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G Sozzi

Publications and source records attributed to G Sozzi.

At least 19 recordsLinked to original sources
PubMed2000

A novel zinc finger gene is fused to EWS in small round cell tumor.

Ewing sarcoma family of tumors share recurrent translocations that fuse EWS from 22q12 to five different members of transcription factors namely FLI-1, ERG, ETV1, E1AF and FEV. Different classes of DNA binding proteins, ATF1, WT1 and CHOP are fused to EWS generating distinct tumor phenotypes: clear cell sarcoma, desmoplastic small round cell tumor, and myxoid liposarcoma, respectively. We have cloned a novel gene located at 22q12 fused to EWS by a submicroscopic inversion of 22q in a small round cell sarcoma showing a translocation (t(1;22)(p36.1;q12). The gene, designated ZSG (Zinc finger Sarcoma Gene), is a putative Cys2-His2 zinc finger protein which contains a POZ transcriptional repressor-like domain at the N-terminus. The rearrangement involves intron 8 of EWS and exon 1 of ZSG creating a chimeric sequence containing the transactivation domain of EWS fused to zinc finger domain of ZSG. This product lacks the transcriptional repressor domain at the N-terminus of ZSG. A rearrangement of the second ZSG allele was also found in tumor cells. This is the first example of an intra-chromosomal rearrangement of chromosome 22, undetectable by cytogenetics, activating EWS in soft tissue sarcoma.

Adolescent↗
PubMed2000

Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms.

The phosphatase 2A (PP2A) is one of the major cellular serine-threonine phosphatases. It was recently shown that the gene encoding for the beta isoform of its subunit A, PPP2R1B, is altered in human lung and colorectal carcinomas, suggesting a role in human tumorigenesis. Here, we report the detection of mutations in breast, lung carcinomas and melanomas in the genes of both alpha (PPP2R1A) and beta isoforms. Mutations affecting PPP2R1B were found in four breast carcinomas, while mutations in PPP2R1A were found in carcinomas of the breast and of the lung and in one melanoma. Most of the mutations affecting PPP2R1B were exons deletions, suggesting abnormal splicing. These splicing abnormalities were detected in tumor samples in the absence of the normal splicing product, and were not found in several normal controls. In one case, a homozygous deletion present in tumor DNA, and not in the matched normal control was demonstrated. Mutations affecting the PPP2R1A gene were nucleotide substitutions changing highly conserved amino acids and one frame-shift. Although the frequency of alterations is low, the inclusion of both isoforms of subunit A in the genes mutated in human cancer and the addition of breast cancer to the list of neoplasms in which PPP2R1B is altered, strengthen the potential role of PP2A in human tumorogenesis.

Amino Acid Substitution↗
PubMed2000

Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma.

Synovial sarcomas (SS) are characterized by a chromosomal translocation t(X;18)(p11.2;q11.2) which usually fuses the SYT gene from chromosome 18 to SSX1 or SSX2 genes on chromosome X. Also, a variant SYT-SSX4 fusion gene has recently been shown in a single SS case. In addition to these cytogenetic changes, bcl-2 expression, as assessed by immunohistochemistry, has been reported to be an almost general constitutive alteration of SS. In the present work, we analyze a series of 36 SS surgical samples (from 34 patients) by RT-PCR for the presence of the SYT-SSX1 or the SYT-SSX2 fusion transcript. The analysis was extended to SYT-SSX4 on SYT-SSX1-negative and SYT-SSX2-negative cases only. Our results showed a significant correlation between the SYT-SSX2 fusion and the monophasic SS histologic subtype. SYT-SSX1 fusion transcripts were present in both monophasic and biphasic tumors. The SYT-SSX4 fusion type was detected in a single monophasic SS. In the same series of SS cases, we also confirmed and extended the previously reported constitutive expression of bcl-2 protein, by using both immunohistochemical and western blot analysis. Moreover, we demonstrated that the BCL-2 gene is not rearranged or amplified at genomic level, indicating that the high levels of bcl-2 expression observed in SS might result from transcriptional activation of the gene and/or protein stabilization. Finally, we show that bcl-2 is not phosphorylated in tumors from patients who had been preoperatively treated with radio/chemotherapy, in tumors from untreated patients, or in an SS cell line (CME-1) after in vitro treatment with cytotoxic concentrations of DNA-damaging agents or taxanes. These data indicate that SS cells are unable to activate an apoptosis pathway involving bcl-2 phosphorylation/inactivation and may provide a possible explanation for the limited effectiveness of conventional pharmacological treatments of this tumor type.

Adolescent↗
PubMed2000

The expression of MDM2/CDK4 gene product in the differential diagnosis of well differentiated liposarcoma and large deep-seated lipoma.

Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12q13-15, whereas well differentiated liposarcomas (WDL) show supernumerary ring and giant marker chromosomes, known to contain amplified 12q sequences. The tight correlation between the presence of ring chromosomes and both amplification and overexpression of MDM2 and CDK4 genes suggests the exploration of the possibility that immunocytochemistry (ICC) might assist in the differential diagnosis of lipoma-like well differentiated liposarcomas (LL-WDL) and large deep-seated lipomas (LDSL). For this purpose, 21 cases of the former and 19 cases of the latter tumours were analysed by ICC and, according to the availability of material, by molecular and cytogenetic approaches. All lipomas displayed a null MDM2/CDK4 phenotype, whereas all LL-WDL showed MDM2/CDK4 or CDK4 phenotypes. Southern blot analysis performed on 16 suitable cases, complemented by fluorescence in situ hybridization and classical cytogenetic analysis in 11 cases, was consistent with, and further supported the immunophenotyping data. In conclusion, MDM2/CDK4 product-based immunophenotyping appears to represent a valuable method for the categorization of arguable LDSL.

Adult↗
PubMed2000

Morphologic-cytogenetic analysis of dedifferentiated liposarcomas with an extensive misleading leiomyosarcomatous component.

This report describes two cases of recurrent retroperitoneal dedifferentiated liposarcoma characterized by an extensive leiomyomatous component that prevented the correct diagnosis before the last recurrence. Strong immunoreactivity with smooth muscle and desmin antibodies and ultrastructural features consistent with leiomyosarcoma were observed in the spindle-cell and/or myxoid-like components in all four recurrences in case 1, and in the spindle-cell component of the primary tumor and the first recurrence in case 2. In case 1, the correct diagnosis was suggested by the cytogenetic evidence of ring markers, a hallmark of well-differentiated/dedifferentiated liposarcoma. In case 2, tumor type was yielded mainly by the morphology of the second recurrence, which consisted entirely of a well-differentiated liposarcoma, a sclerosing inflammatory variant, as confirmed by the karyotype. Reevaluation of the first two surgical specimens of each case revealed small areas consistent with well-differentiated liposarcoma that had been previously overlooked. Despite the smooth-muscle antigen profile, both cases retained an mdm2+/p53+/cdk4+ immunophenotype consistent with the genotype.

Aged↗
PubMed1999

The tumor-suppressor gene FHIT is involved in the regulation of apoptosis and in cell cycle control.

Alteration of the FHIT (fragile histidine triad) gene occurs as an early and frequent event in lung carcinogenesis. FHIT gene transfer into lung cancer cell line H460 lacking Fhit protein expression resulted in reversion of tumorigenicity. To gain insight into the biological function of FHIT, we compared the H460 cell line with its Fhit transfectants (H460/FHIT). A significant inhibition of cell growth was observed in H460/FHIT cells. The analysis of apoptosis by in situ terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling revealed a high rate of apoptosis-induced DNA strand breaks in stable clones. In situ results were confirmed by FACScan analysis that showed an apoptotic rate of 44-47% compared with a 15% level in the control H460 cells. Analysis of cell cycle-phase distribution indicated a significant G(0)/G(1) arrest and the presence of a sub-G(1) peak in the stable clones. No significant changes in Bcl2, BclX, and Bax protein expression level were observed in the transfected clones as compared with the control H460 cells whereas a 2-fold increase in Bak protein levels was noticed. An increased level of p21(waf) protein paralleled by an up-regulation of p21(waf) transcripts also was found in Fhit-expressing clones compared with the H460 cell line. No differences in p53 levels were observed in the same cells, suggesting a p53-independent effect. These data suggest that the observed growth-inhibitory effect in FHIT-reexpressing cells could be related to apoptosis and cell cycle arrest and link the tumor-suppressor activity of FHIT to its proapoptotic function.

Acid Anhydride Hydrolases↗
PubMed1999

Advances in cancer cytogenetics.

As the end of the millenium approaches, recognition of the milestones achieved in the field of cancer cytogenetics is mandatory. With regard to cancer cytogenetics, the turning century can be divided in three main era: the pre-banding period that has posed important hypothesis and technical premises, the fruitful banding era that led to the discovery of the critical chromosomal rearrangements and cloning of cancer genes and the more recent revolutionizing era of molecular cytogenetics where technological advances permit a global visualization and high-level resolution of chromosomal alterations. J. Cell. Biochem. Suppls. 32/33:173-182, 1999.

Animals↗
PubMed1999

Multifocal osteosarcoma as second tumor after childhood retinoblastoma.

We present a case of multifocal osteosarcoma (MFOS) arising 11.5 years after successful treatment of bilateral retinoblastoma. The clinical, imaging and pathological findings at onset, after therapy, and during follow-up are described. Fluorescent in situ hybridization did not reveal a deletion of the RB-1 retinoblastoma gene, although the presence of an inactivating mutation invisible to this method cannot be ruled out. The MFOS may have been a second multifocal tumor associated with the original retinoblastoma or a post-irradiation sarcoma with extensive metastases.

Adolescent↗
PubMed1999

Esthesioneuroblastoma is not a member of the primitive peripheral neuroectodermal tumour-Ewing's group.

Esthesioneuroblastoma (ENB) is a rare, site-specific, locally aggressive neuronal malignancy so far thought to belong to primitive peripheral neuroectodermal tumour-Ewing's tumour (pPNETs-ETs). Its anatomical location, in addition to morphologic, immunophenotypic and ultrastructural features, suggests its origin in the neuronal or neuroendocrine cells of the olfactory epithelium. However, the cytogenetic and molecular data currently available appear controversial on the presence of the typical translocation t(11;22)(q24;q12) and of trisomy 8, chromosomal changes that characterize the tumours belonging to the pPNETs-ETs. Herein we have analysed five ENB tumour specimens for trisomy 8 by fluorescence in situ hybridization (FISH), for the presence of EWS gene rearrangements by FISH, reverse transcription polymerase chain reaction and Southern blot analyses, as well as for the expression of the Ewing sarcoma-associated MIC2 antigen by immunohistochemistry. Neither EWS/FLI-I, EWS/ERG and EWS/FEV fusion genes nor MIC2 expression were found in any tumour, whereas trisomy 8 was found in one case only. Moreover, DNA from three cases analysed by Southern blot did not show EWS gene rearrangements. Our results support the evidence that ENB is not a member of the pPNETs-ETs.

Adult↗
PubMed1999

Role of FHIT in human cancer.

Through investigation of hemizygous and homozygous deletions in common human cancers, including lung cancer, we have cloned and characterized a gene at chromosome region 3p14.2, FHIT, that is inactivated in epithelial tumors, particularly in tumors resulting from exposure to environmental carcinogens. In some tumors, particularly those associated with environmental carcinogens, alterations in the FHIT gene occur quite early in the development of cancer. In other cancers, Fhit inactivation seems to be a later event, possibly associated with progression to more aggressive neoplasias. Thus, detection of Fhit expression by immunohistochemistry in premalignant and malignant tissues may provide important diagnostic and prognostic information.

Acid Anhydride Hydrolases↗
PubMed1999

Cytogenetic and molecular characterization of T-cell acute lymphoblastic leukemia as a second tumor after anaplastic large-cell lymphoma in a boy.

We report a case of acute T-cell lymphoblastic leukemia which developed in a boy 8.5 years after successful treatment for anaplastic large-cell lymphoma. Cytogenetic and molecular characterizations of the second tumor were performed. The cytogenetic investigation revealed a complex pattern of karyotypic alterations, including double minutes, ring chromosomes, and a duplication of the p21-32 region of chromosome 1. The microsatellite DNA analysis excluded rearrangement or deletion of the TAL1 gene in the tumor cells; rearrangements of the MLL gene were excluded by Southern blot analysis. To the best of our knowledge, this is the first report of T-cell lymphoblastic leukemia arising after treatment of CD 30+ anaplastic large-cell lymphoma. The different T-cell receptor rearrangement evidenced in the two tumors indicates that this second malignancy most likely emerged de novo, but was plausibly related to the previous radiation and chemotherapy.

Child↗
PubMed1999

Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: a prospect for early diagnosis.

A major problem in lung cancer is the lack of clinically useful tests for early diagnosis and screening of an asymptomatic population by non-invasive diagnostic procedures. Recent studies have demonstrated the possibility to detect genetic alterations in plasma or serum DNA from patients with various cancers. However, these data rely on small series of aggressive tumors with advanced-stage disease. To determine whether genetic changes in plasma are also detectable in patients with limited disease and thereby potentially useful for early detection, we looked for microsatellite instability (allele shift) and loss of heterozygosity in plasma DNA of 87 stage I-III non-small cell lung cancers and 14 controls. Combining two markers with a high rate of instability (D21S1245) and loss of heterozygosity (FHIT locus), a microsatellite alteration was observed in 49 of 87 (56%) non-small cell lung cancer tumors and in 35 of 87 (40%) plasma samples. Thirty of 49 (61%) of the cases showing tumor alterations also displayed a change in plasma DNA; in addition, 5 patients displayed alterations in plasma samples only. None of the control individuals had genetic changes in plasma. No association was found between the frequency of microsatellite alterations in plasma and tumor stage or histology. Of interest, plasma DNA abnormalities were detectable in 43% of pathological stage I cases and in 45% of tumors up to 2 cm in maximum diameter. These findings highlight new prospects for early tumor detection by noninvasive screening procedures based on the analysis of genetic changes in plasma.

Adult↗
PubMed1998

Loss of FHIT function in lung cancer and preinvasive bronchial lesions.

We previously cloned and characterized the tumor suppressor gene FHIT (fragile histidine triad) at chromosome 3p14.2 and found that this gene is altered by deletions in human tumors, including lung cancer. To assess the frequency and specificity of inactivation and its relevance in a clinical setting, we have produced antibodies against the Fhit protein and studied its expression in a series of non-small cell lung cancers and normal bronchial mucosa and a spectrum of preinvasive lesions by immunohistochemistry. The data indicate that the loss of Fhit protein is the most frequent alteration in non-small cell lung cancer (73%) and precancerous lesions (93%), is significantly higher in the tumors of smokers (75%) than in those of nonsmokers (39%; P < 0.0005), and is an independent and more frequent event than p53 overexpression in tumors and precancerous lesions (73 versus 46%). The percentage of cases lacking Fhit expression was higher in the squamous type compared to adenocarcinoma (87 versus 57%; P < 0.00001), whereas other histotypes (large cell, mucoepidermal) showed an intermediate value (69%). Loss of Fhit expression in a very high percentage of primary lung carcinomas and precancerous lesions supports the notion that FHIT alterations play an important role in the growth control of bronchial cells. FHIT inactivation is particularly important in squamous cell carcinomas that are often associated with precursor dysplastic lesions. The overall high frequency and precocity of Fhit loss in lung carcinogenesis and the development of the presently described immunohistochemical approach suggest a potential use of this gene in the early detection of lung cancer and in chemopreventive studies as an intermediate biomarker.

Acid Anhydride Hydrolases↗
PubMed1998

Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans.

As a consequence of a reciprocal translocation t(17;22)(q22;q13) and of supernumerary ring chromosomes derived from the t(17;22), a fusion between the platelet-derived growth factor b-chain (PDGF, c-sis proto-oncogene) and the collagen type 1A1 (COL1A1) genes has been recently described in dermatofibrosarcoma protuberans (DP), an infiltrating skin tumor (Simon et al., 1997). Although PDGFB has been implicated in transforming processes via autocrine and paracrine pathways, by the activation of the cognate receptor, no direct evidence of its involvement in neoplastic transformation of human tumours has been so far provided. In this report, we have tested the DNA from four DPs in the classical DNA transfection assay onto NIH3T3 fibroblast cell line. All the DNAs induced the formation of transformed foci in the transfected cultures whose derived cell lines were shown to contain a fused sequence comprising the human COL1A1 and PDGF genes. The relative breakpoint regions have been sequenced revealing that this gene fusion deleted exon 1 of PDGF and released the growth factor from its normal regulation. All the biochemical and biological assays were consistent with the model of an autocrine mechanism for NIH3T3 transformation by the human rearranged PDGFB gene involving the activation of the endogenous PDGF receptor.

3T3 Cells↗
PubMed1998

Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22.

It has recently been shown that mdm2 overexpression with stabilization of p53 represents a characteristic of retroperitoneal well-differentiated-dedifferentiated, here renamed evolved (WD-E), liposarcomas at the immunocytochemical, molecular, and cytogenetic level. This make-up appears to be confined to half the cases in non-retroperitoneal well-differentiated liposarcomas. Since in different tumours MDM2 amplification involves amplicons encompassing flanking genes, such as CDK4, the possibility was investigated that in these tumours, CDK4 could act as an alternative or additional gene involved in the transformation mechanism. Forty-one retroperitoneal (R)/non-retroperitoneal (NR) well-differentiated-dedifferentiated (WD-DD) and 33 myxoid/round cell liposarcomas were reanalysed by immunocytochemical, molecular (nine cases) and fluorescence in situ hybridization (FISH) (one case) techniques. The results showed that all but one R WD-E cases carried the mdm2+, p53+, cdk4+ immunophenotype. In NR-WD liposarcomas, this immunophenotype was shared in five cases and the remainder showed mdm2+, p53-, cdk4+ in four and mdm2-, p53-, cdk4+ in one case, showing ring chromosomes by FISH analysis. TP53 mutations are confirmed to be closely correlated with NR-DD liposarcomas and no CDK4 involvement was found in the myxoid/round cell liposarcoma group. As well as confirming the synergistic effect of MDM2 and CDK4, these results are consistent with the concept that amplicon(s) excluding MDM2 may contribute to transformation and support a role of CDK4 in opposing p53 function, particularly in NR WD liposarcoma.

Blotting, Southern↗
PubMed1998

A novel EWS-ERG rearrangement generating two hybrid mRNAs in a peripheral primitive neuroectodermal tumour (pPNET) with a t(15;22) translocation.

The occurrence of a t(15;22) translocation in a peripheral primitive neuroectodermal tumour (pPNET) has been previously reported. Molecular examination revealed the presence in tumour mRNA of two hybrid transcripts containing the 5' portion of the EWS gene fused to the 3' portion of the ERG gene. Sequence analyses indicated that both aberrant mRNAs most likely originated from the same rearrangement, which produced different hybrid isoforms due to the presence of an alternatively spliced exon in the ERG gene. To the authors' knowledge, this is the first report of the detection of two hybrid EWS-ERG mRNAs within the same tumour.

Adult↗
PubMed1998

FHIT in human cancer.

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Acid Anhydride Hydrolases↗