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Results: 11 to 19 of 19

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A genetic progression model of Braf(V600E)-induced intestinal tumorigenesis reveals targets for therapeutic intervention.
Rad R, Cadiñanos J, Rad L, Varela I, Strong A, Kriegl L, Constantino-Casas F, Eser S, Hieber M, Seidler B, Price S, Fraga MF, Calvanese V, Hoffman G, Ponstingl H, Schneider G, Yusa K, Grove C, Schmid RM, Wang W, Vassiliou G, Kirchner T, McDermott U, Liu P, Saur D, Bradley A
(2013) Cancer Cell 24: 15-29
MeSH Terms: Animals, Cell Transformation, Neoplastic, Colorectal Neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Drug Screening Assays, Antitumor, MAP Kinase Signaling System, Mice, Microsatellite Instability, Mutation, Neoplasm Invasiveness, Neoplasm Proteins, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Tumor Suppressor Protein p53, Wnt Signaling Pathway
Show Abstract · Added September 27, 2013
We show that BRAF(V600E) initiates an alternative pathway to colorectal cancer (CRC), which progresses through a hyperplasia/adenoma/carcinoma sequence. This pathway underlies significant subsets of CRCs with distinctive pathomorphologic/genetic/epidemiologic/clinical characteristics. Genetic and functional analyses in mice revealed a series of stage-specific molecular alterations driving different phases of tumor evolution and uncovered mechanisms underlying this stage specificity. We further demonstrate dose-dependent effects of oncogenic signaling, with physiologic Braf(V600E) expression being sufficient for hyperplasia induction, but later stage intensified Mapk-signaling driving both tumor progression and activation of intrinsic tumor suppression. Such phenomena explain, for example, the inability of p53 to restrain tumor initiation as well as its importance in invasiveness control, and the late stage specificity of its somatic mutation. Finally, systematic drug screening revealed sensitivity of this CRC subtype to targeted therapeutics, including Mek or combinatorial PI3K/Braf inhibition.
Copyright © 2013 Elsevier Inc. All rights reserved.
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15 MeSH Terms
BRAF: a driver of the serrated pathway in colon cancer.
Rustgi AK
(2013) Cancer Cell 24: 1-2
MeSH Terms: Colonic Neoplasms, Genes, p16, Genes, p53, Humans, Microsatellite Instability, Mutation, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), ras Proteins
Show Abstract · Added July 31, 2013
In this issue of Cancer Cell, Rad and colleagues report findings that underscore the importance of oncogenic BRAF mutation coupled with microsatellite instability, p16Ink4a inactivation, and p53 mutation in the serrated pathway of colon cancer development. These findings provide translational insights into potential therapeutic intervention for BRAF mutant colon cancers.
Copyright © 2013 Elsevier Inc. All rights reserved.
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10 MeSH Terms
Clinical utility of KRAS and BRAF mutations in a cohort of patients with colorectal neoplasms submitted for microsatellite instability testing.
Cushman-Vokoun AM, Stover DG, Zhao Z, Koehler EA, Berlin JD, Vnencak-Jones CL
(2013) Clin Colorectal Cancer 12: 168-78
MeSH Terms: Adult, Biomarkers, Tumor, Colorectal Neoplasms, Female, Follow-Up Studies, Humans, Male, Microsatellite Instability, Middle Aged, Mutation, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), Retrospective Studies, Survival Rate, ras Proteins
Show Abstract · Added March 7, 2014
BACKGROUND - Molecular analysis has become important in colorectal carcinoma (CRC) evaluation. Alterations in KRAS, BRAF, or mismatch repair (MMR) genes may determine therapeutic response or define a hereditary cancer syndrome. Correlation of DNA studies with clinical findings will further clarify the clinical utility of these markers.
PATIENTS AND METHODS - A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted for microsatellite instability (MSI) testing based on clinical history or histologic examination, or both. DNA samples were screened for 7 KRAS mutations and the BRAF p.V600E mutation using fluorescent allele-specific polymerase-chain reaction (PCR) and capillary electrophoresis. Clinical data were collected through chart review.
RESULTS - Fifty-eight male and 53 female patients were studied. The incidence of KRAS and BRAF mutations was 49.5% and 7.2%, respectively. Dideoxy sequencing verified KRAS mutation status in 46 of 49 specimens tested. There was a trend toward significance of individual KRAS mutations on survival (P = .003). Dually positive KRAS and MSI tumors exclusively demonstrated p.G12D and p.G13D mutations (G>A transitions). BRAF-mutated tumors were predominantly right-sided and associated with a borderline worse prognosis. Forty-eight percent of tumors with MSI were present in the left colon or rectum.
CONCLUSION - Allele-specific PCR is an accurate and convenient method to assess KRAS and BRAF mutations and may detect mutations not identified by dideoxy sequencing. KRAS mutation status, in conjunction with morphologic or clinical parameters, may be useful in determining whether a tumor should be tested for MSI. MSI testing should not be considered exclusively in right-sided lesions. BRAF analysis may not be useful in rectal adenocarcinomas and should be evaluated in larger studies.
Copyright © 2013 Elsevier Inc. All rights reserved.
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18 MeSH Terms
PIK3CA and APC mutations are synergistic in the development of intestinal cancers.
Deming DA, Leystra AA, Nettekoven L, Sievers C, Miller D, Middlebrooks M, Clipson L, Albrecht D, Bacher J, Washington MK, Weichert J, Halberg RB
(2014) Oncogene 33: 2245-54
MeSH Terms: Adenocarcinoma, Adenomatous Polyposis Coli Protein, Animals, Cell Nucleus, Colorectal Neoplasms, Cyclin D1, Disease Models, Animal, Epistasis, Genetic, Female, Gene Expression, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microsatellite Instability, Phosphatidylinositol 3-Kinases, Tumor Burden, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added April 12, 2016
Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (β-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.
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20 MeSH Terms
Molecular testing in colorectal cancer: diagnosis of Lynch syndrome and personalized cancer medicine.
Shi C, Washington K
(2012) Am J Clin Pathol 137: 847-59
MeSH Terms: Antibodies, Monoclonal, Carcinoma, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, ErbB Receptors, Humans, Microsatellite Instability, Multiplex Polymerase Chain Reaction, Mutation, Pathology, Molecular, Precision Medicine, Prognosis, Signal Transduction
Show Abstract · Added April 12, 2016
Currently, molecular testing in colorectal cancer (CRC) is aimed at detecting Lynch syndrome and predicting response to anti-epidermal growth factor receptor (EGFR) therapies. However, CRC is a complex disease, with at least 3 molecular pathways of carcinogenesis. The importance of the EGFR signaling pathway in colorectal carcinogenesis is underscored by the availability of anti-EGFR monoclonal antibodies for the treatment of some metastatic CRCs. Potentially, mutations in any of the genes in the EGFR signaling pathway may be associated with prognosis and may predict response to anti-EGFR or other targeted therapies. Although not currently the standard of care, molecular testing of CRCs is expanding to include mutational analysis of the genes in the EGFR pathway, in addition to more widely performed tests for identifying cancers with high microsatellite instability. Multiplex molecular prognostic panels for therapeutic decision making in stage II CRCs also represent expanding use of molecular testing for this common cancer.
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13 MeSH Terms
A pilot study of microsatellite instability and endometrial cancer survival in white and African American women.
Cote ML, Kam A, Chang CY, Raskin L, Reding KW, Cho KR, Gruber SB, Ali-Fehmi R
(2012) Int J Gynecol Pathol 31: 66-72
MeSH Terms: African Americans, Aged, Aged, 80 and over, Analysis of Variance, DNA, Neoplasm, Endometrial Neoplasms, European Continental Ancestry Group, Female, Genetic Markers, Humans, Hysterectomy, Logistic Models, Michigan, Microsatellite Instability, Microsatellite Repeats, Middle Aged, Neoplasm Staging, Pilot Projects, Prognosis, Retrospective Studies, Survival Analysis
Show Abstract · Added March 5, 2014
Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States and can be classified on the basis of various pathologic, molecular, and genetic features, including microsatellite instability (MSI). As MSI is generally associated with a more favorable outcome in colorectal cancers, it is feasible that microsatellite instability may also influence endometrial cancer survival. We examined MSI and survival in 45 African American and 31 white women diagnosed with endometrial cancer at a large, urban cancer center. Fifty-five tumors were classified as type I and 21 tumors were classified as type II. Unconditional logistic regression models found that microsatellite stable tumors were more frequently observed in white women compared with African American women (odds ratio, 8.61; 95% confidence interval, 1.01-73.69). Type I tumors with MSI were not found to be significantly associated with smoking status, tumor stage, or age. Only one type II tumor was classified as MSI. Neither race nor MSI status was a predictor of death from all causes or only endometrial cancer-related deaths were considered in univariate and multivariate survival models. The potential significance of a larger proportion of MSI tumors found in African American women with type I endometrial cancer should be assessed in a larger prospective study.
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21 MeSH Terms
MRE11 deficiency increases sensitivity to poly(ADP-ribose) polymerase inhibition in microsatellite unstable colorectal cancers.
Vilar E, Bartnik CM, Stenzel SL, Raskin L, Ahn J, Moreno V, Mukherjee B, Iniesta MD, Morgan MA, Rennert G, Gruber SB
(2011) Cancer Res 71: 2632-42
MeSH Terms: Benzimidazoles, Cell Line, Tumor, Colorectal Neoplasms, DNA Damage, DNA Repair Enzymes, DNA-Binding Proteins, Enzyme Inhibitors, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MRE11 Homologue Protein, Microsatellite Instability, Mutation, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Rad51 Recombinase, Recombination, Genetic
Show Abstract · Added March 5, 2014
Microsatellite instability (MSI) is displayed by approximately 15% of colorectal cancers (CRC). Defective DNA mismatch repair generates mutations at repetitive DNA sequences such as those located in the double strand break (DSB) repair gene MRE11. We assessed the mutational status of MRE11 in a panel of 17 CRC cell lines and 46 primary tumors and found a strong correlation with MSI status in both cell lines and tumors. Therefore, we hypothesized that deficiency in MRE11 may sensitize CRC cells to poly(ADP-ribose) polymerase (PARP-1) inhibition based on the concept of synthetic lethality. We further assessed the activity of the PARP-1 inhibitor, ABT-888, in CRC cell lines and observed preferential cytotoxicity in those MSI cell lines harboring mutations in MRE11 compared with both wild-type cell lines and microsatellite stable (MSS) cell lines. A significant correlation between MRE11 expression levels and cytotoxicity to ABT-888 at 10 μM was observed (R² = 0.915, P < 0.001). Using two experimental approaches, including short hairpin RNA knocking down MRE11 in the wild-type and MSS cell line SW-480 and a second cell line model transfected with mutant MRE11, we experimentally tried to confirm the role of MRE11 in conferring sensitivity to PARP-1 inhibition. Both models led to changes in proliferation in response to ABT-888 at different concentrations, and a drug-response effect was not observed, suggesting a possible contribution of additional genes. We conclude that MSI colorectal tumors deficient in DSB repair secondary to mutation in MRE11 show a higher sensitivity to PARP-1 inhibition. Further clinical investigation of PARP-1 inhibitors is warranted in MSI CRCs.
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19 MeSH Terms
Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009.
Van Cutsem E, Dicato M, Arber N, Berlin J, Cervantes A, Ciardiello F, De Gramont A, Diaz-Rubio E, Ducreux M, Geva R, Glimelius B, Glynne Jones R, Grothey A, Gruenberger T, Haller D, Haustermans K, Labianca R, Lenz HJ, Minsky B, Nordlinger B, Ohtsu A, Pavlidis N, Rougier P, Schmiegel W, Van de Velde C, Schmoll HJ, Sobrero A, Tabernero J
(2010) Ann Oncol 21 Suppl 6: vi1-10
MeSH Terms: Antineoplastic Agents, Biomarkers, Carcinoembryonic Antigen, Colorectal Neoplasms, ErbB Receptors, Humans, Microsatellite Instability, Mutation, Neoplasm Metastasis, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), Spain, ras Proteins
Show Abstract · Added March 20, 2014
The article summarizes the expert discussion and recommendations on the use of molecular markers and of biological targeted therapies in metastatic colorectal cancer (mCRC), as well as a proposed treatment decision strategy for mCRC treatment. The meeting was conducted during the 11th ESMO/World Gastrointestinal Cancer Congress (WGICC) in Barcelona in June 2009. The manuscript describes the outcome of an expert discussion leading to an expert recommendation. The increasing knowledge on clinical and molecular markers and the availability of biological targeted therapies have major implications in the optimal management in mCRC.
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15 MeSH Terms
Gene expression patterns in mismatch repair-deficient colorectal cancers highlight the potential therapeutic role of inhibitors of the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway.
Vilar E, Mukherjee B, Kuick R, Raskin L, Misek DE, Taylor JM, Giordano TJ, Hanash SM, Fearon ER, Rennert G, Gruber SB
(2009) Clin Cancer Res 15: 2829-39
MeSH Terms: Algorithms, Antineoplastic Agents, Benzoquinones, Cell Cycle, Cell Line, Tumor, Chromones, Colorectal Neoplasms, Computational Biology, DNA Mismatch Repair, Drug Evaluation, Preclinical, Enzyme Inhibitors, Gene Expression Profiling, Humans, Hydroxamic Acids, Immunosuppressive Agents, Lactams, Macrocyclic, Microsatellite Instability, Morpholines, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Sirolimus
Show Abstract · Added March 5, 2014
PURPOSE - High-frequency microsatellite-instable (MSI-H) tumors account for approximately 15% of colorectal cancers. Therapeutic decisions for colorectal cancer are empirically based and currently do not emphasize molecular subclassification despite an increasing collection of gene expression information. Our objective was to identify low molecular weight compounds with preferential activity against MSI colorectal cancers using combined gene expression data sets.
EXPERIMENTAL DESIGN - Three expression/query signatures (discovery data set) characterizing MSI-H colorectal cancer were matched with information derived from changes induced in cell lines by 164 compounds using the systems biology tool "Connectivity Map." A series of sequential filtering and ranking algorithms were used to select the candidate compounds. Compounds were validated using two additional expression/query signatures (validation data set). Cytotoxic, cell cycle, and apoptosis effects of validated compounds were evaluated in a panel of cell lines.
RESULTS - Fourteen of the 164 compounds were validated as targeting MSI-H cell lines using the bioinformatics approach; rapamycin, LY-294002, 17-(allylamino)-17-demethoxygeldanamycin, and trichostatin A were the most robust candidate compounds. In vitro results showed that MSI-H cell lines due to hypermethylation of MLH1 are preferentially targeted by rapamycin (18.3 versus 4.4 mumol/L; P = 0.0824) and LY-294002 (15.02 versus 10.37 mumol/L; P = 0.0385) when compared with microsatellite-stable cells. Preferential activity was also observed in MSH2 and MSH6 mutant cells.
CONCLUSION - Our study shows that the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is of special relevance in mismatch repair-deficient colorectal cancer. In addition, we show that amalgamation of gene expression information across studies provides a robust approach for selection of potential therapies corresponding to specific groups of patients.
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21 MeSH Terms