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1.
Article in English | MEDLINE | ID: mdl-29308099

ABSTRACT

BACKGROUND: Extensive clinical and genetic heterogeneity of inherited cancers has allowed multi-gene panel testing to become an efficient means for identification of patients with an inherited predisposition to a broad spectrum of syndromic and nonsyndromic forms of cancer. This study reports our experience with a 27-gene inherited cancer panel on a cohort of 630 consecutive individuals referred for testing at our laboratory with the following objectives: 1. Determine the rates for positive cases and those with variants of uncertain clinical significance (VUS) relative to data published in the recent literature, 2. Examine heterogeneity among the constituent genes on the panel, and 3. Review test uptake in the cohort relative to other reports describing outcomes for expanded panel testing. METHODS: Clinical and genomic data were reviewed on 630 individuals tested on a panel of 27 genes selected on the basis of high (≥ 40%) or moderate to low (≤ 40%) lifetime risk of hereditary cancer. These patients were not enriched for adherence to the National Comprehensive Cancer Network (NCCN) criteria for Hereditary Breast and Ovarian Cancer (HBOC) or Lynch Syndrome (LS) and constitute a referral laboratory cohort. RESULTS: Sixty-five individuals with variants classified as pathogenic or likely pathogenic across 14 genes were identified for an overall positive rate of 10.3%. Although a family history of cancer constituted a major reason for referral, accounting for 84% of our cohort, excluding patients with a known familial variant did not have a significant impact on the observed positive rate (9% vs 10.3%). More than half (58%) of the pathogenic or likely pathogenic variants were observed in high or moderate to low risk genes on the panel, while only 42% occurred in classic HBOC or LS-associated genes. CONCLUSION: These results provide the actual percentage of family or personal history of cancer that can be attributed to pathogenic or likely pathogenic variants in one or more of the genes on our panel and corroborate the utility of multi-gene panels over sequential testing to identify individuals with an inherited predisposition to cancer.

4.
Dev Biol ; 305(1): 358-76, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17367777

ABSTRACT

Construction of the brain is one of the most complex developmental challenges. Wnt signals shape all tissues, including the brain, and the tumor suppressor adenomatous polyposis coli (APC) is a key negative regulator of Wnt/Wingless (Wg) signaling. We carried out the first assessment of the role of APC proteins in brain development, simultaneously inactivating both APC1 and APC2 in clones of cells in the Drosophila larval optic lobe. We focused on the medulla, where epithelial neural progenitors shift from symmetric to asymmetric divisions across the lateral-medial axis. Loss of both APCs triggers dramatic defects in optic lobe development. Double mutant cells segregate from wild-type neighbors, while double mutant neurons form tangled axonal knots, suggesting changes in cell adhesion. Strikingly, phenotypes are graded along the anterior-posterior axis. Activation of Wg signaling downstream of APC mimics these phenotypes, a dominant-negative TCF blocks them, and a known Wg target, decapentaplegic, is activated in double mutant clones, strongly suggesting that the phenotypes result from activated Wg signaling. We also explored the roles of classic cadherins in differential adhesion. Finally, we propose a model suggesting that Wg signaling regulates fine scale cell fates along the anterior-posterior axis, in part by creating an adhesion gradient and consider possible alternate explanations for our observations.


Subject(s)
Body Patterning/physiology , Drosophila Proteins/metabolism , Drosophila/embryology , Optic Lobe, Nonmammalian/embryology , Signal Transduction/physiology , Tumor Suppressor Proteins/metabolism , Wnt Proteins/metabolism , Animals , Cadherins/metabolism , Cell Adhesion/physiology , Cell Differentiation/physiology , Crosses, Genetic , Drosophila Proteins/genetics , Immunohistochemistry , Models, Biological , Stem Cells/metabolism , Tumor Suppressor Proteins/genetics
5.
Development ; 133(12): 2407-18, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16720878

ABSTRACT

Adenomatous polyposis coli (APC) is mutated in colon cancers. During normal development, APC proteins are essential negative regulators of Wnt signaling and have cytoskeletal functions. Many functions have been proposed for APC proteins, but these have often rested on dominant-negative or partial loss-of-function approaches. Thus, despite intense interest in APC, significant questions remain about its full range of cellular functions and about how mutations in the gene affect these. We isolated six new alleles of Drosophila APC2. Two resemble the truncation alleles found in human tumors and one is a protein null. We generated ovaries and embryos null for both APC2 and APC1, and assessed the consequences of total loss of APC function, allowing us to test several previous hypotheses. Surprisingly, although complete loss of APC1 and APC2 resulted in strong activation of Wingless signaling, it did not substantially alter cell viability, cadherin-based adhesion, spindle morphology, orientation or selection of division plane, as predicted from previous studies. We also tested the hypothesis that truncated APC proteins found in tumors are dominant negative. Two mutant proteins have dominant effects on cytoskeletal regulation, affecting Wnt-independent nuclear retention in syncytial embryos. However, they do not have dominant-negative effects on Wnt signaling.


Subject(s)
Alleles , Cytoskeletal Proteins , Drosophila Proteins , Drosophila melanogaster/genetics , Protein Isoforms , Tumor Suppressor Proteins , Animals , Armadillo Domain Proteins/genetics , Armadillo Domain Proteins/metabolism , Cell Adhesion/physiology , Cell Nucleus/metabolism , Cell Nucleus/ultrastructure , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/physiology , Female , Humans , Male , Mutation , Ovary/anatomy & histology , Ovary/metabolism , Phenotype , Protein Isoforms/genetics , Protein Isoforms/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Signal Transduction/physiology , Spindle Apparatus/metabolism , Spindle Apparatus/ultrastructure , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Wnt Proteins/genetics , Wnt Proteins/metabolism , Wnt1 Protein
6.
Biochem Biophys Res Commun ; 313(3): 546-51, 2004 Jan 16.
Article in English | MEDLINE | ID: mdl-14697224

ABSTRACT

TGFbeta controls hepatocyte growth through cell cycle arrest and apoptosis, and resistance to TGFbeta is a mechanism of malignant transformation. The aim of this study was to assess differences in TGFbeta-mediated growth inhibition in normal and cirrhotic hepatocytes. Cirrhosis was induced in mice and normal and cirrhotic hepatocytes were isolated by collagenase perfusion and treated with or without TGFbeta (5 ng/ml). DNA synthesis, Smad protein expression, and DNA binding activity were determined. TGFbeta reduced DNA synthesis to a greater degree in normal hepatocytes than in cirrhotic hepatocytes (87% vs. 68%; p<0.05). Smad protein expression was decreased in cirrhotic hepatocytes and Smad 2/3/4 complex formation was suppressed. Furthermore, cirrhotic hepatocytes had decreased DNA binding activity at 120 min following TGFbeta treatment. In conclusion, decreased Smad protein expression may impair TGFbeta-mediated growth inhibition in cirrhotic hepatocytes.


Subject(s)
DNA-Binding Proteins/metabolism , Down-Regulation , Hepatocytes/metabolism , Trans-Activators/metabolism , Transforming Growth Factor beta/metabolism , Active Transport, Cell Nucleus , Animals , Blotting, Western , Cell Division , Cell Transformation, Neoplastic , Collagenases/metabolism , DNA/metabolism , DNA-Binding Proteins/biosynthesis , Fibrosis , Male , Mice , Mice, Inbred BALB C , Protein Binding , Signal Transduction , Smad Proteins , Smad2 Protein , Smad3 Protein , Smad4 Protein , Thymidine/chemistry , Time Factors , Trans-Activators/biosynthesis
7.
Dev Biol ; 250(1): 91-100, 2002 Oct 01.
Article in English | MEDLINE | ID: mdl-12297098

ABSTRACT

The regulation of signal transduction plays a key role in cell fate choices, and its disregulation contributes to oncogenesis. This duality is exemplified by the tumor suppressor APC. Originally identified for its role in colon tumors, APC family members were subsequently shown to negatively regulate Wnt signaling in both development and disease. The analysis of the normal roles of APC proteins is complicated by the presence of two APC family members in flies and mice. Previous work demonstrated that, in some tissues, single mutations in each gene have no effect, raising the question of whether there is functional overlap between the two APCs or whether APC-independent mechanisms of Wnt regulation exist. We addressed this by eliminating the function of both Drosophila APC genes simultaneously. We find that APC1 and APC2 play overlapping roles in regulating Wingless signaling in the embryonic epidermis and the imaginal discs. Surprisingly, APC1 function in embryos occurs at levels of expression nearly too low to detect. Further, the overlapping functions exist despite striking differences in the intracellular localization of the two APC family members.


Subject(s)
Drosophila Proteins/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction , Tumor Suppressor Proteins/metabolism , Adenomatous Polyposis Coli Protein , Animals , Armadillo Domain Proteins , Cytoskeletal Proteins , Drosophila Proteins/genetics , Drosophila melanogaster/embryology , Drosophila melanogaster/metabolism , Epidermis/embryology , Epidermis/metabolism , Gene Expression , Intracellular Fluid , Trans-Activators/metabolism , Transcription Factors , Tumor Suppressor Proteins/genetics , Wnt1 Protein
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