The poor prognosis of pancreatic cancer has remained unchanged for many years, with a 5-year survival of less than 5 %. Current methods for diagnosing pancreatic cancer are inadequate at identifying ...small tumors that can be resected by surgery. Characterization of gene expression patterns in pancreatic cancer provided a list of genes that are specifically overexpressed in cancer cells. These genes are putative novel markers for the diagnosis and the prognosis of pancreatic cancer and for the development of targeted therapies. Gene expression analysis should lead to the discovery of molecular markers for early detection of pancreatic cancer that could benefit patients at high risk of developing pancreatic cancer.
Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome ...have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (
P
= 0.004). Five primary candidate genes (
CFLAR, CASP10, CASP8, FZD7
and
BMPR2
) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
TCF1 (transcription factor 1) encoding hepatocyte nuclear factor 1α (HNF1α) is mutated in 50% of liver cell adenomas, a benign tumor closely associated with oral contraceptive use. These genetic ...alterations inactivate both alleles, leading to the absence of wild-type HNF1α expression in liver cell adenomas. To search for a role of HNF1α in other hormone-related neoplasias, we screened for HNF1α mutations in a series of 36 endometrial carcinomas, 29 breast carcinomas and 20 ovarian epithelial tumors. HNF1α mutations were identified in 4/36 (11%) of endometrial tumors. No mutation was found in ovarian and breast tumors. HNF1α mutations were somatic in all cases, monoallelic in three cases and biallelic in one case. These results suggest that HNF1α may contribute to endometrial carcinogenesis through complete HNF1α inactivation like in liver cell adenoma or by haploinsufficiency like in MSI-H colorectal cancer.
HARP (heparin affin regulatory peptide) is a heparin binding growth factor implicated in cellular growth and differentiation. Previously, HARP had been localized in the human mammary, in both ...alveolar epithelial and myoepithelial cells although HARP mRNAs were only expressed by myoepithelial cells J. Histochem. Cytochem. 45 (1997) 1. In the present study, we demonstrate that HARP is secreted in human mature milk with concentrations ranging from 17.68
±
6.4
ng/ml in mature milk to 59.9±11.22
ng/ml in colostrum. In vitro, HARP was found to be mitogenic on human mammary epithelial and myoepithelial cell lines and correlated with the expression of its high affinity receptor tyrosine kinase ALK (anaplastic lymphoma kinase). In vivo, ALK is expressed in both mammary epithelial and myoepithelial cells, suggesting that HARP could act in vivo as a paracrine and autocrine growth factor in the regulation of the mammary gland development and its homeostatic maintenance during pregnancy and lactation.
The aim of this study was to investigate HER-2/neu (c-erbB2) overexpression/amplification in carcinoma of the uterine cervix using immunohistochemistry and fluorescent in situ hybridization (FISH) to ...assess whether anti-p185c-erbB2 therapy might have potential benefits in patients with advanced invasive cervical carcinoma. The authors used a protocol for p185c-erbB2 immunohistochemistry (clone CB11) that has been previously calibrated using FISH as the gold standard, showing a 98% accuracy rate in a large series of breast carcinomas. Immunolabeling for p185c-erbB2 was present in 24 of 82 (29%) of the tumors, but only 2 tumors (2%) with a labeling of more than 60% of the cells were considered positive for overexpression. FISH analysis did not find HER-2/neu gene amplification in these cases, although five other tumors showed weak and/or focal immunolabeling. There was no correlation between the presence of immunolabeling and age, histologic type, or clinical stage. Overexpression/amplification of HER-2/neu is uncommon in invasive cervical carcinoma, suggesting that there is little indication for using anti-p185c-erbB2 therapy in the treatment of these patients.
Molecular pathogenesis of pancreatic cancer Hilgers, Werner; Rosty, Christophe; Hahn, Stephan A
Hematology/oncology clinics of North America,
02/2002, Letnik:
16, Številka:
1
Journal Article
Recenzirano
Our understanding of the biology of pancreatic carcinoma has greatly benefited from studies of the genetic alterations in this tumor type. The p16-CDK4-cyclinD-Rb pathway, the p53 tumor suppressor ...pathway, and the DPC4/Smad4 pathway are genetically inactivated in the majority of sporadic pancreatic carcinomas, whereas oncogenic K-ras signaling is almost ubiquitously activated. These genetic data have provided the basis to shape a first genetic progression model of this tumor type. Furthermore, a number of well defined genetic syndromes which are associated with an inherited risk for pancreatic carcinoma have been identified recently.
Malignant rhabdoid tumors are rare and aggressive neoplasms of childhood, occurring in the kidney or in various extrarenal locations. Most cytogenetic studies of these tumors have shown the frequent ...involvement of chromosome 22, including translocations and/or deletions, with a critical region for a rhabdoid tumor gene mapping to chromosome segment 22q11, close to BCR. We report a case of an extrarenal rhabdoid tumor with a t(1;22)(p36;q11.2) that was associated with deletions of chromosomes 1 and 22. We have performed fluorescence in situ hybridization to bracket the translocation breakpoints on both chromosomes and microsatellite analysis to establish the deletion of chromosome 22 more precisely. The chromosome 22 translocation breakpoint is localized close to BCR, in the region covered by the overlapping YACs 446B5 and 361D9, and it is associated with a proximal hemizygous deletion of approximatively 2 Mb. On chromosome 1, the translocation breakpoint maps to a 25 cM region, proximal to D1Z2 and distal to PND, and is also associated with an estimated deletion of 8 Mb. Moreover, microsatellite analysis has demonstrated a homozygous deletion of chromosome 22 for three contiguous loci, immediately distal to BCR. This result suggests that a tumor suppressor gene involved in rhabdoid tumor oncogenesis could be localized in this region of chromosome 22. Genes Chromosomes Cancer 21:82–89, 1998. Published 1998 Wiley‐Liss, Inc.
This article is a US Government work and, as such, is in the public domain in the United States of America.
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