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PubMed1985

Frequent immunoglobulin and T-cell receptor gene rearrangements in "histiocytic" neoplasms.

The authors have analyzed the DNA of immunoglobulin and T-cell receptor genes in a series of 6 malignancies which were judged to be of histiocytic derivation on the basis of morphologic criteria. They found that 4 of these cases showed rearrangements of the beta T-cell receptor genes in spite of the lack of any specific immunohistochemical markers for B or T cells. One case showed rearrangements of both heavy and light chain immunoglobulin genes and probably represents either a sinusoidal large cell lymphoma or a B-cell lymphoma with activation of histiocytes simulating malignant histiocytosis. A single case lacked both immunoglobulin and T-cell receptor rearrangements consistent with immunologic analyses that suggested its origin from an interdigitating reticulum cell. The result of this study in conjunction with the authors' previous immunologic observations suggests that many presumed histiocytic malignancies actually represent T-cell lymphomas. Alternatively, beta T-cell receptor rearrangement may be a common feature of tumors that show monocyte/histiocytic differentiation.

Antibodies, Monoclonal↗
PubMed1997

Phenotypic diversity of neoplastic chondrocytes and extracellular matrix gene expression in cartilaginous neoplasms.

Chondrocyte differentiation is characterized by distinct cellular phenotypes, which can be identified by specific extracellular matrix gene expression profiles. By applying in situ analysis on the mRNA and protein level in a series of benign and malignant human chondrogenic neoplasms, we were able to identify for the first time different phenotypes of neoplastic chondrocytes in vivo: 1) mature chondrocytes, which synthesized the characteristic cartilaginous extracellular tumor matrix, 2) cells resembling hypertrophic chondrocytes of the fetal growth plate, 3) cells resembling so-called dedifferentiated chondrocytes, and 4) well differentiated chondrocytic cells, which expressed type I collagen, indicating the presence of post-hypertrophic differentiated neoplastic chondrocytes. Chondrocytes exhibiting a range of phenotypes were found to be present in the same neoplasm. The different observed phenotypes, including the dedifferentiated phenotype, were in contrast to the anaplastic cells of high-grade chondrosarcomas. Comparison of expression data with tumor morphology revealed a relationship between the cellular phenotypes, the tumor matrix composition, and the matrix and cell morphology within the neoplasms. The distinctly different phenotypes of neoplastic chondrocytes are the basis of the characteristic high biochemical and morphological heterogeneity of chondroid neoplasms and shed light on their biological and clinical behavior.

Aggrecans↗
PubMed1996

Expression of mucin carbohydrate antigens (T, Tn and sialyl Tn) and MUC-1 gene product in intraductal papillary-mucinous neoplasm of the pancreas.

Aberrant or incomplete glycosylation of mucins results in expression of T, Tn, and sialyl-Tn (STn) antigens in various malignant neoplasms. MUC-1 gene product (a mucin core protein of mammary type) is known to alter or overexpress in several malignant tumors. However, expression of these mucin-related antigens has rarely been examined in intraductal papillary-mucinous neoplasm (IPN) of the pancreas. The authors examined immunohistochemically the expression of these antigens and MUC-1 gene product in nine IPN. In normal pancreas (n = 5), pancreatic ducts did not express T, Tn, or STn antigens, but expressed MUC-1 gene product. Among the nine IPNs, two (22%) expressed T antigen, nine (100%) expressed Tn antigen, and seven (78%) expressed STn antigen. MUC-1 gene product was expressed in nine (100%) IPNs. In invasive ductal adenocarcinoma of the pancreas (n = 6), all cases showed strong expression of Tn and STn antigens and the MUC-1 gene product, but expressed no T antigen. The expression of these antigens and MUC-1 gene product was focal in IPN, whereas it was diffuse in invasive ductal adenocarcinoma of the pancreas. These data suggest that aberrant or incomplete glycosylation occurs in epithelial mucins of IPN, that IPN is a borderline or low grade malignant neoplasm in terms of mucin-related antigen expression, and that mucin core protein (MUC-1 gene product) does not alter during pancreatic ductal carcinogenesis.

Adenocarcinoma, Papillary↗
PubMed1991

[Analyses of T cell receptor and its clinical implications in T cell neoplasms].

We studied gene rearrangement and expression of immunoglobulin heavy (IgH) chain, T cell receptor (TCR) beta, gamma and delta chains in neoplastic T cells from patients with leukemia and lymphoma. Rearrangements of TCR beta and gamma chain genes were observed in most of T cell neoplasms. TCR delta chain gene rearrangements or deletions were detected in all 77 T cell neoplasms; 6 of 9 CD3- T cell neoplasms showed rearrangement, whereas biallelic deletion of TCR delta chain gene was the most common pattern in CD3+ T cell neoplasm (65 of 68 patients). One patient with CD3- T cell leukemia had TCR delta chain gene rearrangement with a germline configuration of TCR beta, gamma and IgH chain genes. TCR gamma and delta chain gene transcripts were detected in most of the CD3- T cell neoplasms, whereas mature TCR alpha and beta chain mRNA were demonstrated in the majority of the CD3+ T cell neoplasms. In 6 patients with CD7+ CD3- CD4- CD8- MPO- leukemia, only 2 patients had rearrangements and weak expressions of IgH, TCR gamma and delta chain genes. We also present two cases of double negative (CD3+ CD4- CD8-) leukemia; one is TCR gamma delta bearing LGL, the other is TCR alpha beta bearing ATL. These results suggest that most of T cell neoplasms preserve a pattern of genotypic and phenotypic expression reflecting their developmental pathways and differentiation levels of TCR bearing normal T cells.

Cell Differentiation↗
PubMed2002

Determination of allelic deletion of multiple endocrine neoplasm type 1 (MEN1) gene in acute myeloid leukemia (AML) by application of FISH-TSA technique.

We have used the single and dual color fluorescence in situ hybridization (FISH) technique combined with a new detection system, tyramide signal amplification (TSA), by using the multiple endocrine neoplasm type 1 (MEN1) gene and chromosome 11 specific alpha satellite DNA probes for the study of the allelic deletion of the MEN1 gene. The MEN1 gene is a new tumor suppressor gene and has been recently cloned on chromosome 11q13. FISH combined with the TSA detection system was performed on bone marrow interphase nuclei of 22 patients with acute myeloid leukemia (AML). The FISH-TSA analysis revealed the mono allelic deletion of the MEN1 gene in 4 out of 22 patients (18.18%), 2 of 9 AML-M2 patients (22.2%), 1 of 6 AML-M4 patients (16.6%), and 1 of 4 AML-M5 patients (25.0%). Our study indicates that allelic deletion of the MEN1 gene is not a major cause or a primary event in tumorigenesis of AML, although the long arm (q13 region) of chromosome 11 involves a chromosomal rearrangement in AML.

Adolescent↗
PubMed2003

Promoter hypermethylation of multiple genes in astrocytic gliomas.

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. To determine the frequency and timing of hypermethylation during carcinogenesis of astrocytic tumors, we analysed promoter methylation status of ten tumor-associated genes (MGMT, GSTP1, DAPK, p14ARF, THBS1, TIMP-3, p73, p16INK4A, RB1 and TP53) in a series of 88 astrocytic gliomas, including 24 diffuse astrocytomas; 21 anaplastic astrocytomas, and 43 glioblastomas (33 primary and 10 secondary), as well as two non-neoplastic brain samples, by methylation-specific PCR. Aberrant CpG island methylation was detected in all ten genes analysed, and all but one sample displayed anomalies in at least one gene. The methylation index (number methylated genes/total genes analysed) was 0.3, 0.38, 0.33 and 0.29 for diffuse astrocytomas, anaplastic astrocytomas and secondary and primary glioblastomas, respectively. Some differences may be established regarding the methylation profiles of specific genes and tumor types: MGMT, THBS1, TIMP-3, and p16INK4A appear hypermethylated in low-grade tumors (at least in 45% of cases), whereas GSTP1, DAPK, and p14ARF are mostly changed in 15-50% of the higher grade forms versus <10% in low-grade tumors. Some variation also exists regarding the methylation values for p73 and RB1 (10-40% of cases) among all groups. TP53 presented hypermethylation rates <10% in all tumor subtypes. Our findings thus suggest that methylation represents a common mechanism that contributes to inactivating cancer-related genes in astrocytic neoplasms. This epigenetic change is, in general, an early event in the development of astrocytic neoplasms but this gene silencing mechanism may also appear as a late event involving some loci.

Adult↗
PubMedDate not supplied

Detection of a novel alteration of the Axin gene in various pediatric neoplasms.

The Wnt signaling pathway is conserved in various species from worms to mammals, and plays critical roles in development, cellular proliferation and differentiation. As part of Wnt signal transduction, the function of the Axin complex is inhibited, leading to the accumulation of beta-catenin protein. Axin gene mutations have been detected in several kinds of human cancers. In this study, we investigated Axin gene alterations in a series of 58 pediatric neoplasms including neuroblastomas, teratomas, rhabdomyosarcomas. Forty-eight non-tumor tissues were used as a control series to compare gene alterations and their frequencies between tumors and normal tissues. The whole coding region of the Axin gene was examined by PCR-SSCP method using 24 sets of the primers. Samples revealing aberrant band patterns were subjected to direct sequencing analysis. In total, we identified six variants in the exons and four intronic nucleotide substitutions in the tumor series. Similar sequence variants except a rare sequence variant at codon 98 (CCG right curved arrow CTG) were observed in the control series and these were regarded as non-pathogenetic polymorphisms. Our results indicated that a tumor-associated mutation of the Axin gene is generally a rare event in our series of pediatric neoplasms.

Axin Protein↗
PubMed1991

Induction of nm23 gene expression in human colonic neoplasms and equal expression in colon tumors of high and low metastatic potential.

Levels of expression of the murine nm23 gene inversely correlate with metastatic potential in several rodent tumor model systems. Expression of the human nm23 homologue also is lower in human breast cancers of high metastatic potential than in breast cancers of low metastatic potential. In the present study, we examined changes in nm23 expression during colon carcinogenesis as found in 18 matched pairs of normal and neoplastic human colon tissues. We found that a 0.8-kilo-base nm23 transcript was expressed in all samples of morphologically normal colon mucosa. In 16 of 18 colon neoplasms, nm23 expression was further increased in the neoplastic, compared with the morphologically normal, colon mucosa from the same individual. Expression of nm23 was elevated over normal mucosa in 3 of 3 polyps, in 2 of 3 nonmetastatic cancers, and in 11 of the 12 cancers that were metastatic at the initial presentation. The levels of nm23 expressed were similar in the 12 metastatic colon neoplasms and in the 6 colon neoplasms of lower clinical stage. In addition, nm23 expression was maintained in culture in each of 12 cell lines initiated from human colon neoplasms and did not differ between lines established from neoplasms of high or low metastatic capability. We concluded that nm23 was expressed in normal colon mucosa. Expression of nm23 increased during early stages of colon carcinogenesis and remained increased in metastatic colon cancer. Therefore, in the colon, tissue-specific events dissociate nm23 expression from loss of tumor metastatic competence.

Adenocarcinoma↗
PubMed1988

Inactivation of the retinoblastoma susceptibility gene in human breast cancers.

Mutational inactivation of the retinoblastoma susceptibility (RB) gene, a recessive cancer gene, has been implicated in the genesis of retinoblastoma and certain other human neoplasms. This gene is now shown to be inactivated in two of nine human breast cancer cell lines examined. The RB gene of one cell line had a homozygous internal duplication of a 5-kilobase region containing exons 5 and 6. The RB messenger RNA transcript was correspondingly lengthened, and its translation was probably terminated prematurely due to a shifted reading frame. The other cell line had a homozygous deletion of the RB gene that removed the entire gene beyond exon 2. The RB gene product, pp110RB, was not detectable in either cell line by immuno-precipitation with specific antibodies. These findings are significant in relation to proposed genetic mechanisms of breast cancer formation.

Breast Neoplasms↗
PubMed2001

Significant correlation between the breakpoints of rare clonal aberrations in benign solid tumors and the assignment of HMGIY retropseudogenes.

Recently, we described a mechanism by which a retropseudogene, during evolution, becomes an exon of a pre-existing active gene. Similar mechanisms may account for the activation of processed genes by chromosomal rearrangements in neoplasms. Because genes of the high-mobility group protein family HMGI(Y) are known to be involved in the development of a variety of benign solid tumors, it was the aim of the present study to analyze breakpoints of clonal chromosome abnormalities in that group of benign tumors for a possible correlation with retropseudogenes of the HMGIY gene. Whereas the HMGIYL1 retrospeudogene has recently been mapped to Xp22.1, we assigned a further retropseudogene by FISH to 4q13, and database research allowed us to assign a third retropseudogene to 12q24.1. Sequence analyses of these retropseudogenes revealed high-identity indices to the HMGIY gene and no frame-shift divergences. Breakpoint information was obtained from cytogenetic aberrations in uterine leiomyomas, lipomas, pleomorphic adenomas, and pulmonary chondroid hamartomas because, in all of these tumor entities, cytogenetic subgroups involving genes of the HMGI(Y) family exist. Chromosomal bands harboring HMGIY retropseudogenes were affected with a significantly higher frequency than expected under the assumption of purely randomly occurring breakages. These results support our hypothesis that HMGIY-related retropseudogenes can be affected by chromosomal rearrangements in benign human tumors.

Base Sequence↗
PubMed2026

Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.

Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity.

Humans↗
PubMed1995

Pattern of gene alterations in intraductal breast neoplasms associated with histological type and grade.

To reveal any association between the histological type and grade of intraductal breast neoplasms and the manner of accumulation of gene alterations, eight types of gene alterations, i.e., loss of heterozygosity (LOH) on chromosomal arms 16p, 16q, 17p, 17q, and 18q, amplification of the c-erbB-2 and hst-1/int-2 genes, and mutation of the p53 gene, were examined by Southern blot analysis or single-strand conformation polymorphism analysis in a total of 60 cases of intraductal breast cancer and 18 nonmalignant proliferative lesions. Among the histological types and three histological grade groups of intraductal carcinomas, the gene alterations which occurred most frequently were LOH on 16q alone in non-comedo type and Grade 1, alterations of c-erbB-2, 17p, and 16q in comedo type and Grade 2, and alterations of 17q and p53 as well as those of 16q, 17p, and c-erbB-2 in Grade 3. LOH on 16q and 18q was frequent in intraductal carcinoma of the intracystic papillary type, whereas LOH on 18q alone was detected in 27% of papillomas. Among intraductal carcinomas, the mean number of gene alterations was largest in comedo type and Grade 3, whereas it was smallest in non-comedo type and Grade 1. It was possible that LOH on 18q and 16q was involved frequently in papillary tumori-genesis and acquisition of malignant phenotype, respectively, whereas most of the other gene alterations were involved in acquisition of aggressive biological properties by intraductal carcinoma cells. It was also possible that the phenotype of breast neoplasms was determined by the combination of gene alterations at a relatively early developmental stage.

Breast Neoplasms↗