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Biomedical subjects

Paola Dal Cin

Publications and source records attributed to Paola Dal Cin.

At least 19 recordsLinked to original sources
PubMed2007

Molecular analysis of the JAZF1-JJAZ1 gene fusion by RT-PCR and fluorescence in situ hybridization in endometrial stromal neoplasms.

Nonrandom cytogenetic abnormalities of chromosomes 6, 7, and 17 have been reported within low-grade endometrial stromal sarcomas (LGESSs), and among these abnormalities, the t(7;17)(p15;q21) is the most common aberration described. Previously we had shown that this translocation joins 2 genes, JAZF1 and JJAZ1, located on chromosomes 7 and 17, respectively. To determine the frequency of the t(7;17), we analyzed 4 stromal nodules and 24 LGESS by both reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization (FISH). In addition, we examined 4 cases of highly cellular leiomyoma, a benign morphologic mimic of LGESS. Overall, evidence for the JAZF1-JJAZ1 fusion was found in 60% of endometrial stromal neoplasms analyzed (8/16 ESS and 4/4 stromal nodules). One LGESS demonstrated only rearrangement of 7p15 by FISH analysis and karyotypic analysis of this case showed t(6;7)(p21;p15). The fusion was not detected in any highly cellular leiomyomas. Our data suggest that the JAZF1-JJAZ1 fusion is a frequent, although nonuniform, feature of endometrial stromal neoplasia, irrespective of benign versus malignant classification and smooth muscle differentiation. In addition, the detection of the fusion by reverse transcriptase-polymerase chain reaction or FISH for JJAZ1 at 7p15 may be diagnostically useful.

Chromosomes, Human, Pair 17↗
PubMed2006

A renal cell carcinoma with components of both chromophobe and papillary carcinoma.

We report a case of a morphologically unusual renal cell carcinoma with features of both chromophobe and papillary carcinoma. Immunohistochemical analysis of high molecular weight cytokeratins (HMWCK), cytokeratin 7 (CK7), cytokeratin 19 (CK19), c-Kit, and alpha-methylacyl-CoA racemase (AMACR) demonstrated differential profiles for the two components of the tumor, consistent with the respective patterns commonly observed for pure chromophobe and papillary renal cell carcinomas. Specifically, the chromophobe tumor cells expressed CK7 and c-Kit weakly, while HMWCK, CK19, and AMACR were not detectable. In contrast, the papillary tumor cells expressed uniformly HMWCK, CK7, and c-Kit and focally CK19 and AMACR. Fluorescence in situ hybridization analysis of nuclei isolated from paraffin-embedded tumor tissue detected monosomy 1, disomy 7, and monosomy 17, a common and characteristic finding in chromophobe carcinomas, in a majority of, but not all tumor cells, whereas a population characterized by disomy 1, trisomy 7, and trisomy 17, a frequent finding in papillary carcinoma, was not identifiable. Electron microscopic analysis revealed numerous characteristic small cytoplasmic vesicles in the chromophobe areas, which were absent in the papillary component. This case illustrates the rare coexistence of two distinct and admixed histologic types of renal cell carcinoma.

Aged↗
PubMed2006

EWS-CREB1: a recurrent variant fusion in clear cell sarcoma--association with gastrointestinal location and absence of melanocytic differentiation.

PURPOSE: Clear cell sarcoma (CCS) usually arises in the lower extremities of young adults and is typically associated with a t(12;22) translocation resulting in the fusion of EWS (EWSR1) with ATF1, a gene encoding a member of the cyclic AMP-responsive element binding protein (CREB) family of transcription factors. CCS arising in the gastrointestinal tract is rare and its pathologic and molecular features are not well defined. EXPERIMENTAL DESIGN: We report a novel variant fusion of EWS to CREB1, a gene at 2q32 encoding another CREB family member highly related to ATF1, detected in three women with gastrointestinal CCS. All three cases contained an identical EWS-CREB1 fusion transcript that was shown by reverse transcription-PCR. In two of the cases tested, EWS gene rearrangement was also confirmed by fluorescence in situ hybridization and the EWS-CREB1 genomic junction fragments were isolated by long-range DNA PCR. RESULTS: Morphologically, all three tumors lacked melanin pigmentation. By immunohistochemistry, there was a strong and diffuse S100 protein reactivity, whereas all melanocytic markers were negative. Ultrastructurally, two of the cases lacked melanosomes. The melanocyte-specific transcript of MITF was absent in two cases, and only weakly expressed in the third case. The Affymetrix gene expression data available in one case showed lower expression of the melanocytic genes MITF, TYR, and TYRP1, compared with four EWS-ATF1-positive CCSs of non-gastrointestinal origin. CONCLUSIONS: EWS-CREB1 may define a novel subset of CCS that occurs preferentially in the gastrointestinal tract and shows little or no melanocytic differentiation. Thus, evidence of melanocytic lineage or differentiation is not a necessary feature of sarcomas with gene fusions involving CREB family members.

Activating Transcription Factor 1↗
PubMed2006

FAS death domain deletions and cellular FADD-like interleukin 1beta converting enzyme inhibitory protein (long) overexpression: alternative mechanisms for deregulating the extrinsic apoptotic pathway in diffuse large B-cell lymphoma subtypes.

PURPOSE: Large B-cell lymphomas (LBCL) arise from normal antigen-exposed B cells at germinal center (GC) or post-GC stages of differentiation. Negative selection of normal low-affinity or self-reactive GC B-cells depends on CD95 (FAS)-mediated apoptosis. FAS mutations that result in deletion of the cytoplasmic death domain destabilize the trimeric receptor and inhibit FAS-mediated apoptosis. This apoptotic pathway is also inhibited when the nuclear factor kappaB (NFkappaB) target, cellular FADD-like interleukin 1beta converting enzyme inhibitory protein (cFLIP), interacts with the death-inducing signaling complex, assembled around the FAS death domain. Herein, we ask whether FAS death domain mutations and NFkappaB-mediated overexpression of cFLIP represent alternative mechanisms for deregulating the extrinsic apoptotic pathway in LBCL subtypes defined by gene expression profiling [oxidative phosphorylation, B-cell receptor/proliferation, and host response diffuse LBCLs and primary mediastinal LBCLs]. EXPERIMENTAL DESIGN: The FAS receptor was sequenced, FAS death domain mutations identified, and cFLIP expression assessed in a series of primary LBCLs with gene expression profiling-defined subtype designations and additional genetic analyses [t(14;18) and t(3;v)]. RESULTS: FAS death domain deletions were significantly more common in oxidative phosphorylation tumors, which also have more frequent t(14;18), implicating structural abnormalities of either the extrinsic or intrinsic pathway in this diffuse LBCL subtype. In marked contrast, host response tumors, which have up-regulation of multiple NFkappaB target genes and increased NFkappaB activity, express significantly higher levels of cFLIP(long). CONCLUSIONS: These data suggest that the gene expression profiling-defined LBCL subtypes have different mechanisms for deregulating FAS-mediated cell death and, more generally, that these tumor groups differ with respect to their underlying genetic abnormalities.

Apoptosis↗
PubMed2006

Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features.

Cytogenetic analysis of uterine leiomyomata (UL) shows that about 40% of these benign tumors have simple, clonal chromosomal rearrangements. In contrast, their presumed malignant counterpart, leiomyosarcomas (LMSs), typically has complex numerical and structural abnormalities. Several variants of benign uterine smooth-muscle tumors are defined by histologic phenotypes intermediate between typical UL and LMS, and currently, little is known about their cytogenetic and molecular genetic features. From a subset of more than 800 karyotyped ULs, we identified a group of nine cases exhibiting near-diploid karyotypes with loss of almost the entire short (p) arm of chromosome 1 [i.e., del(1)(p11p36)]. Loss of 1p was often associated with other aberrations, particularly loss of chromosomes 19 and/or 22. Of eight UL for which the histologic diagnosis was known, four were diagnosed as cellular UL; one displayed both hypercellularity and nuclear atypia. Loss of heterozygosity (LOH) analysis for chromosomal regions 1p36.23 and 1p21.1 demonstrated allelic loss for either a portion or the majority of 1p in 5 of 10 additional archival UL diagnosed with either cellular or atypical histology. RNA from two UL with loss of 1p was profiled using Affymetrix GeneChips, and those profiles were compared to our previously reported smooth-muscle tumor expression profile. The transcriptional profiles of tumors with 1p deletion were more similar to those of leiomyosarcoma than to profiles of myometrium and UL, as determined by hierarchical cluster analysis. Comparison of the transcriptional profiles for UL with and without 1p-- revealed 53 genes with differential regulation. Loss of 1p appears to define a subgroup of UL distinct from those previously recognized. Furthermore, 1p-- appears to be associated with a specific histologic phenotype. The similarity between the transcriptional profiles of LMS and UL with 1p-- suggests the possibility of a common pathogenetic mechanism.

Chromosome Aberrations↗
PubMed2006

Mantle cell lymphoma arising within primary nodal marginal zone lymphoma: a unique presentation of two uncommon B-cell lymphoproliferative disorders.

Mantle cell lymphoma and primary nodal marginal zone lymphoma are uncommon tumors thought to arise within discrete anatomic compartments of the B-cell follicle. We report an unusual composite lymphoma comprised of these two neoplasms within an isolated lymph node in a 72-year-old woman. Strikingly, both tumors were completely confined to the respective microanatomic sites of their proposed nonneoplastic lymphoid counterparts, in keeping with early detection of these lesions. The tumors were distinguished by a combination of morphologic, phenotypic, and cytogenetic findings, and the presence of dual, unrelated neoplasms was confirmed by molecular diagnostic studies. After local radiation treatment, there was no recurrence or evidence of systemic disease over more than 2 years. These findings underscore the unique characteristics of these B-cell tumors and support the notion that early in disease development both neoplasms are confined to the distinct anatomic compartments of their postulated normal B-cell counterparts.

Aged↗
PubMed2006

HMGA2 rearrangement in a case of vulvar aggressive angiomyxoma.

The histogenesis of aggressive angiomyxoma, an uncommon mesenchymal neoplasm of the vulvar, pelvic, and perineal soft tissues, is poorly understood, although the neoplastic cells exhibit a myofibroblastic phenotype. Cytogenetic studies of aggressive angiomyxoma are scarce; however, a nonrandom involvement of the 12q15 region where the high mobility group (HMG) protein HMGA2, an architectural transcription factor expressed primarily during embryogenesis, is located has been suggested. HMGA2 involvement has also been described in a variety of benign gynecologic mesenchymal neoplasms. We report an additional case of HMGA2 rearrangement in vulvar aggressive angiomyxoma, using fluorescence in situ hybridization.

Adult↗
PubMed2005

ELF4 is fused to ERG in a case of acute myeloid leukemia with a t(X;21)(q25-26;q22).

We report a novel chromosomal translocation in AML, t(X;21)(q25-26;q22), resulting in a fusion transcript between two ETS domain family members, ELF4 (at Xq25) and ERG (at 21q22). ERG has been associated previously with other fusion partners, specifically FUS and EWSR1, and implicated in both AML and Ewing's sarcoma. RT-PCR analysis of RNA isolated from bone marrow samples from the patient demonstrates that the translocation occurs within intron 1 of ERG isoform 1 (ERG-1) and intron 2 of ELF4 resulting in an in-frame fusion joining exon 2 from ELF4 with exon 2 of ERG. This is the first reported case of an ELF4-ERG fusion and identification of the specific ERG exon involved in the fusion that differentiates ERG isoforms. In addition, this case also directly implicates a new role for ELF4 in cancer.

Acute Disease↗
PubMed2005

Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes.

Aneurysmal bone cysts (ABC) are locally aggressive bone tumors that often feature chromosome 17p13 rearrangements. One of the ABC 17p13 rearrangements--t(16;17)(q22;p13)--was recently shown to create a CDH11-USP6 fusion in which the USP6/TRE17 oncogene is overexpressed through juxtaposition with the CDH11 promoter. Herein, we characterize four different ABC translocations involving 17p13, and we show that each is associated with a novel USP6 fusion oncogene. Specifically, we demonstrate that t(1;17), t(3;17), t(9;17), and t(17;17) result in USP6 fusions with TRAP150 (thyroid receptor-associated protein 150), ZNF9 (ZiNc Finger 9), Osteomodulin, and COL1A1 (Collagen 1A1), respectively. The oncogenic mechanism in these fusion genes is akin to CDH11-USP6, with the USP6 coding sequences juxtaposed to the promoter regions in each of the four novel translocation partners. The novel fusion partners appear well suited to drive USP6 transcription in the bone/mesenchymal context: osteomodulin is expressed strongly in osteoblastic lineages, and the COL1A1 promoter has an oncogenic role in the mesenchymal cancer dermatofibrosarcoma protuberans. In summary, these studies show that USP6 oncogenic activation results from heterogeneous genomic mechanisms involving USP6 transcriptional upregulation by juxtaposition with ectopic promoters.

Bone Cysts, Aneurysmal↗
PubMed2005

Monophasic synovial sarcoma of the liver.

We report a hepatic monophasic synovial sarcoma in a 60-year-old woman who presented with right upper quadrant pain subsequent to an intrahepatic bleed from a highly vascular tumor mass. Imaging studies showed a dominant tumor mass in the right hepatic lobe with multiple satellite nodules. A detailed physical examination and radiologic workup failed to reveal a primary tumor elsewhere. A right partial hepatectomy was performed with a preoperative differential diagnosis of angiosarcoma versus hepatocellular carcinoma. The morphologic, immunophenotypic, and cytogenetic findings (t(X;18)(p11.2;icq11.2)) were consistent with a monophasic synovial sarcoma. Postoperative clinical evaluation of the extremities and a positron emission tomographic scan performed 4 weeks after surgery showed no evidence of recurrent or metastatic disease. The patient was started on an aggressive 4-drug chemotherapy regimen, but died 3 months thereafter from widespread metastatic disease. No autopsy was performed. The presence of multiple lesions in the liver certainly suggests the possibility of metastatic disease. It would, however, be very unusual for a synovial sarcoma to present as an occult primary, and the negative radiologic workup 1 month after the partial hepatectomy also argues against this possibility. The clinical presentation, radiographic findings, and subsequent course in this patient was therefore most consistent with a primary monophasic synovial sarcoma of the liver.

Carcinoma, Hepatocellular↗
PubMed2004

Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with recognized variability in clinical outcome, genetic features, and cells of origin. To date, transcriptional profiling has been used to highlight similarities between DLBCL tumor cells and normal B-cell subtypes and associate genes and pathways with unfavorable outcome. To identify robust and highly reproducible DL-BCL subtypes with comprehensive transcriptional signatures, we used a large series of newly diagnosed DLBCLs, whole genome arrays, and multiple clustering methods. Tumors were also analyzed for known common genetic abnormalities in DLBCL. There were 3 discrete subsets of DLBCL-"oxidative phosphorylation," "B-cell receptor/proliferation," and "host response" (HR)-identified characterized using gene set enrichment analysis and confirmed in an independent series. HR tumors had increased expression of T/natural killer cell receptor and activation pathway components, complement cascade members, macrophage/dendritic cell markers, and inflammatory mediators. HR DLB-CLs also contained significantly higher numbers of morphologically distinct CD2+/CD3+ tumor-infiltrating lymphocytes and interdigitating S100+/gamma interferon-induced lysosomal transferase-positive (GILT+) CD1a-/CD123- dendritic cells. The HR cluster shared features of histologically defined T-cell/histiocyte-rich B-cell lymphoma, including fewer genetic abnormalities, younger age at presentation, and frequent splenic and bone marrow involvement. These studies identify tumor microenvironment and host inflammatory response as defining features in DLBCL and suggest rational treatment targets in specific DLBCL subsets.

Cluster Analysis↗
PubMed2004

Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF.

Benign uterine leiomyomata are the most common tumors in women of reproductive age. One recurring chromosomal aberration in uterine leiomyomata is rearrangement of 10q22. Chromosome 10 breakpoints were mapped by fluorescence in situ hybridization to intervals ranging from 8.9 to 72.1 kb within the third intron of MORF (monocytic leukemia zinc finger protein-related factor or MYST4) in four uterine leiomyomata tested. Additional Southern hybridization experiments confirmed that the breakpoint lies within the third intron and narrowed the interval to 2.1 kb in one uterine leiomyomata. MORF is a member of the MYST family of histone acetyltransferase and previously has been found rearranged in some types of acute myeloid leukemia (AML). This is the first instance in which disruption of a histone acetyltransferase has been reported in another tumor type. The breakpoints in uterine leiomyomata would fall in the NH2-terminal portion of the protein between a conserved domain found in histones H1 and H5 and the PHD zinc fingers, the CH2CH zinc finger, or the CoA binding site, which is distinct from the breakpoints reported in AML. Mapping of the 17q21 breakpoint by fluorescence in situ hybridization within a specific region in three tumors revealed several positional candidates including GCN5L2, a gene with histone acetyltransferase activity similar to those fused to MORF in AML. Of note, two of three uterine leiomyomata were of the cellular subtype. Involvement of MORF in four uterine leiomyomata with chromosomal rearrangements involving 10q22 and 17q21 suggests a role for this histone acetyltransferase and altered chromatin regulation in uterine mesenchymal neoplasia.

Acetyltransferases↗
PubMed2004

USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst.

Aneurysmal bone cyst (ABC) is a locally aggressive osseous lesion that typically occurs during the first two decades of life. ABC was regarded historically as a nonneoplastic process, but recent cytogenetic data have shown clonal rearrangements of chromosomal bands 16q22 and 17p13, indicating a neoplastic basis in at least some ABCs. Herein we show that a recurring ABC chromosomal translocation t(16;17)(q22;p13) creates a fusion gene in which the osteoblast cadherin 11 gene (CDH11) promoter region on 16q22 is juxtaposed to the entire ubiquitin-specific protease USP6 (Tre2) coding sequence on 17p13. CDH11-USP6 fusion transcripts were demonstrated only in ABC with t(16;17) but other ABCs had CDH11 or USP6 rearrangements resulting from alternate cytogenetic mechanisms. CDH11 is expressed strongly in bone, and our findings implicate a novel oncogenic mechanism in which deregulated USP6 transcription results from juxtaposition to the highly active CDH11 promoter.

Adolescent↗
PubMed2004

Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling.

Uterine smooth muscle tumors range from the very common benign leiomyoma to the uncommon, but frequently lethal, leiomyosarcoma. Morphological and clinical differences between these tumors are presumed to result from differences in gene expression. To test this hypothesis, RNAs from four normal uterine myometria, seven uterine leiomyomas, and nine uterine leiomyosarcomas were profiled using microarrays of oligonucleotides representing about 7,000 unique probe sets. RNAs whose levels distinguished any of the three sample types were selected by analysis of variance (ANOVA). The 153 (2.2% of the total) probe sets representing 146 unique genes with the highest test statistic selected for further analysis met minimum ratio and range thresholds between groups. Cluster analysis distinguished benign and malignant samples at the first node, and myometrium and leiomyoma were resolved in a secondary node. Downregulation of specific genes in uterine leiomyosarcoma was the most common pattern of differential gene expression selected by the three-way ANOVA. Four extrauterine leiomyosarcomas had profiles most similar to that of the uterine leiomyosarcomas. Functional analysis of the 146 genes did not reveal any strong biological theme. These genes were distributed throughout the genome, but there was slight overrepresentation of genes on 1p and 2q. These genes define a tumor signature for uterine smooth muscle neoplasia, and they suggest that the molecular pathways in leiomyoma and leiomyosarcoma are distinct.

Chromosome Banding↗