Constance A. Griffin

Johns Hopkins Medicine, Baltimore, Maryland, United States

Are you Constance A. Griffin?

Claim your profile

Publications (235)1193.44 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Therapy-related myeloid neoplasms (t-MN) are well-recognized complications of high-dose cytotoxic therapy (HDT), such as autologous stem cell transplant (ASCT). Clonal marrow cytogenetic abnormalities (CMCA) in the setting of normal bone marrow pathology have also been reported after HDT, but their significance remains unclear. We retrospectively evaluated occurrences of CMCA and t-MN in 785 patients treated with HDT at Johns Hopkins University between 1997 and 2007. Most patients received ASCT, but 106 patients who received high-dose cyclophosphamide (HiCy) without ASCT were also included in this study, as this is our institutional standard for malignant and non-malignant lymphoproliferative disorders in need of HDT. Twenty-two patients developed t-MN, with an estimated cumulative incidence of 3.5% at four years. Eleven patients developed isolated CMCA, either transient or persistent without pathologic evidence of t-MN. Altogether, only 20 of the patients with reported CMCA subsequently developed t-MN during the follow-up period. Therefore, in the absence of pathologic evidence of t-MN, CMCA should not be considered diagnostic of t-MN.
    No preview · Article · Apr 2014 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early and late effects of cancer treatment are of increasing concern with growing survivor populations, but relevant data are sparse. We sought to determine the prevalence and hazard ratio of such effects in breast cancer cases. Women with invasive breast cancer and women with no cancer history recruited for a cancer research cohort completed a mailed questionnaire at a median of 10 years post-diagnosis or matched reference year (for the women without cancer). Reported medical conditions including lymphedema, osteopenia, osteoporosis, and heart disease (congestive heart failure, myocardial infarction, coronary heart disease) were assessed in relation to breast cancer therapy and time since diagnosis using Cox regression. The proportion of women currently receiving treatment for these conditions was calculated. Study participants included 2,535 women with breast cancer and 2,428 women without cancer (response rates 66.0 % and 50.4 %, respectively) Women with breast cancer had an increased risk of lymphedema (Hazard ratio (HR) 8.6; 95 % confidence interval (CI) 6.3-11.6), osteopenia (HR 2.1; 95 % CI 1.8-2.4), and osteoporosis (HR 1.5; 95 % CI 1.2-1.9) but not heart disease, compared to women without cancer Hazard ratios varied by treatment and time since diagnosis. Overall, 49.3 % of breast cancer cases reported at least one medical condition, and at 10 or more years post-diagnosis, 37.7 % were currently receiving condition-related treatment. Responses from survivors a decade following cancer diagnosis demonstrate substantial treatment-related morbidity, and emphasize the need for continued medical surveillance and follow-up care into the second decade post-diagnosis.
    No preview · Article · Apr 2014 · Breast Cancer Research and Treatment
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Potential bone marrow donors are screened to ensure the safety of both the donor and recipient. At our institution, potential donors with abnormal peripheral blood cell counts, a personal history of malignancy, or age >60 years are evaluated to ensure that they are viable candidates for donation. Evaluation of the marrow includes morphologic, flow cytometric and cytogenetic studies. 122 potential donors were screened between the years of 2001-2011, encompassing approximately 10% of all donors. The median age of the screened potential donors was 59 years, and included 59 men and 63 women. The donors were screened because of age >60 years old (33), anemia (22), cytopenias other than anemia (27), elevated peripheral blood counts without a concurrent cytopenia (20), elevated peripheral blood counts with a concurrent cytopenia (10), history of malignancy (4), abnormal peripheral blood differential (3), prior graft failure (1), history of treatment with chemotherapy (1), and body habitus (1). Marrow abnormalities were detected in 9% (11/122) of donors. These donors were screened because of anemia (5/22; 23%), age >60 years (2/33; 6%), history of malignancy (2/4; 50%), elevated peripheral blood counts (1/20; 5%), and body habitus (1/1; 100%). Abnormalities included plasma cell dyscrasia (3), abnormal marrow cellularity (3), clonal cytogenetic abnormalities (2), low-grade myelodysplastic syndrome (1), a mutated JAK2 V617F allele (1), and monoclonal B-cell lymphocytosis (1). Our experience indicates that extended screening of potential donors identifies a significant number of donors with previously undiagnosed marrow abnormalities.
    Preview · Article · Jun 2013 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
  • [Show abstract] [Hide abstract]
    ABSTRACT: Xp11 translocation renal cell carcinomas (RCCs) are characterized by chromosome translocations involving the Xp11.2 breakpoint, resulting in gene fusions involving the TFE3 transcription factor. In archival material, the diagnosis can often be confirmed by TFE3 immunohistochemistry (IHC), but variable fixation (especially prevalent in consultation material) can lead to equivocal results. A TFE3 break-apart fluorescence in situ hybridization (FISH) assay has been developed to detect TFE3 gene rearrangements; however, the utility of this assay in a renal tumor consultation practice has not been examined. We reviewed 95 consecutive renal tumor consultation cases submitted to rule in or rule out Xp11 translocation RCC. Thirty-one cases were positive for TFE3 rearrangements by FISH. Patients ranged from 6 to 67 years of age (mean=30 y; median=28 y). Novel or distinctive morphologic features of these cases included extensive cystic change simulating multilocular cystic RCC (3 cases), sarcomatoid transformation (3 cases), oncocytic areas mimicking oncocytoma (1 case), trabecular architecture mimicking a carcinoid tumor (1 case), colonization of renal pelvic urothelium mimicking urothelial carcinoma in situ (1), and focal desmin and diffuse racemase immunoreactivity (1 case each). Twenty-six of the 31 TFE3 FISH-positive RCCs were unequivocally positive for TFE3 by IHC, but 4 were equivocal, and 1 was negative. Of the 64 cases that were negative by TFE3 FISH, 50 were negative by TFE3 IHC, and 14 were equivocal. Thirty-two of the 64 TFE3 FISH-negative cases could be classified into other accepted RCC subtypes: 23 as clear cell RCC, 5 as papillary RCC, 3 as clear cell papillary RCC, and 1 as chromophobe RCC. The other 32 cases remained unclassified, including 3 cathepsin K-positive RCC that closely resembled Xp11 translocation RCC. In conclusion, TFE3 FISH is highly useful in renal tumor consultation material, often resolving cases with equivocal TFE3 IHC results. Given the difficulty of optimizing TFE3 IHC, TFE3 FISH is for most laboratories the optimal test for establishing the diagnosis of Xp11 translocation RCC.
    No preview · Article · May 2013 · The American journal of surgical pathology
  • [Show abstract] [Hide abstract]
    ABSTRACT: A subset of renal cell carcinomas (RCCs) is characterized by t(6;11)(p21;q12), which results in fusion of the untranslated Alpha (MALAT1) gene to the TFEB gene. Only 21 genetically confirmed cases of t(6;11) RCCs have been reported. This neoplasm typically demonstrates a distinctive biphasic morphology, comprising larger epithelioid cells and smaller cells clustered around basement membrane material; however, the full spectrum of its morphologic appearances is not known. The t(6;11) RCCs differ from most conventional RCCs in that they consistently express melanocytic immunohistochemical (IHC) markers such as HMB45 and Melan A and the cysteine protease cathepsin K but are often negative for epithelial markers such as cytokeratins. TFEB IHC has been proven to be useful to confirm the diagnosis of t(6;11) RCCs in archival material, because native TFEB is upregulated through promoter substitution by the gene fusion. However, IHC is highly fixation dependent and has been proven to be particularly difficult for TFEB. A validated fluorescence in situ hybridization (FISH) assay for molecular confirmation of the t(6;11) RCC in archival formalin-fixed, paraffin-embedded material has not been previously reported. We report herein the development of a break-apart TFEB FISH assay for the diagnosis of t(6;11)(p21;q12) RCCs. We validated the assay on 4 genetically confirmed cases and 76 relevant expected negative control cases and used the assay to report 8 new cases that expand the clinicopathologic spectrum of t(6;11) RCCs. An additional previously reported TFEB IHC-positive case was confirmed by TFEB FISH in 46-year-old archival material. In conclusion, TFEB FISH is a robust, clinically validated assay that can confirm the diagnosis of t(6;11) RCC in archival material and should allow a more comprehensive clinicopathologic delineation of this recently recognized neoplastic entity.
    No preview · Article · Aug 2012 · The American journal of surgical pathology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Serrated (hyperplastic) polyposis (SP) is a rare disorder with multiple colorectal hyperplastic polyps and often sessile serrated adenomas/polyps (SSA/P) or adenomas. Although associated with colorectal cancer, the course of SP is not well described. Design 44 patients with SP were studied. The results of 146 colonoscopies with median follow-up of 2.0 years (range 0–30) and a median of 1.0 years (range 0.5–6) between surveillance colonoscopies were evaluated. Findings from oesophogastroduodenoscopy examinations were analysed. Results The mean age at diagnosis of SP was 52.5±11.9 years (range 22–78). In two pedigrees (5%) another family member had SP. None of 22 patients had gastroduodenal polyps. All patients had additional colorectal polyps at surveillance colonoscopy. SSA/P or adenomas were found in 25 patients (61%) at first colonoscopy and 83% at last colonoscopy. Recurrent SSA/P or adenomas occurred in 68% of patients at surveillance colonoscopy. Three patients had colorectal cancer. Eleven patients (25%) underwent surgery (mean time from diagnosis of SP 2.0±0.9 years). After surgery all seven surveyed patients developed recurrent polyps in the retained colorectum (4/7 had SSA/P or adenomas). No association was found between colorectal neoplasia and sex, age at diagnosis of SP or initial number of colorectal polyps. Conclusions In SP, rapid and unrelenting colorectal neoplasia development continues in the intact colorectum and retained segment after surgery. These findings support the possibility of annual colonoscopic surveillance, consideration for colectomy when SSA/P or adenomas are encountered and frequent postoperative endoscopic surveillance of the retained colorectum.
    Full-text · Article · Apr 2012 · Gut
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Most patients with CLL with a poor-risk cytogenetic profile have an unmutated IGHV sequence. Limited clinical information exists for patients with CLL who have a poor-risk cytogenetic profile and a mutated or good-risk IGHV status. We retrospectively screened all patients with CLL seen at our institution from 2006 onward who harbored a del(11q) or del(17p) CLL detected by fluorescence in situ hybridization (FISH) analysis for whom an IGHV analysis was requested. In 66 evaluable patients, 50 (76%) had an unmutated IGHV sequence. Thirty-nine patients (59%) had del(11q) and 27 patients (41%) had del(17p); no patient in this series had both del(11q) and del(17p). The patients' initial clinical presentations were similar in both mutational groups. Patients with an unmutated IGHV sequence were more likely to receive treatment and to have a shorter survival, with an estimated 3-year overall survival (OS) of 81% compared with 100% in the group with a mutated IGHV sequence (log rank, P = .06). These data suggest that IGHV mutational status has prognostic relevance even in patients with CLL who are defined as poor risk by genomic FISH analysis.
    Full-text · Article · Jan 2012 · Clinical lymphoma, myeloma & leukemia
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34(+)CD38(-) cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34(+) subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34(+)CD38(-) cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34(+)CD38(-)ALDH(int) leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34(+)CD38(-) cells and identifies those AML cells associated with relapse.
    Preview · Article · Jan 2012 · Blood
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The risk of pancreatic cancer is increased in patients with a strong family history of pancreatic cancer or a predisposing germline mutation. Screening can detect curable, noninvasive pancreatic neoplasms, but the optimal imaging approach is not known. We determined the baseline prevalence and characteristics of pancreatic abnormalities using 3 imaging tests to screen asymptomatic, high-risk individuals (HRIs). We screened 225 asymptomatic adult HRIs at 5 academic US medical centers once, using computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasonography (EUS). We compared results in a blinded, independent fashion. Ninety-two of 216 HRIs (42%) were found to have at least 1 pancreatic mass (84 cystic, 3 solid) or a dilated pancreatic duct (n = 5) by any of the imaging modalities. Fifty-one of the 84 HRIs with a cyst (60.7%) had multiple lesions, typically small (mean, 0.55 cm; range, 2-39 mm), in multiple locations. The prevalence of pancreatic lesions increased with age; they were detected in 14% of subjects younger than 50 years old, 34% of subjects 50-59 years old, and 53% of subjects 60-69 years old (P < .0001). CT, MRI, and EUS detected a pancreatic abnormality in 11%, 33.3%, and 42.6% of the HRIs, respectively. Among these abnormalities, proven or suspected neoplasms were identified in 85 HRIs (82 intraductal papillary mucinous neoplasms and 3 pancreatic endocrine tumors). Three of 5 HRIs who underwent pancreatic resection had high-grade dysplasia in less than 3 cm intraductal papillary mucinous neoplasms and in multiple intraepithelial neoplasias. Screening of asymptomatic HRIs frequently detects small pancreatic cysts, including curable, noninvasive high-grade neoplasms. EUS and MRI detect pancreatic lesions better than CT.
    Full-text · Article · Jan 2012 · Gastroenterology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in <1% in the general population. The threonine at amino acid position 992 lies in the tyrosine kinase domain of MET and a change to isoleucine at this position has been shown to promote metastatic behavior in cell-based models. The average age of CRC diagnosis in patients in this study is 63 years in mutation carriers, which is 8 years earlier than the general population average for CRC. Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.
    Full-text · Article · Oct 2011 · BMC Cancer
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Deletion or loss of heterozygosity (LOH) in chromosomes 1p and 19q in oligodendrogliomas (ODGs) have diagnostic, prognostic, and therapeutic implications. Current clinical assays are limited because the probes or primers interrogate only limited genomic segments. We investigated the use of single nucleotide polymorphism (SNP) arrays for identifying genomic changes in gliomas from FFPE tissues. DNA was extracted from FFPE tissues of 30 brain tumor cases (15 ODGs and 15 non-ODGs) and assayed on the Illumina array with 300,000 markers. SNP results were compared with standard short tandem repeat (STR) assays of chromosomes 1p and 19q. Fifteen ODGs had LOH by STR and deletion by array on both 1p and 19q. Ten non-ODGs had no evidence of LOH on 1p and 19q by STR, seven of which had no abnormalities for these chromosomes; three had partial deletions by SNP array. Five non-ODG cases had partial LOH or deletion by both assays. No major discordance was found between SNP array and STR results. Advantages of SNP arrays include no need for an accompanying normal sample, the ability to find small segmental deletions, the potential to distinguish between deletions and copy neutral LOH, and whole-genome screening to allow discovery of new, significant loci. Assessment of genomic changes in routine glioma specimens using SNP arrays is feasible and has great potential as an accurate clinical diagnostic test.
    Full-text · Article · Sep 2011 · The Journal of molecular diagnostics: JMD
  • [Show abstract] [Hide abstract]
    ABSTRACT: Among prognostic factors for chronic lymphocytic leukemia (CLL), immunoglobulin heavy chain variable region (IGHV) mutation status and DNA analysis appear to be the most important. However, there is limited clinical outcome information for patients with the favorable-risk del(13q) and poor-risk unmutated IGHV. We retrospectively screened all patients with CLL at our institution between 2004 and June 2010 for del(13q) who also had an IGHV analysis. Unmutated IGHV was found in 38/79 patients; age, Rai stage, prior therapy, and time to evaluation were similar to those for patients with mutated IGHV. Unmutated patients were nearly four times more likely to harbor additional chromosomal aberrations compared to mutated patients (p < 0.001). During a median follow-up of 4.5 years, unmutated patients were more likely to demonstrate Rai stage progression (69% vs. 31%, log-rank p < 0.001) and to receive treatment (5-year cumulative probability of treatment: 65% vs. 32%, p < 0.001). Patients with unmutated CLL also had a shorter overall survival (5-year survival probability: 72% vs. 100%, p < 0.001). When limiting analysis to the 47 patients with del(13q) as a sole chromosomal abnormality, the 13 (28%) unmutated patients were more likely to demonstrate Rai progression (p < 0.001), to receive treatment (p = 0.02), and to have a shorter overall survival (p = 0.13) than the 34 mutated patients. These data suggest that del(13q) conveys an indolent course only in patients with IGHV-mutated CLL.
    No preview · Article · Aug 2011 · Leukemia & lymphoma
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Small cell carcinoma (SCC) of the pancreas is a rare malignancy with a poor prognosis. We established and characterized a primary human pancreatic SCC cell line, designated A99. Cancer tissue was obtained from the liver metastasis of an SCC of the pancreas and xenografted into nude mice. The first-pass xenograft was then used to establish a cultured cell line called A99. Cellular morphology, immunohistochemical properties, tumorigenic potential, and genetic alterations of this new line were characterized. A99 cells grew consistently in culture, formed colonies in soft agar, and grew as subcutaneous xenografts when inoculated into nude mice. A99 cells were positive for pancytokeratin, synaptophysin, chromogranin A, neuron-specific enolase, CD57 (Leu7), CD56, protein gene product 9.5, thyroid transcription factor 1, Smad4, p53, and p16, but not for CD99, PDX-1, or retinoblastoma protein. Sequencing analysis revealed homozygous point mutations of KRAS and TP53. Cytogenetic analysis revealed complex chromosomal rearrangements including marker chromosomes. A99 is the first cell line reported to be derived from a primary SCC of the pancreas. The establishment of this cell line may serve as a useful model system for studying the cell biology of this rare cancer or for evaluating novel targeted agents in preclinical models.
    Full-text · Article · Aug 2011 · Pancreas
  • Source
    Dataset: Figure S3
    [Show abstract] [Hide abstract]
    ABSTRACT: Structure of the human DKK1 promoter region. The human DKK1 promoter has a TATA box near the transcription site (TSS) and four GATA binding motif within 1 kb upstream from TSS. *, putative GATA binding site No. 1 (reverse); #, putative GATA binding site No. 2 (forward); ▴, putative GATA binding site No. 3 (forward); ¢, putative GATA binding site No. 4 (reverse). TATA box is enclosed by box. Sequences for the primer sets that be used in CHIP assay were indicated in bold type. TSS, transcription start site; Primer F1 (forward) and R1 (reverse) for amplifying the region containing three GATA binding motifs No. 1, 2 and 3. Primer F2 (forward) and R2 (reverse) for amplifying the region containing one GATA binding motif No. 4. The same region also contains four TCF-binding sites: TBE1, TBE2, TBE3 and TBE4. (TIF)
    Preview · Dataset · Jul 2011
  • Source
    Dataset: File S1
    [Show abstract] [Hide abstract]
    ABSTRACT: Oligonucleotide Sequences Used in Current Study. (DOC)
    Preview · Dataset · Jul 2011
  • Source
    Dataset: Figure S2
    [Show abstract] [Hide abstract]
    ABSTRACT: RT-PCR for GATA6 expression in human normal and pancreatic cancer cell lines. β-actin is used as a loading control for each sample. (TIF)
    Preview · Dataset · Jul 2011
  • Source
    Dataset: Figure S1
    [Show abstract] [Hide abstract]
    ABSTRACT: Western Blotting for GATA6 and DKK1 in Pancreatic Cancer Cell Lines. The specificity of antibodies against GATA6 and DKK1 is shown by full-screen Western blotting. Exposures of both 2 and 5 minutes are shown. (TIF)
    Preview · Dataset · Jul 2011
  • Source
    Dataset: Figure S5
    [Show abstract] [Hide abstract]
    ABSTRACT: Effect of Dickkopf-1 on cell proliferation in Pancreatic Cancer Cell Lines. Panc1, A10.7 and Hs766t cell lines that have relatively high DKK1 expression levels were transfected with a mock siRNA or DKK1 siRNA and then subjected to (A) real-time PCR for DKK1 expression in DKK1-knock down cells or (B) cell proliferation assays. (C) Real-time PCR for DKK1 expression in Panc 4.14 cells after transfection with a mock or DKK1 expression vector. When appropriate, all experimental data shown represents the summary three independent experiments. **, p < 0.01; ***, p < 0.001. (TIF)
    Preview · Dataset · Jul 2011
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1.
    Full-text · Article · Jul 2011 · PLoS ONE
  • Source
    Dataset: Figure S4
    [Show abstract] [Hide abstract]
    ABSTRACT: Expression and Methylation of Dickkopf-1 in Pancreatic Cancer Cell Lines. (a) Quantitative RT-PCR of DKK1-4 in immortalized normal and pancreatic cancer cell lines. All values are normalized to levels in HPNE. (b) Promoter methylation of DKK1 in immortalized normal and pancreatic cancer cell lines.Methylation is detected in cell lines MiaPaca2, Hs766t, Panc 4.14, PK8 and PK9. All primer sequences are provided in Supplemental Information. (TIF)
    Preview · Dataset · Jul 2011

Publication Stats

11k Citations
1,193.44 Total Impact Points

Institutions

  • 1988-2014
    • Johns Hopkins Medicine
      • • Department of Pathology
      • • Department of Gynecology & Obstetrics
      Baltimore, Maryland, United States
  • 1984-2013
    • Johns Hopkins University
      • • Department of Pathology
      • • Division of Gastroenterology
      • • Department of Medicine
      • • Department of Physiology
      Baltimore, Maryland, United States
  • 2001
    • University of Nice-Sophia Antipolis
      Nice, Provence-Alpes-Côte d'Azur, France
  • 1997
    • Hopkins School
      New Haven, Connecticut, United States
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1995
    • University of Chicago
      Chicago, Illinois, United States
  • 1994
    • National Institute on Aging
      Baltimore, Maryland, United States
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1986-1988
    • The Children's Hospital of Philadelphia
      • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
    • Wistar Institute
      • Melanoma Research Center
      Filadelfia, Pennsylvania, United States
  • 1987
    • Pennsylvania State University
      University Park, Maryland, United States