999

CDH1

Arc-1|CD324|CDHE|ECAD|LCAM|UVO;cadherin 1, type 1, E-cadherin (epithelial);CDH1;cadherin 1, type 1, E-cadherin (epithelial)

CAM 120/80|E-Cadherin|cadherin 1, E-cadherin (epithelial)|cadherin-1|calcium-dependent adhesion protein, epithelial|cell-CAM 120/80|epithelial cadherin|uvomorulin

16q22.1

protein-coding

PURPOSE: The aim of present study was to investigate the methylation and expression status of spleen tyrosine kinase (SYK) in human hepatocellular carcinoma (HCC) and to evaluate this information for its ability to predict disease prognosis. E-cadherin and TIMP-3 methylation was also analyzed here as control because both were associated with poor prognosis in some types of tumors. EXPERIMENTAL DESIGN: We analyzed the methylation status of SYK, E-cadherin, and TIMP-3 in 124 cases of HCC and assessed the correlation of such methylations with clinicopathologic variables and prognosis after tumor resection. RESULTS: We found that SYK, E-cadherin, and TIMP-3 genes were methylated in 27%, 27%, and 42% of HCC neoplastic tissues, respectively. The loss of SYK mRNA or Syk protein expression was highly correlated with SYK gene methylation. The patients with methylated SYK in neoplastic tissues had a significantly lower overall survival rate after hepatectomy than those with unmethylated SYK. No significant difference in overall survival rates, however, was found between groups of patients with methylated and unmethylated E-cadherin or TIMP-3. Patients with negative Syk protein expression had a significantly lower overall survival rate than those with positive Syk protein expression. Multivariate analyses indicatedthat factors affecting overall survival were tumor-node-metastasis stage, child-Pugh classification, SYK methylation, or Syk protein status. CONCLUSIONS: Our results indicate that SYK methylation and loss of Syk expression in HCC neoplastic tissues are independent biomarkers of poor patient outcome and that determination of SYK methylation or Syk expression status may offer guidance forselecting appropriate treatments.

Hepatoblastoma comprises only 1% of ALL cancers in childhood. Because of its lowfrequency, a small number of prognostic factors are described in hepatoblastoma and most of them are related to resectability. Microarray studies showed a largenumber of underexpressed genes in hepatoblastoma. Because aberrant DNA methylation has been recognized as an alternative mechanism for tumor suppressorgene inactivation, this could be involved with gene downregulation in these tumors. Despite the rarity of hepatoblastoma, this study evaluated the methylation pattern of 25 genes in 20 paraffin-embedded tumor specimens and fivenon-neoplastic liver samples (normal control) by quantitative methylation-specific PCR (QMSP). The examination of the methylation profile of hepatoblastoma samples and normal liver specimens revealed a high tumor-specificDNA hypermethylation in the promoter regions of five genes (APC, CDH1, MT1G, RASSF1A, and SOCS1). Furthermore, MT1G hypermethylation showed a significant correlation with poor prognosis of patients with hepatoblastoma. This study represents the first quantitative evaluation of promoter hypermethylation in hepatoblastoma and demonstrated that aberrant methylation is a frequent event inthis malignancy. Furthermore, our data provide evidence that MT1G hypermethylation may be useful as prognostic indicator for this disease and suggest that patients with hepatoblastoma may benefit from demethylating drug treatments.

BTI - GeneReviews#. Hereditary diffuse gastric cancer (HDGC) is autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. Diffuse gastric cancer is also referred to as signet ring carcinoma or isolated cell-type carcinoma. The average age of onset of HDGCis 38 years, with a range of 14-69 years. The majority of the cancers in individuals with a CDH1 mutation occur before age 40 years. The estimated cumulative risk of gastric cancer by age 80 years is 80% for both men and women.Women also have a 39%-52% risk for lobular breast cancer. The International Gastric cancer Linkage Consortium defined HDGC as the presence of two or more documented cases of diffuse gastric cancer in first- or second-degree relatives with at least one case diagnosed prior to age 50 years OR three or more documented cases of diffuse gastric cancer in first- or second-degree relatives,regardless of age of onset. CDH1 is currently the only gene in which mutations are known to cause hereditary diffuse gastric cancer. Treatment of manifestations: Ideally, management of individuals who have a CDH1 cancer-predisposing mutation is either intense surveillance for early detection and treatment of gastric cancer or prophylactic gastrectomy. Surveillance: To date, the optimal management of individuals at risk for a cancer-predisposing mutation has been controversial because of the unproven value of surveillance regimes and the potential morbidity and mortality from prophylactic gastrectomy.Hereditary diffuse gastric cancer is inherited in an autosomal dominant manner. The vast majority of individuals with a mutation predisposing to diffuse gastriccancer have inherited it from one parent. De novo mutations have not been reported. Each child of a proband has a 50% risk of inheriting the cancer-predisposing mutation. Prenatal testing for pregnancies at increased riskis possible if the disease-causing mutation in the family is known; however, requests for prenatal testing for conditions which (like HDGC) do not affect intellect and have some treatment available are not common.#CI- Copyright (c) 1993-2013, University of Washington, Seattle. ALL rights reserved.#FED - Pagon, Roberta A#ED- Pagon RA#FED - Adam, Margaret P#ED- Adam MP#FED - Bird, Thomas D#ED- Bird TD#FED - Dolan, Cynthia R#ED- Dolan CR#FED - Fong, Chin-To#ED- Fong CT#FED - Stephens, Karen#ED- Stephens K#FAU - Kaurah, Pardeep

Colorectal adenocarcinoma (CRAC) is exceedingly rare in the pediatric population(fewer than 2 cases per 1 million children). There are 2 major categories of pediatric colorectal adenocarcinoma syndromes: polyposis-related and hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome. Germ line mutations in DNA mismatch repair (MMR) genes (eg, MLH1, MSH2, PMS2, MSH6) have been established as the molecular genetic basis of Lynch syndrome. Another prognosticfactor in adult CRAC is the reduced expression of epithelial cadherin (E-cadherin), which has been associated with poor outcome in some adult CRAC cases; however, its role in predicting prognoses in pediatric cases remains unclear. Seven pediatric patients with primary CRAC were reviewed. Available molecular genetic test results were evaluated, and immunohistochemical labeling for MMR proteins and E-cadherin were performed on 5 patients. Four of the 5 patients in our study with available paraffin blocks showed loss of MMR protein expression, consistent with Lynch syndrome. In cases stained for E-cadherin, 3 were strongly positive and 2 were weakly positive; however, with the small sample size and the relatively short follow-up period, an accurate correlation between E-cadherin and prognosis cannot be reached with any degree of certainty. Our findings highlight the importance of genetic testing for MMR gene mutations in children with colorectal cancer and suggest further investigation into the prognostic role of E-cadherin in pediatric CRAC.

Current treatment of paediatric hepatocellular carcinoma (HCC) is often inefficient due to advanced disease at diagnosis and resistance to common drugs.The aim of this study was to generate a cell line derived from a paediatric HCC in order to expand research in this field. We established the HC-AFW1 cell line from a liver neoplasm of a 4-year-old boy through culturing of primary tumor specimens. The cell line has been stable for over one year of culturing and has a doubling time of 40 h. The tumour cells have an epithelial histology and expressHCC-associated proteins such as Alpha-fetoprotein (AFP), Glypican 3, E-cadherin,CD10, CD326, HepPar1 and Vimentin. Forty-nine amino acids in exon 3 of beta-Catenin that involve the phosphorylation sites of GSK3 were absent and beta-Catenin is detectable in the cell nuclei. Cytogenetic analysis revealed large anomalies in the chromosomal map. Several alterations of gene copy numberswere detected by genome-wide SNP array. Among the different drugs tested, cisplatin and irinotecan showed effective inhibition of tumour cell growth in a proliferation assay at concentrations below 5 microg/ml. Subcutaneous xenotransplantation of HC-AFW1 cells into NOD/SCID mice resulted in fast growingdedifferentiated tumours with high levels of serum AFP. Histological analyses ofthe primary tumour and xenografts included national and international expert pathological review. Consensus reading characterised the primary tumour and the HC-AFW1-derived tumours as HCC. HC-AFW1 is the first cell line derived from a paediatric HCC without a background of viral hepatitis or cirrhosis and represents a valuable tool for investigating the biology of and therapeutic strategies for childhood HCC.