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M Ladanyi

Publications and source records attributed to M Ladanyi.

At least 19 recordsLinked to original sources
PubMed1992

Follicular lymphoma with t(8;14)(q24;q32): a distinct clinical and molecular subset of t(8;14)-bearing lymphomas.

The presence of the translocation t(8;14)(q24;q32) has not been well described in follicular lymphoma (FL). In a consecutive series of 278 karyotypically abnormal non-Hodgkin's lymphomas (NHL), six patients with FL showing a t(8;14) without a t(14;18)(q32;q21) were identified. They ranged in age from 45 to 73 years. The cell type was mixed in four patients, small-cleaved in one, and large-cleaved in one; four cases also contained diffuse areas. All cases tested displayed monoclonal surface Ig. The clinical courses were consistent with the histologic subtypes, being less aggressive than other t(8;14)-bearing NHL. In five cases, frozen tissue was available for Southern blotting. The BCL2 gene showed a germline configuration when studied with the MBR, MCR, and 5' cDNA probes. The MYC gene also appeared unrearranged using an exon-1 probe with EcoRI or HindIII digestion. Analysis of the Ig heavy chain (IgH) gene with a JH region probe and BamHI or EcoRI digestion showed only one rearranged band in all cases, indicating that the 14q32 breakpoint did not lie in either the J or switch-mu (SM) regions. In four cases, the exon-1/intron-1 border of the MYC gene, a target area for point mutations in cases of t(8;14) that do not display rearrangements of the MYC gene, was enzymatically amplified and sequenced; no point mutations were identified. The indolent behavior of our six cases, and the finding that the molecular structure of the t(8;14) in these cases does not follow the pattern of breakpoint sites and point mutations defined in other histologic subtypes of NHL with this translocation, suggest that the t(8;14) in these cases is cytogenetically and molecularly distinct from the t(8;14) seen in high-grade NHLs, and is relatively ineffectual in terms of MYC deregulation, or that other genetic elements at these chromosomal sites may be involved. Further analysis of these tumors may provide insights into MYC deregulation and BCL2-independent FL.

Aged↗
PubMed1992

Detection of rearrangements of the BCL2 major breakpoint region in follicular lymphomas. Correlation of polymerase chain reaction results with Southern blot analysis.

The translocation t(14;18)(q32;q21) occurs in 70% of follicular lymphomas and places the BCL2 proto-oncogene, normally located at 18q21, under the control of the immunoglobulin heavy chain (IgH) gene at 14q32. Its detection by the polymerase chain reaction (PCR), made possible by the close clustering of most of the BCL2 breakpoints in the major breakpoint region (MBR) of the gene, has numerous clinical applications. Since the PCR covers shorter lengths of DNA than Southern blotting, PCR-based tests may be more susceptible to microheterogeneity in breakpoint location. There have been no published studies of the impact of breakpoint microheterogeneity on the detection rate of this translocation by PCR. We studied 30 follicular lymphomas with the t(14;18), in which a BCL2 MBR rearrangement had previously been demonstrated and mapped by conventional Southern blotting, by PCR with the commonly used IgH and BCL2 MBR primers. Twenty-five cases (83%) had a junction fragment demonstrable by PCR. All three cases in which the MBR rearrangement mapped outside of the 4.3-kb HindIII fragment containing the MBR, as determined by Southern blotting, were negative by PCR. In addition, two cases with rearrangements within the HindIII fragment were also negative. All negative results were repeated at least once and were confirmed to be true negatives by actin PCR. Our results suggest that negative PCR results in this setting are attributable to small variations in BCL2 MBR breakpoint location and cannot be interpreted without the corresponding conventional Southern blotting data. With this caveat in mind, PCR analysis for the t(14;18) remains an extremely useful technique, especially in the follow-up and monitoring for minimal residual disease in previously characterized cases of follicular lymphoma.

Base Sequence↗
PubMed1992

Analysis of BCL2 and MYC expression in non-Hodgkin's lymphomas by in situ hybridization: correlation with chromosome translocations.

We have used an in situ hybridization method for analysis of expression of BCL2 and MYC on cytospun preparations of normal and malignant lymphoid cell lines and tissue sections of normal and malignant lymph nodes. The probes comprised 50-mer antisense oligonucleotides starting at the ATG codons of exon 3 of BCL2 and exon 2 of MYC. We studied the expression of these two genes in frozen tissue sections of biopsy specimens derived from normal and hyperplastic lymph nodes, B-cell lymphomas carrying the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, and T-cell lymphomas with clonal chromosome abnormalities. While all proliferating cells expressed both genes, BCL2 expression was increased two- to threefold in follicular lymphomas with t(14;18) and MYC expression was increased two- to four-fold in high-grade lymphomas with t(8;14). These results are consistent with previous data on deregulated expression of these genes obtained from study of lymphoma cell lines carrying the relevant translocations.

Base Sequence↗
PubMed1992

Proto-oncogene analysis in multiple myeloma.

The genetic basis for the development of multiple myeloma (MM) remains poorly understood, in part because MM has thus far been relatively refractory to cytogenetic analysis. The few cases karyotyped have pointed to involvement of 11q13, site of the BCL1 proto-oncogene, or of 8q24, site of the MYC proto-oncogene. A recent molecular study detected rearrangements distal to the MYC gene in 16% of MM, using the MLVI-4 probe. The immunocytochemical demonstration of BCL2 protein overexpression in at least some cases of MM has suggested the possibility of translocation-mediated deregulation of the BCL2 proto-oncogene. The configuration of the BCL2 gene in MM, however, has not yet been defined using all available breakpoint probes. To address these issues, we studied 17 patients with plasma cell dyscrasias (16 MM, 1 plasmacytoma) by Southern blotting using the major breakpoint region (MBR), minor cluster region (MCR), and 5' cDNA (pB16) BCL2 breakpoint probes; with the BCL1 major translocation cluster (MTC) breakpoint probe; and with a probe to the MYC-associated MLVI-4 region (PA1.3SB). In all 17 cases, rearrangement of one or both alleles of the immunoglobulin heavy chain gene had been demonstrated, thereby confirming the presence of tumor DNA in the samples studied. None of the cases tested showed a rearrangement with the MBR BCL2 (0/16), MCR BCL2 (0/17), 5' cDNA BCL2 (0/16), BCL1 MTC (0/15), or MLVI-4 (0/15) probes. These results suggest that if BCL2 deregulation does indeed occur in MM, a mechanism other than translocation must be involved in most cases. Furthermore, rearrangements distal to the MYC gene, in the region of the MLVI-4 probe, may be less common than previously thought. Finally, a significant proportion of translocation breakpoints in band 11q13 may not be detected by the BCL1 MTC probe in MM, as is true in lymphomas.

Aged↗
PubMed1991

MYC rearrangement and translocations involving band 8q24 in diffuse large cell lymphomas.

The configuration of the MYC gene in diffuse large cell lymphomas (DLCL) with translocations involving band 8q24 [t(8q24)] has not been systematically studied. We collected cytogenetic and clinical data on 171 consecutive cases of DLCL, including cleaved, noncleaved, and immunoblastic types, of which 96 had DNA available and 124 had abnormal karyotypes. The cases with DNA available were evaluated for MYC rearrangement (MYC-R) by Southern hybridization of EcoRI-digested tumor DNA using an exon-1 probe, a combination of probe and enzyme known to detect over 85% of breaks in sporadic Burkitt's lymphoma. In cases studied at diagnosis, MYC-R, t(8;14)(q24;q32), or other t(8q24) were not prognostically significant. Among the 124 cases with karyotypic abnormalities, seropositivity for human immunodeficiency virus was significantly more common in cases with a t(8q24) (72%) than in cases without it (9%) (P less than .05). Of the four cases with an MYC -R, two had a t(8;14), one had a t(7;8;14)(p15;q24;q32), and one had a t(8;?)(q24;?) and a del(8)(q24). In the three previous cases with translocations involving 8q24 and 14q32, comigration of the rearranged MYC band with either the J region or the switch-mu region of the Ig heavy chain gene could not be demonstrated, leaving the 14q32 breakpoint undefined at the molecular level. Among the remaining 72 cases where both an abnormal karyotype and molecular data were available, 11 had a t(8q24), either t(8;14) or t(8;22)(q24;q11), in the absence of an MYC-R. In these cases, the 8q24 break was presumably located outside of the EcoRI MYC fragment. All 15 cases with a t(8q24) were also screened for point mutations in the PvuII site in the first exon of MYC; two cases that were not MYC-R showed loss of this restriction site. These results indicate that in most DLCL with t(8;14) or other t(8q24), the 8q24 breakpoint lies away from the MYC gene; in a minority of these cases, point mutations in regulatory noncoding regions were detected.

Adult↗
PubMed1991

Structural alterations in the 5' region of the BCL2 gene in follicular lymphomas with BCL2-MBR or BCL2-MCR rearrangements.

We report a new class of molecular lesions in the 5' region of the BCL2 protooncogene when it undergoes a t(14;18) translocation-associated rearrangement in the major break cluster (MBR) or minor break cluster (MCR) regions. Among 52 tumors assayed for BCL2 rearrangements using the MBR, MCR, and 5' probes, seven (six with MBR and one with MCR translocation breaks) showed aberrant bands in unique enzyme digests of DNA hybridized with the 5' probe. The aberrant bands in four tumors were in HindIII digests, in two they were in EcoRI digests, while the aberrant band in one was in a BamHI digest. The two EcoRI bands and two of the four HindIII bands were of identical sizes. Germline polymorphisms as the source of these bands was ruled out by appropriate control experiments. These results suggest that the bands were derived from point mutations or small deletions in the 5' region of BCL2. The significance of this alteration to BCL2 function in translocation-carrying tumors remains to be determined.

Biomarkers, Tumor↗
PubMed1991

Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: correlations between recurrent aberrations, histology, and exposure to cytotoxic treatment.

Cytogenetic abnormalities in non-Hodgkin's Lymphoma (NHL) provide a model system for the analysis of the role of multiple genomic aberrations in human malignancy. In order to define correlations with histology, tumor evolution, and the effects of genotoxic exposure, cytogenetic analysis was performed on 434 specimens of NHL derived from 423 patients consecutively ascertained over a 5-year period (1984-1989). Six recurring translocations (RT) were observed: t(14;18)(q32;q21), t(8;14)(q24;q32), t(11;14)(q13;q32), t(3;22)(q27;11), t(2;5)(p23;q35), and t(1;6)(q21;q25). No translocation was specific to a single histologic subtype. Other structural chromosome abnormalities were analyzed according to break site; groups of related breaks were considered together for statistical analysis. Recurring other structural and numerical aberrations (ROA) encountered in greater than 10% of specimens included rearrangements with breaks at bands 1p32-36, 1q21-23, 6q21-25, and trisomies of chromosomes 7 and 12. ROA with one of these breaks or numerical abnormalities were the sole abnormalities in at least two cases. Correlations were observed among ROA and between ROA and histologic subtypes. Trisomy 7, breaks at 1q21-23, 1p32-36, 6q21-25, and 7q32 were associated with t(14;18); trisomy 18 was associated with trisomy 3; and structural abnormalities of chromosome 17 were associated with breaks at 1p32-36 and 6q21-25. Trisomy 7 and trisomy 12 were more frequent in t(14;18)-bearing intermediate to high grade tumors compared to low grade tumors. Trisomy 12 and breaks at band 1p22 were associated with large cell diffuse lymphomas. Incidence rates of reciprocal translocations, ROA, and measures of karyotypic complexity, including number of breakpoints and marker chromosomes were compared in pretreatment and posttreatment samples. Karyotypic complexity was greater in the posttreatment samples, reflecting an increased frequency of nonrecurring and low incidence aberrations. These results better define the association of genomic aberrations and tumorigenesis, histologic transformation, and tumor progression.

Alkylating Agents↗
PubMed1991

Clonal cytogenetic abnormalities in Hodgkin's disease.

Cytogenetic studies of Hodgkin's disease (HD), in contrast to those of non-Hodgkin's lymphoma (NHL), have been limited to small numbers of cases with infrequently recurring aberrations, underscoring the need for additional studies in establishing a coherent cytogenetic picture of HD. Over a 6 1/2-year period, we received 95 specimens of HD for cytogenetic analysis. Analyzable chromosome preparations were obtained in 70 cases, of which 57 (81%) showed only normal metaphases. In the remaining 13 cases (19%), karyotypic abnormalities were observed that were nonclonal in 3 and clonal in 10. The latter 10 cases included 6 of the nodular sclerosis subtype, 3 mixed cellularity, and 1 lymphocyte-depleted; 8 of the specimens were obtained pretreatment and 2 posttreatment. Two of the cases had a clonal numerical aberration, monosomy 17 in one and trisomy 13 in the other, as their sole abnormality. The remaining 8 cases showed complex karyotypes with multiple structural rearrangements; in 3 of these, the abnormal clone was near-tetraploid. Bands involved more than once included 1p36, 1q21, and 4q35, each in 2 cases. Arms involved more than once included 6q (6q13,6q23), 9p (9p13,9p21), and 5q (5q15,5q35). Three patients had loss of part or all of 6q (del(6)(q13),del(6)(q23),i(6p). Bands 14q32 and 18q21 were not involved in any case, contrary to some previous reports. Our results confirm the frequent occurrence of 1p, 1q, and 6q abnormalities in HD. In addition, we have identified a 5q35 breakpoint, which has recently been shown to be highly specific for Ki-1-positive NHL in a case of typical nodular sclerosis HD. Its presence in HD may represent a cytogenetic link between the two entities, which are immunophenotypically related but clinically and histologically distinct.

Aneuploidy↗
PubMed1990

11p13-15 is a specific region of chromosomal rearrangement in gastric and esophageal adenocarcinomas.

In a cytogenetic analysis of 9 gastric and lower esophageal adenocarcinomas, we detected nonrandom rearrangements involving the region 11p13-15 in 8, thus identifying for the first time a specific chromosomal lesion in these tumors. In addition, rearrangements involving 3p21, translocations among the D group chromosomes, and i(5p) were each observed in more than half of the cases. The overall pattern of aberrations encountered in adenocarcinomas of gastric and lower esophageal origin was similar, suggesting that the tumors arising at these anatomical sites are biologically related. We also encountered cytogenetic evidence for gene amplification in the form of homogeneously staining regions and double-minute chromosomes in primary as well as metastatic lesions, which is consistent with amplification of a number of cellular oncogenes in these tumors detected by others and us at the molecular level. These cytogenetic findings are discussed in relation to nonrandom chromosome abnormalities and gene amplification reported in other types of adenocarcinoma.

Adenocarcinoma↗
PubMed1990

Gene amplification in gastric and esophageal adenocarcinomas.

In a United States series of 28 gastric/esophageal adenocarcinomas of poorly to moderately differentiated histopathology, we detected gene amplification in 21% of the tumors. Using the modified DNA in-gel renaturation assay to detect down to 7-8 copies of amplified DNA sequences, we identified 3 gastric tumors with amplified DNA sequences and confirmed by Southern hybridization analysis that HER-2/neu was amplified greater than 5-fold in these specimens. Immunohistochemical staining of tumor tissue sections with p185 HER-2/neu antibodies demonstrated that only the 3 gastric adenocarcinomas with corresponding HER-2/neu gene amplification displayed membrane immunoreactivity. Amplification of c-met was identified in 2 tumors, and this was the first study to assay for multiple copies of this protooncogene in fresh gastric tumor tissues. Amplification of c-erbB was observed in one tumor, and no evidence for amplification of int-2 was obtained in this series of adenocarcinomas.

Adenocarcinoma↗
PubMed1990

Cytogenetic and immunohistochemical evidence for the germ cell origin of a subset of acute leukemias associated with mediastinal germ cell tumors.

Most acute leukemias occurring in patients with mediastinal germ cell tumors (MGCTs) appear to be primary rather than therapy-related; however, no data have been obtained to date to confirm the hypothesized germ cell origin of the leukemias in this syndrome. We identified six male patients with this syndrome treated at Memorial Sloan-Kettering Cancer Center: in all six, the leukemia was studied immunohistochemically for various hematologic and germ cell antigens; in four, the karyotype of the leukemia was available; in one, the MGCT had also been karyotyped. In three patients, we found evidence of a germ cell origin of the acute leukemias. A 19-year-old male developed an acute myeloblastic leukemia 11 months after presenting with an MGCT; karyotypes of the two tumors showed them to be clonally related, both showing an i(12p), a cytogenetic marker of germ cell tumors. A 16-year-old male with probable Klinefelter's syndrome presented simultaneously with acute monocytic leukemia and an MGCT; although the MGCT was not karyotyped, the leukemia showed an i(12p). A 23-year-old male developed concurrently an MGCT and acute myelomonocytic leukemia; the leukemia cells coexpressed myelomonocytic antigens (HAM56, My4, My9) and cytokeratin, suggesting dual differentiation, myeloid and germ cell. Evidence for a germ cell origin of the acute leukemias in the three other patients was not obtained, although in all three the MGCT and the leukemia occurred simultaneously, supporting an etiologic relationship. Hence, these leukemias may represent another form of non-germ cell malignancy developing in germ cell tumors. All patients died of the leukemia, with a median survival of less than 2 months. This syndrome may be a useful pathologic model for the study of germ cell differentiation and hematopoietic ontogeny.

Adolescent↗
PubMed1990

Cytogenetic and molecular analysis of human male germ cell tumors: chromosome 12 abnormalities and gene amplification.

We report karyotypic analysis of 24 male germ cell tumors (GCTs) with clonally abnormal karyotypes biopsied from testicular and extragonadal lesions from 20 patients belonging to the histologic categories seminoma, teratoma, embryonal carcinoma, choriocarcinoma, and endodermal sinus tumor. Chromosomes 1, 7, 9, 12, 17, 21, 22, and the X chromosome were nonrandomly gained in these tumors. Nonrandom structural changes affected most frequently chromosomes 1 and 12, the latter as i(12p) and/or del(12)(q13----q22). The i(12p) was seen in 90% of tumors which included all histologic subtypes and gonadal as well as extragonadal presentation. Our present results, along with those from published data on fresh GCT biopsies, establish that i(12p) is a highly nonrandom chromosome marker of all histologic as well as anatomic presentations of GCTs. in contrast, we found del(12)(q13----q22) exclusively in nonseminomatous GCTs (NSGCTs) and mixed GCTs (MGCTs) occurring in 44% of such lesions. Because successful cytogenetic analysis of fresh tumor specimens is not always possible, we developed a method based on DNA analysis to detect i(12p) as increased copy number of 12p. In addition to the changes affecting chromosome 12 identified above, we have detected, for the first time, cytological evidence of gene amplification in the form of homogeneously staining regions (HSRs) and double minute chromosomes (dmins) in treated as well as untreated primary extragonadal and metastatic GCTs and confirmed the presence of amplified DNA in one of these tumors at the molecular level by the in-gel renaturation method. Hybridization of DNA from cultured cells from an HSR-bearing tumor with a panel of probes for genes known to be amplified or otherwise perturbed in diverse tumor systems did not identify the amplified gene, suggesting amplification of a novel gene or genes. This study comprises the largest series of GCT cytogenetics attempted so far. Notably, it includes data on a series of primary mediastinal tumors, a group which previously has not been studied in any detail.

Blotting, Southern↗
PubMed1990

Immunohistochemical, molecular, and cytogenetic analysis of a consecutive series of 20 peripheral T-cell lymphomas and lymphomas of uncertain lineage, including 12 Ki-1 positive lymphomas.

Although several independent series of non-Hodgkin's lymphomas (NHLs) have been subjected to cytogenetic studies or analyses of lineages by assaying for clonal immunophenotypes and clonal rearrangements affecting immunoglobulin (IG) and T-cell receptor (TCR) genes, no published reports exist of series of non-B-cell NHLs on which cytogenetic, immunohistochemical, and IG and TCR gene rearrangement studies have been undertaken together. Among 343 NHLs ascertained prospectively between January 1984 and December 1988 at the Memorial Sloan-Kettering Cancer Center, 278 cases with clonal chromosome abnormalities were identified. Of the latter, 20 were non-B-cell NHLs, which in turn comprised 15 peripheral T-cell lymphomas (PTCLs) and 5 lymphomas of uncertain lineage (LULs). The LULs either were biogenotypic, had discordant immunophenotype and immunogenotype, or showed no evidence of B-cell, T-cell, or histiocytic derivation. Of the 15 PTCLs, eight expressed the Ki-1 antigen and four of these had translocations involving the band 5q35 [t(5q35)]. Of the five LULs, four expressed the Ki-1 antigen and one of these had a translocation involving band 5q35. Previous studies have associated t(5q35) with Ki-1 positive NHLs characterized histologically by a pleomorphic diffuse large cell morphology. In our series of 12 Ki-positive non-B-cell NHLs, five (42%) had a 5q35 translocation. They were histologically indistinguishable from the subset without the translocation. The frequent lineage uncertainty exhibited by Ki-1 positive NHLs of similar histology and cytogenetic abnormalities suggests their derivation from an early uncommitted lymphoid cells.

Antigens, Differentiation↗
PubMed1990

Ki-1 antigen expression defines a favorable clinical subset of non-B cell non-Hodgkin's lymphoma.

Immunohistochemical and immunophenotypic analyses were performed on 278 cases of karyotypically abnormal non-Hodgkin's lymphoma (NHL). Excluding cases of lymphoblastic lymphoma or mycosis fungoides, 20 cases showed evidence of non-B cell lineage. T cell lineage was proven by genotypic and immunophenotypic analyses in 15 of the 20 cases; five were of ambiguous lineage. All of the non-B lineage cases were of diffuse histology with a large cell component (DLCL). Twelve cases expressed the Ki-1 antigen; five of these cases also demonstrated a translocation with a break at 5q35. Patients with Ki-1 positive DLCL and t(5q35) had a younger median age compared with non-B cell DLCL without t(5q35). The Ki-1 positive patients had a higher frequency of skin involvement and lower incidence of bone marrow involvement compared with Ki-1 negative DLCL. Survival analysis was performed on 86 cases of B cell DLCL and 18 cases of non-B cell DLCL which were serially ascertained prior to receiving cytotoxic chemotherapy. Median duration of complete remission was significantly longer in the B cell compared with the non-B cell DLCL groups; there was only a trend for decreased overall survival in the non-B cell group. Among the subset of non-B cell lymphomas, overall survival of patients with Ki-1 expressing DLCL was significantly longer than those with Ki-1 negative DLCL, who had a median survival of less than a year. These results show that immunophenotypic, immunohistochemical, and cytogenetic markers can define subsets of patients with non-B cell lymphomas with differing clinical characteristics and outcome.

Adolescent↗
PubMed1989

Benign metastasizing giant cell tumors of bone. A DNA flow cytometric study.

Approximately 2% of histologically benign giant cell tumors (BGCT) of bone are complicated by lung metastases, which can progress despite their benign histologic appearance. Almost all BGCT studied by DNA flow cytometry (FCM) have been reported to be diploid. However, the very few cases with lung metastases previously analyzed were all aneuploid. To assess the usefulness of DNA FCM in predicting the metastatic potential of BGCT, seven metastasizing BGCT were studied by DNA FCM using paraffin-embedded tissue. Five were purely diploid, one was tetraploid, and one was aneuploid. The primary and the metastasis showed the same DNA distribution in all but the tetraploid case, in which the metastasis was purely diploid. A single patient, who was in the diploid group, had unresectable tumor in the lungs; she remains alive with stable disease at 30 months. The other six patients, who underwent complete resections of their lung metastases, are free of disease. These results suggest that DNA FCM is not a sensitive method for predicting the metastatic potential of BGCT since most metastasizing cases appear to be diploid.

Aneuploidy↗
PubMed1989

Leukemic differentiation of a mediastinal germ cell tumor.

The biological basis for acute leukemia associated with mediastinal germ cell tumors has remained unexplained due to lack of critical data that would illuminate the genetic relationship between the two tumors in a given patient. Here we present results of serial cytogenetic investigations on the pretreatment and posttreatment mediastinal yolk sac tumor and immature teratoma biopsies and two separate leukemic bone marrow aspirates from a patient who developed acute nonlymphocytic leukemia 11 months after the initial diagnosis of the germ cell tumor. Presence of an i(12p) in all tumor clones and trisomy 21 in one clone in the posttreatment mediastinal tumor and all leukemic clones establishes the common origin of all tumor clones and shows that in this case the leukemia was derived from the malignant germ cell clone.

Adult↗