Seasonal variation of vitamin D in patients on hemodialysis.

Background: Seasonal and racial differences in serum 25-hydroxyvitamin D levels have been studied extensively in the general population but not in patients with end-stage renal disease (ESRD).

Methods: Serum 25-hydroxyvitamin D levels, the best available index of vitamin D nutrition, was measured at the end of summer (September) in 142 chronic hemodialysis patients and again at the end of winter (April) in 73 of these 142 patients, to determine the prevalence and risk factors for vitamin D deficiency.

Results: The prevalence of vitamin D depletion, as defined by serum 25-hydroxyvitamin D level of less than 20 ng/ml (50 nmol/l), was 54% at the end of summer and further increased to 86% by the end of winter (p < 0.

Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels.

Aberrant DNA methylation and microRNA expression play important roles in the pathogenesis of pancreatic cancer. While interrogating differentially methylated CpG islands in pancreatic cancer, we identified two members of miR-200 family, miR-200a and miR-200b, that were hypomethylated and overexpressed in pancreatic cancer. We also identified prevalent hypermethylation and silencing of one of their downstream targets, SIP1 (ZFHX1B, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition.

Cyclooxygenase-deficient pancreatic cancer cells use exogenous sources of prostaglandins.

Genes that are differentially expressed in pancreatic cancers and under epigenetic regulation are of considerable biological and therapeutic interest. We used global gene expression profiling and epigenetic treatment of pancreatic cell lines including pancreatic cancer cell lines, pancreatic cancer-associated fibroblasts, and cell lines derived from nonneoplastic pancreata. We examined expression and epigenetic alterations of cyclooxygenase-1 (COX-1) and COX-2 in pancreatic cancers and normal pancreas and performed proliferation, knockdown, and coculture experiments to understand the role of stromal sources of prostaglandins for pancreatic cancers.

Inhibiting the cyclin-dependent kinase CDK5 blocks pancreatic cancer formation and progression through the suppression of Ras-Ral signaling.

Cyclin-dependent kinase 5 (CDK5), a neuronal kinase that functions in migration, has been found to be activated in some human cancers in which it has been implicated in promoting metastasis. In this study, we investigated the role of CDK5 in pancreatic cancers in which metastatic disease is most common at diagnosis. CDK5 was widely active in pancreatic cancer cells.

Aberrant MicroRNA-155 expression is an early event in the multistep progression of pancreatic adenocarcinoma.

Background/aims: Pancreatic intraepithelial neoplasia (PanIN) is the most common noninvasive precursor to invasive pancreatic adenocarcinoma. Misexpression of microRNAs (miRNAs) is commonly encountered in invasive neoplasia; however, miRNA abnormalities in PanIN lesions have not been documented.

Methods: Three candidate miRNAs (miR-21, miR-155, and miR-221) previously reported as overexpressed in pancreatic cancers were assessed in 31 microdissected PanINs (14 PanIN-1, 9 PanIN-2, 8 PanIN-3) using quantitative reverse transcription PCR (qRT-PCR).

Pancreatic cancer DNMT1 expression and sensitivity to DNMT1 inhibitors.

DNA methyltransferase I (DNMT1) is the major methyltransferase responsible for methylating DNA and is overexpressed in many cancers. DNMT1 is also a therapeutic target for chemotherapy and chemoprevention. We hypothesized that loss of DNMT1 copy number could result in reduced DNMT1 levels and greater sensitivity to DNMT1 inhibitors.

In vivo and in vitro propagation of intraductal papillary mucinous neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) are one of the three known curable precursor lesions of invasive pancreatic ductal adenocarcinoma, an almost uniformly fatal disease. Cell lines from IPMNs and their invasive counterparts should be valuable to identify gene mutations critical to IPMN carcinogenesis, and permit high-throughput screening to identify drugs that cause regression of these lesions. To advance the study of the biological features of IPMNs, we attempted in vivo and in vitro growth of selected IPMNs based on the hypothesis that IPMNs could be grown in the most severely immunodeficient mice.

Overexpression of smoothened activates the sonic hedgehog signaling pathway in pancreatic cancer-associated fibroblasts.

Purpose: Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAF) contribute to tumor growth by actively communicating with cancer cells. Our aim is to identify signaling pathways involved in tumor-stromal cell interactions in human pancreatic cancer.

Experimental Design: We established primary fibroblast cultures from human pancreatic adenocarcinomas and nonneoplastic pancreas tissues.

Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma.

Background: Specific populations of highly tumorigenic cells are thought to exist in many human tumors, including pancreatic adenocarcinoma. However, the clinical significance of these tumor-initiating (ie, cancer stem) cells remains unclear. Aldehyde dehydrogenase (ALDH) activity can identify tumor-initiating cells and normal stem cells from several human tissues.

A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33.

We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.

Importance of age of onset in pancreatic cancer kindreds.

Background: Young-onset cancer is a hallmark of many familial cancer syndromes, yet the implications of young-onset disease in predicting risk of pancreatic cancer among familial pancreatic cancer (FPC) kindred members remain unclear.

Methods: To understand the relationship between age at onset of pancreatic cancer and risk of pancreatic cancer in kindred members, we compared the observed incidence of pancreatic cancer in 9040 individuals from 1718 kindreds enrolled in the National Familial Pancreas Tumor Registry with that observed in the general US population (Surveillance, Epidemiology, and End Results). Standardized incidence ratios (SIRs) were calculated for data stratified by familial vs sporadic cancer kindred membership, number of affected relatives, youngest age of onset among relatives, and smoking status.

Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients.

PURPOSE: Histologic findings in 51 pancreata resected from patients with a strong family history of pancreatic cancer were compared with the findings in 40 pancreata resected from patients with sporadic pancreatic cancer. None of the patients in the familial group had a known inherited syndrome other than familial pancreatic cancer. EXPERIMENTAL DESIGN: Precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and incipient IPMN, were quantified.

Elevated cancer mortality in the relatives of patients with pancreatic cancer.

Most inherited cancer syndromes are characterized by the familial clustering of cancers at several organ sites. To determine if cancers, other than pancreatic cancer, cluster in pancreatic cancer kindreds, we examined mortality patterns among the relatives of National Familial Pancreatic Tumor Registry probands. Over 200,000 person-years of follow-up from 8,564 first-degree relatives of probands and 1,007 spouse controls were included in these analyses.

Ultrasensitive detection of KRAS2 mutations in bile and serum from patients with biliary tract carcinoma using LigAmp technology.

Patients with biliary tract carcinoma have a poor prognosis. Early detection efforts are urgently needed to ameliorate the dismal prognosis for these patients. Mutations of the KRAS2 gene are one of the most common genetic aberrations in this cancer.

Serum fatty acid synthase as a marker of pancreatic neoplasia.

Markers of early pancreatic cancer and its precursors are needed to improve the uniformly poor prognosis of this disease. Fatty acid synthase (FAS) catalyzes the synthesis of long-chain fatty acids and is overexpressed in most human solid tumors. We therefore evaluated serum FAS as a marker of pancreatic adenocarcinoma.

Widespread activation of the DNA damage response in human pancreatic intraepithelial neoplasia.

Pancreatic intraepithelial neoplasia (PanIN) lesions are the most common non-invasive precursors of pancreatic adenocarcinoma. We postulated that accumulating DNA damage within the PanIN epithelium activates checkpoint mechanisms. Tissue microarrays were constructed from 81 surgically resected primary pancreatic adenocarcinomas and an independent set of 58 PanIN lesions (31 PanIN-1, 14 PanIN-2, and 13 PanIN-3).

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components.

Depth of tumor invasion better predicts prognosis than the current American Joint Committee on Cancer T classification for distal bile duct carcinoma.

Background: The American Joint Committee on Cancer (AJCC) T classification system for cholangiocarcinoma does not take into account the unique pathologic features of the bile duct. As such, the current AJCC T classification for distal cholangiocarcinoma may be inaccurate.

Methods: A total of 147 patients with distal cholangiocarcinoma were identified from a single institution database.

SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer.

Purpose: Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas.

Experimental Design: We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas.

Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer.

Aberrant expression of microRNAs (miRNAs) has emerged as an important hallmark of cancer. However, the putative mechanisms regulating miRNAs per se are only partially known. It is well established that many tumor suppressor genes in human cancers are silenced by chromatin alterations, including promoter methylation and histone deacetylation.

Genetic mutations associated with cigarette smoking in pancreatic cancer.

Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced >750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen).

Emerging molecular biology of pancreatic cancer.

Pancreatic cancer, like most other cancers, is fundamentally caused by mutations in specific genes. Many of the genes targeted in pancreatic cancer have been identified in the past decade, and an understanding of these genes and their function has helped identify familial forms of pancreatic cancer, define the precursor lesions from which invasive pancreatic cancers arise, and will soon lead to gene-specific therapies for this disease. This article reviews the tumor-suppressor genes, oncogenes, and DNA repair genes targeted in pancreatic cancer, and presents clinical applications based on our understanding of the genetic basis of pancreatic cancer.

Absence of deleterious palladin mutations in patients with familial pancreatic cancer.

It has been reported that germline mutations in the palladin gene (PALLD) cause the familial aggregation of pancreatic cancer, but the evidence is weak and controversial. We sequenced the coding regions of PALLD in 48 individuals with familial pancreatic cancer. We did not find any deleterious mutations and find no evidence to implicate mutations in PALLD as a cause of familial pancreatic cancer.

Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene.

Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2.

KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin.

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to invasive ductal adenocarcinoma of the pancreas. Observations made in genetically engineered mouse models suggest that the acinar/centroacinar compartment can give rise to ductal neoplasia. To integrate findings in mice and men, we examined human acinar cells, acinar-ductal metaplasia (ADM) lesions, and PanINs for KRAS2 gene mutations.