Joseph Testa
Fox Chase Cancer Center, Cancer Biology, Faculty Member
Research Interests:
are reports of LAM recurrence after lung transplantation. Whether shown to contain Y chromosomes (10, 11). These findings these recurrent LAM cells arise from the patient or the lung trans- suggested that a circulating growth factor... more
are reports of LAM recurrence after lung transplantation. Whether shown to contain Y chromosomes (10, 11). These findings these recurrent LAM cells arise from the patient or the lung trans- suggested that a circulating growth factor induced the LAM plant donor is an area of controversy. We used microsatellite marker cell phenotype. fingerprinting and TSC2 gene mutational analysis to study
Research Interests:
The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that... more
The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-αβTCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonst...
Research Interests:
The aim of this study was to determine the role of AKT as a therapeutic target in ovarian clear cell carcinoma (CCC), an aggressive, chemoresistant histologic subtype of ovarian cancer. AKT activation was assessed by immunohistochemistry... more
The aim of this study was to determine the role of AKT as a therapeutic target in ovarian clear cell carcinoma (CCC), an aggressive, chemoresistant histologic subtype of ovarian cancer. AKT activation was assessed by immunohistochemistry (IHC) using human tissue microarrays of primary ovarian cancers, composed of both CCC and serous adenocarcinoma (SAC). The growth-inhibitory effect of AKT-specific targeting by the small-molecule inhibitor, perifosine, was examined using ovarian CCC cell lines in vitro and in vivo. Finally, the activity of perifosine was examined using in CCC-derived tumors that had acquired resistance to anti-VEGF or chemotherapeutics such as bevacizumab or cisplatin, respectively. Interestingly, AKT was frequently activated both in early-stage and advanced-stage CCCs. Treatment of CCC cells with perifosine attenuated the activity of AKT-mTORC1 signaling, inhibited proliferation, and induced apoptosis. The effect of perifosine was more profound under conditions of ...
Research Interests:
Multidrug resistance-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) are closely related mammalian ATP-binding cassette transporters that export organic anions from cells. Transfection studies have... more
Multidrug resistance-associated protein (MRP) and canalicular multispecific organic anion transporter (cMOAT) are closely related mammalian ATP-binding cassette transporters that export organic anions from cells. Transfection studies have established that MRP confers resistance to natural product cytotoxic agents, and recent evidence suggests the possibility that cMOAT may contribute to cytotoxic drug resistance as well. Based upon the potential importance of these transporters in clinical drug resistance and their important physiological roles in the export of the amphiphilic products of phase I and phase II metabolism, we sought to identify other MRP-related transporters. Using a degenerate PCR approach, we isolated a cDNA that encodes a novel ATP-binding cassette transporter, which we designated MOAT-B. The MOAT-B gene was mapped using fluorescence in situ hybridization to chromosome band 13q32. Comparison of the MOAT-B predicted protein with other transporters revealed that it i...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Three patients with acute leukemia, disseminated intravaslar coagulation, and a specific acquired chromosome abnormality (t(15;17)) were found by transmission electron microscopy to have the typical distribution of granules seen in... more
Three patients with acute leukemia, disseminated intravaslar coagulation, and a specific acquired chromosome abnormality (t(15;17)) were found by transmission electron microscopy to have the typical distribution of granules seen in promyelocytes. However, the average granule sizes were 120, 170 and 180 nm, respectively, for the three patients, significantly less than the 250-nm resolution of light microscopy. We regard the leukemia
Research Interests:
Research Interests:
Research Interests:
Research Interests:
AKT2 is a serine/threonine kinase implicated in human ovarian and pancreatic cancers. AKT2 is activated by a variety of growth factors and insulin via phosphatidylinositol 3-kinase (PI3K). However, its normal cellular role is not well... more
AKT2 is a serine/threonine kinase implicated in human ovarian and pancreatic cancers. AKT2 is activated by a variety of growth factors and insulin via phosphatidylinositol 3-kinase (PI3K). However, its normal cellular role is not well understood. To gain insight into the function of AKT2, we performed yeast two-hybrid system to screen for interacting proteins. Using this technique, we identified a
Research Interests:
Krev-1/rap1A is an evolutionarily conserved Ras-family GTPase whose cellular function remains unclear, but which has been proposed to function as a tumor suppressor gene, and may act as a Ras antagonist. To elucidate Krev-1 activity, we... more
Krev-1/rap1A is an evolutionarily conserved Ras-family GTPase whose cellular function remains unclear, but which has been proposed to function as a tumor suppressor gene, and may act as a Ras antagonist. To elucidate Krev-1 activity, we have used LexA-Krev-1 in a two-hybrid screen of a HeLa cell cDNA library. Of the two cDNA classes isolated, one contained a single isolate
Research Interests: Gene expression, Signal Transduction, Gene Mapping, Humans, Oncogene, and 16 moreHomology, Gene, Clinical Sciences, Molecular cloning, Gen, Tumor Suppressor Gene, HeLa cells, Amino Acid Profile, Amino Acid Sequence, Base Sequence, Genetic Mapping, Gtp Binding Proteins, Full Length Movies, cDNA library, Gene Expression Regulation, and Tissue Specificity
The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their in- creased growth and viability. Based upon... more
The ligand hepatocyte growth factor/scatter factor (HGF) and its receptor tyrosine kinase, c-Met, are highly expressed in most human malignant mesotheliomas (MMs) and may contribute to their in- creased growth and viability. Based upon our observation that RNA silencing of fos-related antigen 1 (Fra-1) inhibited c-met expression in rat mesotheliomas (1), we hypothesized that Fra-1 was a key player in
Research Interests:
The first measurements of the 1 / f-noise spectrum in copper oxide superconductors are presented. The key features of our results are (1) no noise is found in the superconducting state, (2) in the normal state the noise is large,... more
The first measurements of the 1 / f-noise spectrum in copper oxide superconductors are presented. The key features of our results are (1) no noise is found in the superconducting state, (2) in the normal state the noise is large, comparable in magnitude to that in metal-...
Research Interests:
Renal oncocytosis is a rare condition characterized by the presence of numerous oncocytomas and oncocytic changes in the renal tubules. Other than oncocytomas associated with the Birt-Hogg-Dube (BDH) syndrome, the genetics of oncocytosis... more
Renal oncocytosis is a rare condition characterized by the presence of numerous oncocytomas and oncocytic changes in the renal tubules. Other than oncocytomas associated with the Birt-Hogg-Dube (BDH) syndrome, the genetics of oncocytosis is not known. Whether oncocytomas and oncocytosis are similar to BDH syndrome, in which the tumors diploid (as most oncocytomas are), or show chromosomal losses may be
Research Interests:
Previous DNA analyses have demonstrated that 9pl3-p22 is a frequent site of chromosomal loss in leukemia, glioma, melanoma, and lung and bladder carcinomas. Recent cytogenetic studies have revealed recurrent alterations of 9p in malignant... more
Previous DNA analyses have demonstrated that 9pl3-p22 is a frequent site of chromosomal loss in leukemia, glioma, melanoma, and lung and bladder carcinomas. Recent cytogenetic studies have revealed recurrent alterations of 9p in malignant mesothelioma (MM). We have performed gene dosage studies of 23 MM cell lines, using probes for several 9p21-p22 loci (IFNB, IFNA/IFNW, D9S3, D9S126, D9S169, and D9S171
Research Interests:
Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle... more
Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the α-chain of hepatocyte growth factor. The therapeutic potential of NK4 has been demonstrated in a variety of tumor types. However, the mechanisms by which NK4 inhibits tumor growth have not been well delineated. In this study, it is shown that the NK4 adenovirus (Ad-NK4) potently inhibits cell viability, invasiveness and tumorigenicity of human MM cells. Significantly, this study demonstrates for the first time that Ad-NK4 inhibits cancer stem-like cell (CSC) properties as assessed by spheroid formation assay, side population analysis and flow cytometric sorting of CD24 cells. In addition to inhibiting phosphorylation of Met and AKT, Ad-NK4 markedly suppressed the active form of β-catenin, a key mediator of both Wnt and AKT pathways. It...
Research Interests:
Research Interests:
Research Interests: Research Design, Breast Cancer, Quality of life, Biopsy, Humans, and 20 moreFemale, Feasibility Studies, Male, Radionuclide imaging, Mastectomy, Lancet, Clinical Sciences, Aged, Middle Aged, Adult, Prognosis, Reproducibility of Results, Radiopharmaceuticals, Sentinel Node Biopsy, Sensitivity and Specificity, New England Journalof Medicine, Predictive value of tests, Axilla, Lymphatic System, and Lymph nodes
(ra,blFN) would reduce the proportion of bone marrow Phil- adelphia chromosome (Ph) cells in chronic-phase chronic myelogenous leukemia (CML) by treating 107 previously untreated patients dailywith ra,blFN at 5 X 1 O6IU/mZsub-... more
(ra,blFN) would reduce the proportion of bone marrow Phil- adelphia chromosome (Ph) cells in chronic-phase chronic myelogenous leukemia (CML) by treating 107 previously untreated patients dailywith ra,blFN at 5 X 1 O6IU/mZsub- cutaneously. Patients with complete remission, partial re- mission, or partial hematologic remission received treat- ment until progression; those with progressive disease were taken off study and observed for
Research Interests:
Research Interests:
Malignant mesotheliomas (MMs) are very aggressive tumors that respond poorly to standard chemotherapeutic approaches. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in tumor aggressiveness, in part by mediating... more
Malignant mesotheliomas (MMs) are very aggressive tumors that respond poorly to standard chemotherapeutic approaches. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in tumor aggressiveness, in part by mediating cell survival and reducing sensitivity to chemotherapy. Using antibodies recognizing the phosphorylated/activated form of AKT kinases, we observed elevated phospho-AKT staining in 17 of 26 (65%) human MM specimens. In addition,
Research Interests:
The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SDI1 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to... more
The cyclin-dependent kinase inhibitor p21WAF1/CIP1/SDI1 (p21) plays a crucial role in DNA repair, cell differentiation, and apoptosis through regulation of the cell cycle. A2780 human ovarian carcinoma cells, which are sensitive to cisplatin and paclitaxel, express wild-type p53 and exhibit a p53-mediated increase in p21 in response to the chemotherapeutic agents. Here, we demonstrate that phosphatidylinositol 3-kinase (PI3K) and its
Research Interests:
All cellular ets proteins contain a region of high amino acid identity to those found in the last two exons of the ets-i gene (C domain). We have identified and characterized a new member of the human ETS gene family, ERGB. The ERGB gene... more
All cellular ets proteins contain a region of high amino acid identity to those found in the last two exons of the ets-i gene (C domain). We have identified and characterized a new member of the human ETS gene family, ERGB. The ERGB gene shows extensive amino acid identity to the human ERG and the mouse FIi-i genes. The ERGB
Research Interests:
The p53 tumor suppressor gene is frequently mutated and the K-ros oncogene is occasionally mutated in primary specimens of human lung carcinomas. These mutated genes also cooperate in the immortalization and neoplastic transformation of... more
The p53 tumor suppressor gene is frequently mutated and the K-ros oncogene is occasionally mutated in primary specimens of human lung carcinomas. These mutated genes also cooperate in the immortalization and neoplastic transformation of rodent cells. To determine whether these mutations are necessary for maintenance of the immortalized and/or neoplastically transformed states of human bronchial epithelial cells, the p53 gene
Research Interests:
The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. An ever-increasing list of AKT substrates has precisely... more
The AKT1, AKT2, and AKT3 kinases have emerged as critical mediators of signal transduction pathways downstream of activated tyrosine kinases and phosphatidylinositol 3-kinase. An ever-increasing list of AKT substrates has precisely defined the multiple functions of this kinase family in normal physiology and disease states. Cellular processes regulated by AKT include cell proliferation and survival, cell size and response to nutrient availability, intermediary metabolism, angiogenesis, and tissue invasion. All these processes represent hallmarks of cancer, and a burgeoning literature has defined the importance of AKT alterations in human cancer and experimental models of tumorigenesis, continuing the legacy represented by the original identification of v-Akt as the transforming oncogene of a murine retrovirus. Many oncoproteins and tumor suppressors intersect in the AKT pathway, finely regulating cellular functions at the interface of signal transduction and classical metabolic regulation. This careful balance is altered in human cancer by a variety of activating and inactivating mechanisms that target both AKT and interrelated proteins. Reprogramming of this altered circuitry by pharmacologic modulation of the AKT pathway represents a powerful strategy for rational cancer therapy. In this review, we summarize a large body of data, from many types of cancer, indicating that AKT activation is one of the most common molecular alterations in human malignancy. We also review mechanisms of activation of AKT kinases, examples of therapeutic modulation of the AKT pathway in animal models, and the current status of efforts to target molecular components of the AKT pathway for cancer therapy and, possibly, cancer prevention.
Research Interests:
Research Interests:
Research Interests: Gamma Rays, Multidisciplinary, Cell line, Humans, Mutation, and 15 moreFemale, Animals, Renal cell Carcinoma, Male, Karyotyping, Genetic linkage analysis, Tumor Suppressor Gene, Dose Response Relationship, Rats, Rat Model, Ionizing Radiation, Chromosome Disorders, Adenoma, Tumor Progression, and DNA sequence
Research Interests:
Research Interests:
Gene expression changes in rat asbestos-induced malignant mesothelioma (MM) cells were investigated by differential mRNA display. A mRNA transcript identified by this approach was abundant in normal rat mesothelial cells but not expressed... more
Gene expression changes in rat asbestos-induced malignant mesothelioma (MM) cells were investigated by differential mRNA display. A mRNA transcript identified by this approach was abundant in normal rat mesothelial cells but not expressed in rat MM cell lines. Northern blot analysis confirmed that this transcript is uniformly silenced in rat MM cell lines and primary tumors. Nucleotide sequence analysis revealed that this transcript is encoded by the rat glypican 3 gene (GPC3), whose human homolog is mutated in the Simpson-Golabi-Behmel overgrowth syndrome. Allelic loss at the GPC3 locus was infrequent (6.9%) in MM cell lines, and no mutations were found. GPC3 transcript levels were markedly decreased in 16 of 18 primary tumors and 17 of 22 human MM cell lines. Most of the cell lines were shown to have aberrant methylation of the GPC3 promoter region. In two of four human MM cell lines tested, GPC3 expression was restored after 2-deoxy 5-azacytidine (DAC)-mediated demethylation of its promoter region. Ectopic expression of GPC3 inhibited in vitro colony formation of human MM cells. Collectively, these data suggest that down-regulation of GPC3 is a common occurrence in MM and that GPC3, an X-linked recessive overgrowth gene, may encode a negative regulator of mesothelial cell growth.
Research Interests:
Research Interests: Cell Cycle, Pancreatic Cancer, Mitosis, Humans, Mice, and 15 moreAnimals, Oncogene, Monoclonal Antibodies, T cells, Clinical Sciences, Western blot, Cell Cycle regulation, Amino Acid Profile, Transfection, Cell Proliferation, Human Fibroblasts, Subcellular Fractions, Time Course, Nude mice, and Interphase
Research Interests: Ovarian Cancer, Transcription Factors, Gene Mapping, Cell line, Humans, and 21 moreFemale, Animals, Oncogene, C2H2 zinc fingers, Polymerase Chain Reaction, Proline, Transcription Factor, Clinical Sciences, Molecular cloning, Zinc Finger, Tumor Suppressor Gene, Rats, Epithelium, Glutamine, Amino Acid Profile, Rat Model, Amino Acid Sequence, Ovary, Cell Cycle Proteins, DNA binding proteins, and Nucleotides
AKT2, an oncogene encoding a protein serine-threonine kinase implicated in phosphatidylinositol-3-OH kinase signaling, is amplified in some human ovarian and pancreatic carcinomas. We previously demonstrated that the tumorigenicity and... more
AKT2, an oncogene encoding a protein serine-threonine kinase implicated in phosphatidylinositol-3-OH kinase signaling, is amplified in some human ovarian and pancreatic carcinomas. We previously demonstrated that the tumorigenicity and invasiveness of pancreatic ductal adenocarcinoma (PDAC) cell lines with amplified AKT2 could be markedly reduced by transfection with antisense AKT2 constructs. To evaluate further the extent of AKT2 alterations in PDAC, DNA and immunohistochemical analyses were performed to assess amplification or overexpression of AKT2, respectively, in 72 PDACs. Thirty-five PDACs were subjected to Southern analyses, and AKT2 amplification was detected in seven tumors (20%). Forty-one formalin-fixed PDAC specimens were examined immunohistochemically with an anti-AKT2 monoclonal antibody, and moderate to intense staining was observed in eight tumors (20%). AKT2 immunostaining paralleled AKT2 genomic status in each of four cases in which both Southern and immunohistochemical analyses were performed. No obvious relationship was observed between AKT2 status and tumor TNM stage or grade. These observations suggest the utility of immunohistochemical analysis in assessing alterations of AKT2 in human cancers. Furthermore, the role played by the AKT2 kinase in the signaling pathways of various mitogenic growth factors implicated in the development of pancreatic cancer suggests that alteration of AKT2 may be an important component in the pathogenesis of a substantial subset of PDACs.
Research Interests:
Research Interests:
A case with myelodysplasia in which a single clone contained both 5q- and Ph chromosomes at diagnosis is presented. The patient subsequently developed leukocytosis and at that time was found to have acquired an additional chromosomal... more
A case with myelodysplasia in which a single clone contained both 5q- and Ph chromosomes at diagnosis is presented. The patient subsequently developed leukocytosis and at that time was found to have acquired an additional chromosomal abnormality, i(17)(q10). This case illustrates the role of three different genetic changes that impart different clinical characteristics, i.e. myelodysplastic as well as myeloproliferative changes, as part of a multistep leukemogenic process.
Research Interests:
Research Interests:
Research Interests:
The incidence of malignant mesothelioma (MM) shows a strong epidemiological association with exposure to asbestos fibers. Recently, simian virus 40 (SV40) DNA sequences have been reported in MM tumor specimens from the United States and... more
The incidence of malignant mesothelioma (MM) shows a strong epidemiological association with exposure to asbestos fibers. Recently, simian virus 40 (SV40) DNA sequences have been reported in MM tumor specimens from the United States and several European countries, and the SV40 tumor virus has been implicated as a potential co-factor in the etiology of this disease. However, several large studies from the US, Finland, and Turkey did not detect SV40 sequences in MM samples. To address this discrepancy, MM specimens from Turkey and the US were analyzed in the same laboratory under identical conditions to detect the presence of SV40 DNA. We detected SV40 sequences in 4 of 11 specimens from the United States, but in none of the 9 Turkish samples examined. These findings suggest that geographical differences exist with regard to the involvement of SV40 in human tumors.
Research Interests:
The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and... more
The AKT2 gene is one of the human homologues of v-akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine-threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large-scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern-blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern-blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto-oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness.
Research Interests: Cancer, Humans, Female, Aged, Middle Aged, and 3 moreBreast carcinoma, Prognosis, and Adenocarcinoma
Research Interests:
About 80% of malignant mesotheliomas (MM) in the Western World develop in individuals with higher than background exposure to asbestos. Only a fraction of those exposed to asbestos develop mesothelioma, indicating that additional factors... more
About 80% of malignant mesotheliomas (MM) in the Western World develop in individuals with higher than background exposure to asbestos. Only a fraction of those exposed to asbestos develop mesothelioma, indicating that additional factors play a role. Simian virus 40 (SV40), a DNA tumor virus that preferentially causes mesothelioma in hamsters, has been detected in several human mesotheliomas. The expression
Research Interests:
Research Interests:
We used comparative genomic hybridization (CGH) to identify recurrent chromosomal imbalances in tumor DNA from 25 malignant ovarian carcinomas and two ovarian tumors of low malignant potential (LMP). Many of the carcinoma specimens... more
We used comparative genomic hybridization (CGH) to identify recurrent chromosomal imbalances in tumor DNA from 25 malignant ovarian carcinomas and two ovarian tumors of low malignant potential (LMP). Many of the carcinoma specimens displayed numerous imbalances. The most common sites of copy number increases, in order of frequency, were 8q24.1, 20q13.2-qter, 3q26.3-qter, 1q32, 20p, 9p21-pter, and 12p. DNA amplification was identified in 12 carcinomas (48%). The most frequent sites of amplification were 8q24.1-24.2, 3q26.3, and 20q13.2-qter. Other recurrent sites of amplification included 7q36, 17q25, and 19q13.1-13.2. The most frequent sites of copy number decreases were 5q21, 9q, 17p, 17q12-21, 4q26-31, 16q, and 22q. Underrepresentation of 17p was observed in six of 16 stage III/IV tumors, but in none of seven stage I/II tumors, suggesting that this change may be a late event associated with the transition of ovarian carcinomas to a more metastatic disease. Overrepresentation of 3q26.3-qter, 5p14-pter, 8q24.1, 9p21-pter, 20p, and 20q13.2-qter and underrepresentation of 4q26-31 and 17q12-21 also tended to be more common in advanced-stage tumors. All ten grade 3 tumors had copy number increases involving 8q24.1, compared to only three of nine grade 2 tumors. Overrepresentation of 3q26.3-qter and 20q13.2-qter was also observed at a higher frequency in high-grade tumors. One of the two LMP tumors displayed chromosomal alterations, which consisted of overrepresentation of 5p and 9p only. Taken collectively, these findings and data from other CGH studies of ovarian cancers define a set of small chromosome segments that are consistently over- or underrepresented and, thus, highlight sites of putative oncogenes and tumor suppressor genes that contribute to the pathogenesis of these highly malignant neoplasms.
Research Interests:
A detailed cytogenetic analysis of 63 non-small cell lung carcinomas (NSCLCs) was carried out for identification of recurrent chromosomal alterations. Most specimens displayed very complex karyotypes with multiple numerical and structural... more
A detailed cytogenetic analysis of 63 non-small cell lung carcinomas (NSCLCs) was carried out for identification of recurrent chromosomal alterations. Most specimens displayed very complex karyotypes with multiple numerical and structural changes (median number, 31). Losses of chromosomes 9 (65% of cases) and 13 (71%) were the most frequent numerical changes. Loss of the Y was often observed in tumors from males. Gain of chromosome 7 was also frequent (41%). Chromosome arms 1p, 1q, 3p, 3q, 6q, 7q, 8q, 9p, 11q, 17p, and 19q were particularly prone to rearrangement. The chromosome arm most often contributing to losses was 9p (79%). Other arms that were frequently lost included 3p, 6q, 8p, 9q, 13q, 17p, 18q, 19p, 21q, 22q, and the short arm of each acrocentric chromosome. The percentage of cases with loss of 3p was significantly higher in squamous cell carcinomas (94%) than in adenocarcinomas (60%). There was also a statistically significant increase in the proportion of cases with gains of 1q, 7p, and 11q in adenocarcinomas compared to squamous cell carcinomas. Several recurrent isochromosomes and unbalanced exchanges were found. Among these was i(5p), which was observed in nine tumors, eight of which displayed adenomatous features. An i(8q) was identified in six cases, including five adenocarcinomas. Double minutes and/or homogeneously staining regions were seen in seven specimens. These data indicate that numerous chromosome alterations contribute to the pathogenesis of NSCLC and that, amid this widespread genomic disarray, recurrent abnormalities exist that could have biological and clinical implications.
Research Interests: Lung Cancer, Humans, Female, Male, Karyotyping, and 5 moreGenes, Clinical Sciences, Aged, Middle Aged, and Adult
Research Interests:
Comparative genomic hybridization (CGH) was used in a retrospective analysis of chromosomal imbalances in frozen primary tumor specimens from 14 endometrial carcinoma patients. Chromosome changes were detected in nine cases (64%), and... more
Comparative genomic hybridization (CGH) was used in a retrospective analysis of chromosomal imbalances in frozen primary tumor specimens from 14 endometrial carcinoma patients. Chromosome changes were detected in nine cases (64%), and tumor stage and grade tended to parallel the degree of genomic imbalances. Gain of the entire long arm of chromosome 1 was observed in six cases (43%), three of which displayed only this chromosome change. Other common sites of copy number increases included 8q21-->qter (4 cases), 10p15 (4 cases), 10q11-->q24 (3 cases), and 13q21-->qter (3 cases, each with stage III disease). Two of the tumors with gains of chromosome 10 involved the whole chromosome, and this was the sole abnormality in one case. DNA amplification at 5p14-->p15 was identified in one specimen, a stage III tumor having numerous imbalances. DNA microsatellite analysis revealed multiple replication errors (RER), indicative of the RER+ phenotype, in four of 13 (31%) cases evaluated. The RER+ phenotype was observed in four of six stage la tumors but in none of seven stage Ib or stage III tumors. Multiple genomic imbalances detected by CGH were not observed in RER+ tumors but were detected in five of nine tumors without the RER+ phenotype. These investigations demonstrate the feasibility of CGH for the retrospective assessment of chromosomal changes in endometrial carcinoma specimens. Moreover, these data suggest that the etiologies in tumors with and without the RER+ phenotype may differ.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Humans, Protein Kinases, Mice, Female, Animals, and 3 moreCisplatin, Sirolimus, and Antineoplastic Agents
Research Interests: Cancer, Cell Cycle, Ovarian Cancer, Transgenic Mice, Signal Transduction, and 17 moreCell line, Protein Kinases, Mice, Female, Animals, Magnetic Resonance, Phosphorylation, Western blot, Ovarian Carcinoma, Disease Progression, Transgenic Mouse Technology, Sirolimus, Blood Vessel, Protein Kinase Inhibitors, Vascular Endothelial Growth Factor, Matrix Metalloproteinase, and Cell Growth
A review of chromosomal analyses of human lung carcinomas is presented. Karyotypic studies have revealed multiple cytogenetic changes in most small cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). In SCLCs, losses... more
A review of chromosomal analyses of human lung carcinomas is presented. Karyotypic studies have revealed multiple cytogenetic changes in most small cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). In SCLCs, losses from 3p, 5q, 13q, and 17p predominate; double minutes associated with amplification of members of the MYC oncogene family may be common late in disease. In NSCLCs, deletions of 3p, 9p, and 17p, +7, i(5)(p10), and i(8)(q10) often are reported. The recurrent deletions encompass sites of tumor suppressor genes commonly inactivated in lung carcinomas, such as CDKN2 (9p21), RB1 (13q14), and TP53 (17p13). Despite technical advances in cell culture, the rate of successful karyotypic analysis of lung carcinomas has remained low. Alternative molecular cytogenetic methods to assess chromosome changes in lung cancer, particularly comparative genomic hybridization (CGH) analysis, are discussed. Initial CGH studies confirm the existence of many of the karyotypic imbalances identified earlier in lung cancer and have revealed several recurrent abnormalities, such as 10q- in SCLC, that had not been recognized previously. The further application of such molecular cytogenetic approaches should enable investigators to define more precisely the spectrum and clinical implications of chromosome alterations in lung cancer.