肿瘤细胞的杀伤作用.另外,PSC还可以与间质中各种细胞成分如内皮细胞和各种免疫细胞相互作用,在血管生成、免疫逃逸和神经侵犯等方面协助肿瘤进展.因此,阐明PSC与肿瘤细胞以及其他间质成分之间复杂的相互作用至关重要.     

Genome-wide analysis of histone modifications in human pancreatic islets

The global diabetes epidemic poses a major challenge. Epigenetic events contribute to the etiology of diabetes; however, the lack of epigenomic analysis has limited the elucidation of the mechanistic basis for this link. To determine the epigenetic architecture of human pancreatic islets we mapped the genome-wide locations of four histone marks: three associated with gene activation—H3K4me1, H3K4me2, and H3K4me3—and one associated with gene repression, H3K27me3. Interestingly, the promoters of the highly transcribed insulin and glucagon genes are occupied only sparsely by H3K4me2 and H3K4me3. Globally, we identified important relationships between promoter structure, histone modification, and gene expression. We demonstrated co-occurrences of histone modifications including bivalent marks in mature islets. Furthermore, we found a set of promoters that is differentially modified between islets and other cell types. We also use our histone marks to determine which of the known diabetes-associated single-nucleotide polymorphisms are likely to be part of regulatory elements. Our global map of histone marks will serve as an important resource for understanding the epigenetic basis of type 2 diabetes.Genetic and epigenetic factors determine cell fate and function. Recent breakthroughs in genotyping technology have led to the identification of more than 20 loci associated with the risk of type 2 diabetes (Sambuy 2007; Zhao et al. 2009). However, all together these loci explain <5% of the genetic risk for diabetes. Epigenetic events have been implicated as contributing factors for metabolic diseases (Barker 1988; Kaput et al. 2007). Unhealthy diet and a sedentary lifestyle likely lead to epigenetic changes that can, in turn, contribute to the onset of diabetes (Kaput et al. 2007). At present, the underlying molecular mechanisms for disease progression remain to be elucidated.Epigenetic modifications encompass both DNA methylation and histone modifications (Cedar and Bergman 2009). In recent years, genome-wide maps of epigenetic marks have been generated for yeast (Pokholok et al. 2005) and several cell types in mice and humans (Bernstein et al. 2005; Roh et al. 2006; Barski et al. 2007; Mikkelsen et al. 2007; Pan et al. 2007; Zhao et al. 2007). However, no genome-wide map of histone modifications has been reported for the human pancreatic islet, a key player in the etiology of diabetes. In the present study, we have used chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) technology to create a genome-wide map of four histone modifications associated with gene activation or repression in human pancreatic islets.     

Genome profiling of pancreatic adenocarcinoma

Pancreatic adenocarcinoma is one of the most aggressive human cancers. It displays many different chromosomal abnormalities and mutations. By using 244 K high-resolution array-comparative genomic hybridization (aCGH) we studied the genome alterations of 39 fine-needle aspirations from pancreatic adenocarcinoma and eight human adenocarcinoma pancreatic cell lines. Using both visual inspection and GISTIC analysis, recurrent losses were observed on 1p, 3p, 4p, 6, 8p, 9, 10, 11q, 15q, 17, 18, 19p, 20p, 21, and 22 and comprised several known or suspected tumor suppressor genes such as ARHGEF10, ARID1A, CDKN2A/B, FHIT, PTEN, RB1, RUNX1-3, SMAD4, STK11/LKB1, TP53, and TUSC3. Heterozygous deletion of the 1p35-p36 chromosomal region was identified in one-third of the tumors and three of the cell lines. This region, commonly deleted in human cancers, contains several tumor suppressor genes including ARID1A and RUNX3. We identified frequent genetic gains on chromosome arms 1q, 3q, 5p, 6p, 7q, 8q, 12q, 15q, 18q, 19q, and 20q. Amplifications were observed in 16 tumors. AKT2, CCND3, CDK4, FOXA2, GATA6, MDM2, MYC, and SMURF1 genes were gained or amplified. The most obvious amplification was located at 18q11.2 and targeted the GATA6 gene, which plays a predominant role in the initial specification of the pancreas and in pancreatic cell type differentiation. In conclusion, we have identified novel biomarkers and potential therapeutic targets in pancreatic adenocarcinoma.     

胰腺癌的基因诊断

用ＰＣＲ－ＲＦＬＰ技术对２７例胰腺及其周围器官组织细针穿刺标本进行ｃ－Ｋｉ－ｒａｓ第１２密码子突变检测。结果１５例胰腺癌中１４例有ｃ－Ｋｉ－ｒａｓ第１２密码子突变。阳性率达９３．３％；而１１例慢性胰腺炎、胰腺囊肿、胆管炎、胆囊癌、壶腹癌及胃淋巴瘤均无ｃ－Ｋｉ－ｒａｓ第１２密码子突变。本研究结果证实ＰＣＲ－ＲＦＬＰ检测胰腺ｃ－Ｋｉ－ｒａｓ第１２密码子突变是诊断胰腺癌的一种快速、准确、敏感、实用的基因诊断方法。     

Pancreatic adenocarcinoma arising in intrahepatic pancreatic heterotopia

Pancreatic heterotopia, also known as ectopic pancreas, accessory pancreas, or pancreatic rest, is defined as pancreatic tissue occurring in anatomic locations lacking geographic and vascular connections with the eutopic pancreas. Any physiologic process that occurs in normal pancreatic tissue may occur in pancreatic heterotopia, including, although rarely, malignant transformation. For this reason, any significant change in a lesion with imaging should prompt further investigation including obtaining tissue for pathologic evaluation. Histomorphologic criteria are essential in diagnosing malignancy arising in pancreatic heterotopia and include location of the tumour within or near the ectopic pancreatic tissue; the heterotopia must consist of acinar, epithelial and ductal elements; and there must be a clear transition from heterotopic to malignant tissue, preferably, an in-situ component.     

Expression of urocortin in pancreatic ductal adenocarcinoma and pancreatic intraepithelial neoplasia

Urocortin (UCN) is a 40‐aminoacid neuropeptide that regulates angiogenesis and inhibits cell proliferation. Our aim was to examine the relationship of UCN expression to the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC) and histological grade of pancreatic intraepithelial neoplasia (PanIN). Tissue microarray was used to analyze UCN protein expression in 89 surgical specimens including 21 PanIN, 3 PDAC arising from PanIN, and 65 PDAC without PanIN. UCN immunoscores ranging from 0 to 12 were obtained by multiplying intensity (scored on a 3‐point scale) by the percentage of stained cells (scored on a 4‐point scale). Strong expression of UCN was detected in 5 specimens of non‐neoplastic pancreatic ductal epithelia. UCN immunoscore was significantly higher in PanIN‐1 than in PanIN‐2 and PanIN‐3 (p = 0.038) and significantly higher in well‐differentiated PDAC or early American Joint Committee on Cancer (AJCC) stage PDAC than in poorly differentiated or advanced stage PDAC (p = 0.025, p = 0.018). Higher expression of UCN correlates with PDAC tumor grade and AJCC pathologic stage as well as PanIN grade. Immunohistochemical assessment of UCN may help clinicians predict tumor recurrence rate and help pathologists make a proper diagnosis.     

Molecular pathogenesis of pancreatic ductal adenocarcinoma

The statistics are alarming; pancreatic ductal adenocarcinoma (PDA) will be the second leading cause of death amongst all cancers by 2020. More worrisome is that incidence is on the rise, and without more effective cancer control of this disease, the trajectory of the virtually indistinguishable rates of incidence and mortality will remain the reality for years to come. Advances in genomics are beginning to clarify the key issues about the pathogenesis of this aggressive tumour type. New insights into classic pathogenic driver genes, such as KRAS, CDKN2A, TP53 and SMAD4, are portraying alternative roles for these genes beyond their function at the preneoplastic level including metastatic dissemination and chemoresistance. Clinically relevant molecular subtypes have recently emerged, which will aid oncologists in making more informed treatment decisions to improve outcomes in the future. A wealth of data surrounding these issues has been generated over the last 5 years. Below, we attempt to bring readers up to speed on recent research findings in PDA.     

固相配体文库技术分析胰腺癌差异血清蛋白表达谱的研究

 目的：通过胰腺癌患者血清差异蛋白表达谱鉴定胰腺癌的血清学生物标志物。 方法：应用固相配体文库技术处理胰腺癌及非癌对照的血清,然后采用二维电泳技术分析差异点、串联质谱鉴定与胰腺癌变相关的血清差异蛋白质分子;应用ELISA检测凝集素在胰腺癌血清中的表达情况。 结果: 7种蛋白质分子在胰腺癌患者血清中的表达量升高,包括凝集素（clusterin）, 玻连蛋白（vitronectin）,补体C4-A( complement C4-A), 维生素蛋白D结合蛋白（vitamin D-binding protein）,抗凝血酶III（ anitthrombin-III）, 补体C6（complement component C6）, 凝血酶原（prothrombin）;补体C7（complement component C7）血清表达量下降。ELISA检测结果表明胰腺癌患者血清凝集素水平显著高于非癌对照（P<0.05）。 结论: 凝集素可能与胰腺癌的发生发展过程密切相关,血清凝集素检测可能是重要的胰腺癌诊断生物标志物。     

Molecular genetic basis of pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma is a complex genetic disease. As might be expected for a malignancy that is rather homogeneous in clinical presentation and behavior, a distinct subset of genes are found to be genetically inactivated in a majority of the tumors. A yet larger subset of genes experiences genetic inactivation at much lower frequencies. The latter subset could solely reflect a somewhat trivial genetic heterogeneity of the tumor, but more likely will represent the initial insights into pathways whose more widespread importance will be shown in future work. Familial pancreatic cancer susceptibility underlies a significant fraction of the overall incidence. Genetic testing is feasible for many of the causative genes, although the clinical utility remains unsettled. The precursor lesion for pancreatic cancer shares some of the genetic lesions of the more advanced invasive stage, and follows a stepwise progression model both histologically and genetically. Genes Chromosomes Cancer 26:1–12, 1999. © 1999 Wiley‐Liss, Inc.     

Pancreaticoduodenectomy of pancreatic ductal adenocarcinoma in the elderly

PURPOSE: Pancreatic ductal adenocarcinoma has the highest incidence between the ages of 60 and 70 years. As the elderly population has been increasing in the last several decades, the proportion of patients older than 70 years of age with resectable pancreatic cancer is expected to increase in our society. This retrospective observation was performed to evaluate surgical value of pancreaticoduodenectomy for the elderly patients with pancreatic ductal adenocarcinoma. MATERIALS AND METHODS: From January 1990 to June 2005, among the patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, the elder patients older than 70 years of age were retrospectively reviewed. Perioperative surgical outcomes, including general clinicopathologic features, morbidity, mortality, and survival outcomes, were investigated based on available medical records. RESULTS: Seventy-seven patients underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma. Among them, 11 patients (14.3%) were 70 years older. More frequent incidences of morbidity (8 out of 11 vs. 25 out of 65, p=0.049), especially delayed gastric emptying (3 out of 8 vs. 3 out of 66, p=0.035), were observed and overall length of hospital stay was also longer in the elderly (49.2 +/- 13.9 days vs. 36.1 +/- 13.2, p=0.012). However, no significant differences in mortality rate and survival outcomes were noted when comparing with those of the younger patients (p > 0.05). CONCLUSION: We agree with the opinion that age factor can not be absolute contraindication for pancreaticoduodenectomy, however, appropriate preoperative evaluations, proper patient selection considering life expectancy, advanced surgical techniques and detailed perioperative management are mandatory to guarantee the safety of pancreaticoduodenectomy performed in the elderly with pancreatic ductal adenocarcinoma.     

Mast cells and angiogenesis in pancreatic ductal adenocarcinoma

Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression.     

Circulating IL-35 in pancreatic ductal adenocarcinoma patients

IL-35 is a novel inhibitory cytokine that is mainly produced by regulatory T-cells (Tregs) and is required for Treg-mediated immunosuppression. However, the plasma levels of IL-35 in patients with pancreatic ductal adenocarcinoma (PDAC) have never been investigated. In this study, we found that plasma IL-35 levels more significantly increased in PDAC patients than in normal controls (134.53 ± 92.45 pg/mL vs. 14.26 ± 6.56 pg/mL). IL-35 mRNA levels were positively correlated with plasma IL-35 levels (EBI3, R = 0.925, p < 0.01; p35, R = 0.916, p < 0.01). Furthermore, IL-35 expression levels were associated with lymph node metastasis (p = 0.001) and late tumor stage (p = 0.002). For the resected patients, high IL-35 expression levels were associated with large tumor size (p < 0.01), higher TNM classification T staging (p < 0.05), and late tumor stage (p < 0.05). In conclusion, circulating IL-35 in PDAC patients significantly increased, suggesting that regulating the expression of IL-35 may provide a new possible target for the treatment of PDAC patients, especially for the resectable ones.     

Minute pancreatic adenocarcinoma presenting with stenosis of the main pancreatic duct

We describe a case of minute pancreatic ductal adenocarcinoma featuring stenosis of the main pancreatic duct (MPD) and associated with histological findings of periductal elastosis and fibroblast proliferation. A 53-year-old Japanese man with preoperative radiological evidence of MPD stricture and dilation of the distal MPD, and suspected of having pancreatic cancer, underwent successful resection. Neither radiological nor macroscopic examination directly disclosed any tumorous lesions, and a small focus of carcinoma (8 x 8 mm) was only revealed on microscopic examination. The tumor was a poorly differentiated, invasive ductal adenocarcinoma that had invaded the intrapancreatic nerves and veins. Interestingly, the MPD located at the edges of the tumor had not been destroyed by the carcinoma, but its wall had been thickened by elastic tissue and fibroblast proliferation, resulting in stenosis. The peripheral pancreas exhibited secondary obstructive pancreatitis. To date, the detection of small pancreatic tumor masses using imaging procedures remains difficult, and most patients are diagnosed on the basis of pancreatic ductal changes. However, the published work on small pancreatic cancers contains little information about the histological features of the affected MPD. The present findings suggest that MPD strictures are not always provoked by destruction or filling with cancer cells, and that they can be caused by periductal elastosis and fibroblast proliferation in a minute carcinoma. Such changes in the MPD may therefore be of clinical importance in the detection of early stage cancers.     

胰腺癌中主要的基因改变

胰腺导管腺癌是胰腺癌中最常见的组织学类型,其发病隐匿,预后差,死亡率高,治疗手段有限。目前对其致病机制的研究很多,遗传因素和环境因素所造成的分子遗传学改变在其中凸显重要,越来越多的发现都深入到了基因分子水平。对于这些已发现的基因改变,有些已通过体内体外实验予以验证,有些仍未明确,现对其中4个主要通路的特征性分子改变以及相关途径的认识做一简要概括,进一步明确这些基因改变在胰腺癌发病过程中的作用及其研究的现状。     

The cytology of pancreatic foamy gland adenocarcinoma

All cell block specimens from pancreatic fine-needle aspirations (FNAs) obtained between January 1, 2002, and June 30, 2003, were reviewed for foamy gland adenocarcinoma (FGA). All smears from these cases were reviewed for cytologic features, including those previously noted in conventional pancreatic adenocarcinoma. Fifty-two cell block specimens showed adenocarcinoma. Of these, 12 (23%) showed histologic features of FGA. This pattern predominated in 6 cases and was present focally in 6 cases. Although there were relatively low nuclear/cytoplasmic (N/C) ratios, other features of adenocarcinoma were present universally, including loss of cohesiveness, nuclear overlap or loss of "honeycomb" architecture, anisonucleosis (> 4 to 1), irregular nuclear contours, prominent nucleoli, and atypical chromatin. Background necrosis was present in 8 cases. Distinct cell borders were present in 9 cases, and foamy cytoplasm was present in all cases. Pancreatic FGA is a recently described histologic pattern of pancreatic adenocarcinoma. It is not uncommon, and we identified the pattern, at least focally, in 23% of our FNA cell blocks. Although cytologic samples show low N/C ratios, most cytologic features of conventional pancreatic adenocarcinoma are present, and the diagnosis presents little additional difficulty.     

Genetics and biology of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment.     

Association of pancreatic adenocarcinoma up-regulated factor expression in ovarian mucinous adenocarcinoma with poor prognosis

Pancreatic adenocarcinoma up-regulated factor (PAUF) expression is elevated in both ovarian tumors and pancreatic adenocarcinoma. However, PAUF expression in ovarian tumors according to histologic subtype and grade has not been investigated. In this study, we examined various clinicopathologic features of 24 patients with mucinous cystadenoma (MCA), 36 with mucinous borderline tumors (MBTs), and 46 with mucinous adenocarcinomas (MACs) according to PAUF expression status assessed using immunohistochemistry. We found that MACs more frequently stained positive for PAUF than did MCAs and MBTs (P < 0.0001). Although there was no significant differences with respect to other clinicopathologic characteristics of MACs according to PAUF expression status, patients with PAUF-weakly positive and PAUF-strongly positive MACs tended to have a shorter overall survival (OS) than those with PAUF-negative MAC, determined using a Kaplan–Meier analysis (P = 0.1885). After adjusting for various clinicopathologic parameters, PAUF positivity of MACs was a significant predictive factor for disease-free survival (DFS) (negative vs. weakly positive: P = 0.045, hazard ratio [HR] = 57.406, 95% confidence interval [CI]: 1.090-3022.596; and negative vs. strongly positive: P = 0.034, HR = 97.890, 95% CI: 1.412-6785.925). In conclusion, PAUF was more frequently expressed in MAC than in its benign and borderline counterparts, and was associated with a poor OS and DFS in MAC patients. Therefore, we suggest that PAUF may be a practical biomarker for histopathological categorization and a prognostic marker for patients with an ovarian mucinous tumor.