Biomedical subjects

M Ladanyi

Publications and source records attributed to M Ladanyi.

At least 91 records · Page 5Linked to original sources

PubMed1994

Fusion of the EWS and WT1 genes in the desmoplastic small round cell tumor.

The desmoplastic small round cell tumor (DSRCT) is a recently recognized type of primitive sarcoma defined by a predilection for young males, aggressive clinical behavior, widespread abdominal serosal involvement, and a primitive histological appearance with prominent desmoplasia and striking divergent, multilineage differentiation. Previous cytogenetic case reports have identified a recurrent translocation, t(11;22) (p13;q12). We have characterized this translocation at the molecular level in a panel of five DSRCTs using a candidate gene approach. Southern blot analysis revealed recurrent rearrangement of both EWS, located at 22q12, and rearranged in other tumor-specific translocations in Ewing's sarcoma and clear cell sarcoma, and of WT1, the gene at 11p13 involved in a subset of Wilms' tumor. Consistent comigration of the rearranged EWS and WT1 bands in multiple enzyme digests indicated fusion of the genomic sequences, presumably due to the translocation t(11;22) (p13;q12). Northern blotting showed aberrant EWS and WT1 transcripts of the same size, suggesting the presence of a chimeric messenger RNA. This was confirmed by reverse transcriptase polymerase chain reaction using an EWS exon 7 primer and WT1 exon 8 or 9 primers, which revealed single polymerase chain reaction products consistent with a junction of EWS exon 7 to WT1 exon 8. DSRCT thus represents the third primitive sarcoma in which the EWS gene is involved and the first instance of recurrent rearrangement of a tumor suppressor gene, WT1, in a specific tumor type. The different translocation partners of the EWS gene, all of which are putative or definite transcription factor genes, may be responsible for the biological differences between DSRCT, Ewing's sarcoma, and clear cell sarcoma.

Abdominal Neoplasms↗

PubMed1994

Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation.

BACKGROUND: Lymphoma associated with Epstein-Barr virus (EBV) is a complication of bone marrow transplantation that responds poorly to standard forms of therapy. The lymphoma is usually of donor origin. We hypothesized that treatment with infusions of donor leukocytes, which contain cytotoxic T cells presensitized to EBV, might be an effective treatment. METHODS: We studied five patients in whom EBV-associated lymphoproliferative disorders developed after they received a T-cell-depleted allogeneic bone marrow transplant. Biopsy specimens were immunophenotyped, subjected to the polymerase chain reaction to determine the origin of the lymphoma (donor or host) and to detect the presence of EBV, and analyzed by Southern blotting for the presence of the clonal EBV genome and immunoglobulin-gene rearrangement. Patients were treated with infusions of unirradiated donor leukocytes at doses calculated to provide approximately 1.0 x 10(6) CD3+ T cells per kilogram of body weight. RESULTS: Histopathological examination of biopsy specimens from all five patients demonstrated monomorphic, malignant lymphomas of B-cell origin. Each of the four specimens that could be evaluated was of donor-cell origin. Evidence of clonality was found in two of the three samples adequate for study. EBV DNA was detected by the polymerase chain reaction in all five samples. In all five patients there were complete pathological or clinical responses. The responses were first documented histologically within 8 to 21 days after infusion. Clinical remissions were achieved within 14 to 30 days after the infusions and were sustained without further therapy in the three surviving patients for 10, 16, and 16 months. CONCLUSIONS: In a small number of patients, infusions of unirradiated donor leukocytes were an effective treatment for EBV-associated lymphoproliferative disease that arose after allogeneic bone marrow transplantation.

Adult↗

PubMed1994

Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors.

The search for mitochondrial DNA (mtDNA) defects in oncocytic neoplasms has been the subject of several recent studies. We have performed qualitative and quantitative analysis of nuclear and mitochondrial DNAs in a series of 19 renal and 12 thyroid oncocytic tumors to identify specific alterations that might predict the clinical and biological behavior of these tumors. Allelic losses were seen in 2 of 19 renal tumors and 5 of 12 thyroid tumors. Among all loci (3p, 3q, 9q, 10q, 11p, 17p, and 17q) that showed losses, losses at 10q (one renal tumor and three thyroid tumors) were significantly higher (P < 0.05) than expected. Analysis of the COX I region previously reported to be altered in oncocytomas and the delta-loop region of mtDNA showed no detectable abnormalities in the restriction pattern in 10 renal and five thyroid tumors. PCR analysis of the commonly deleted 4,977-bp region failed to detect an increased frequency of mtDNA deletions in tumors compared to the controls. In addition, segmental amplification of the complete mtDNA from a renal oncocytoma using nine sets of primers revealed no gross alteration in mtDNA. Oncocytic tumors showed a mean 5-fold increase in mitochondrial DNA, which was significant (P < 0.001) when compared to corresponding controls. The relative increase in the cellular content of mtDNA may be associated with alterations in the normal coordinated interaction between the nuclear and mitochondrial genomes. Allelic deletions at 10q may be significant in the biology of oncocytic tumors, and their impact on the clinical behavior of these tumors warrants further investigation.

Base Sequence↗

PubMed1994

Reverse transcriptase polymerase chain reaction for the Ki-1 anaplastic large cell lymphoma-associated t(2;5) translocation in Hodgkin's disease.

Hodgkin's disease (HD) and Ki-1 positive anaplastic large cell lymphoma (Ki-1 ALCL) appear pathologically and immunohistochemically related, and a common histogenesis has been postulated in at least some cases. The breakpoints of the t(2;5) (p23;q35) [corrected] translocation, which is reported in about 40% of Ki-1 ALCL, have recently been cloned. They involve a novel tyrosine kinase gene, ALK, at 2p23 and the nucleophosmin gene, NPM, at 5q35. Reverse transcriptase polymerase chain reaction (RT-PCR) using NPM and ALK primers consistently detects a fusion product in Ki-1 ALCL cases with the translocation. To determine if this tumor-specific genetic alteration also occurs in HD, we performed NPM-ALK RT-PCR on RNA samples extracted from 40 lymph node biopsies of HD (25 nodular sclerosis, 11 mixed cellularity, 2 lymphocyte depleted, 2 lymphocyte predominant). Using control samples, the sensitivity of the NPM-ALK RT-PCR assay was shown to be at least 1:10(4). Amplifiable template was confirmed in all samples by RT-PCR using beta-actin primers. None of the 40 cases showed the expected 177-bp RT-PCR product indicative of the translocation. We conclude that the most common primary genetic alteration in Ki-1 ALCL, the t(2;5), is absent or very infrequent in typical cases of HD. These results further support the concept that HD and Ki-1 ALCL are pathogenetically distinct entities.

Base Sequence↗

PubMed1994

Detection of BCL2 rearrangement in archival cytological smears of B-cell lymphomas.

The application of polymerase chain reaction (PCR) to cytological material represents a promising, relatively noninvasive approach to clinical molecular genetic analysis. The detection rate of the t(14;18), the most common translocation in B-cell lymphomas, which results in rearrangement of the immunoglobulin heavy chain (IGH) and BCL2 genes, has not been examined in archival cytological smears. We studied 10 cases of lymphoma that showed a cytogenetic t(14;18) in a surgical specimen and for which were available both lymphoma DNA from the same specimen and prior or subsequent archival cytological smears, either FNA or exfoliative, diagnosed as positive for lymphoma. The paired DNA samples, respectively extracted from the archival smears and frozen surgical biopsy tissue, representing clinical intervals of up to 20 mo, were studied in each case by PCR with IGH and BCL2 major breakpoint region primers. In four cases, the same clonotypical PCR product was seen in both samples. In four other cases, neither sample yielded a PCR product--these cases were also negative by Southern blotting using a BCL2 major breakpoint region probe. In one case, the PCR product could only be demonstrated in DNA from frozen tissue. Finally, in one other case, a PCR product was only detected in DNA from archival cytological smears. Thus, the overall concordance of PCR results in the paired DNA samples was 80%. Our findings suggest that, in cases of B-cell lymphoma previously characterized by PCR, the t(14;18) can be detected in archival cytological smears in the majority of cases, thereby providing valuable data regarding the clonal derivation of metachronous lymphoma samples in which only cytological material is obtained.

Adult↗

PubMed1994

Chromosomal aberrations in soft tissue tumors. Relevance to diagnosis, classification, and molecular mechanisms.

In recent years, significant progress has been made in identifying characteristic chromosomal rearrangements associated with several solid tumor types, notably sarcomas, a relatively rare subset of human cancer. Most sarcomas analyzed have been found to be characterized by recurrent chromosome translocations that are specific to histological types. We have reviewed published reports of chromosomal aberrations in benign and malignant soft tissue tumors and found an incidence of specific translocations in these neoplasms that ranged from 20% to 93% within histological tumor types. Identification of recurrent chromosomal abnormalities in benign tumors has resulted in a reappraisal of the general concept that benign tumors have a normal (diploid) chromosome constitution. The variety of recurrent changes present in the different tumor types attests to the cytogenetic diversity inherent in these tumors. The chromosomal rearrangements in each of the tumor types were unique and did not correspond to cancer-associated aberrations known from other solid or hematopoietic malignancies. Cytogenetics thus provides an essential adjunct to diagnostic surgical pathology in the case of malignant soft tissue tumors, which often present substantial diagnostic challenges. In addition, it represents another approach to determine the histogenetic origin of some tumors and identifies sites of gene deregulation for molecular analysis. Indeed, recent molecular analyses of several sarcoma-associated translocations have identified novel genes and novel mechanisms of their dysregulation.

Chromosome Aberrations↗

PubMed1993

MDM2 gene amplification in metastatic osteosarcoma.

The human homologue of the murine double minute 2 gene (MDM2), a p53-binding protein which may act as a regulator of p53 protein function, has recently been cloned. Initial studies of this gene in a variety of human tumors have shown frequent gene amplification in most types of sarcomas, including osteosarcomas. Amplification of the MDM2 gene may produce a functional inactivation of the p53 protein. To examine possible clinical or pathological correlates of MDM2 gene amplification in osteosarcoma, we studied 28 specimens on 26 patients with high grade osteosarcoma (16 primary, 11 metastatic, and 1 local recurrence) for MDM2 gene amplification by Southern blot analysis, using two MDM2 complementary DNA probes isolated by polymerase chain reaction. Four specimens (14%) showed amplification, including 3 metastases and 1 local recurrence. None of the primary osteosarcoma specimens had detectable MDM2 gene amplification. None of the specimens tested showed MDM2 gene rearrangement. In the present series, MDM2 gene amplification was detected significantly more frequently in metastatic or recurrent osteosarcomas than it was in primary osteosarcomas (P = 0.02). Our data suggest that MDM2 gene amplification may be associated with tumor progression and metastasis in osteosarcoma. Further investigation is warranted on the potential clinicopathological correlates of MDM2 gene amplification in osteosarcoma.

Adolescent↗

PubMed1993

Hypermutation of the MYC gene in diffuse large cell lymphomas with translocations involving band 8q24.

The sequence of the exon 1/intron 1 boundary region of the MYC gene was determined in two diffuse large cell lymphomas (DLCL), one with t(8;14) (q24;q32) and the other with t(8;22) (q24;q11). Both tumors had multiple mutations in this region. Also, both tumors had mutations in the protein binding site in intron 1, which is a frequent target for mutational inactivation in endemic Burkitt's lymphoma (eBL). The translocations at 8q24, and multiple mutations in the exon 1/intron 1 boundary region, are reminiscent of similar findings in eBL. The same underlying oncogenic event that occurs in most eBLs is thus found in some DLCLs.

Base Sequence↗

PubMed1993

EWS rearrangement in Ewing's sarcoma and peripheral neuroectodermal tumor. Molecular detection and correlation with cytogenetic analysis and MIC2 expression.

The translocation t(11;22)(q24;q12) can be identified in its classical or variant form in approximately 90% of cases of Ewing's sarcoma (ES) and peripheral neuroectodermal tumor (PNET). In this tumor group in which the histopathologic diagnosis is often one of exclusion, the cytogenetic demonstration of this translocation has become an invaluable positive diagnostic marker. With the recent cloning of the breakpoint regions of the t(11;22), molecular genetic approaches to the detection of this translocation have become possible. By Southern blotting, the position of the breakpoints on chromosome 22 has been found to be tightly clustered within a 7-kilobase (kb) fragment of the genomic DNA, within a gene designated EWS. In the present study, we examined the efficacy of an EWS complementary DNA (cDNA) probe in detecting the t(11;22) in Southern blots of EcoRI- or HindIII-digested DNA extracted from cases of ES and PNET. We also compared the results of the molecular and cytogenetic analysis with the expression of the ES cell surface antigen MIC2, as demonstrated by immunoperoxidase staining with the monoclonal antibodies O13 and HBA71. Twenty-three specimens were studied, including 18 ES and five PNET. Of 16 cases with clonally abnormal karyotypes, 14 (88%) showed a typical or variant t(11;22). Rearrangements were demonstrated within the EWS gene with the EWS cDNA probe in 20 of 23 specimens (87%), including all of the 14 cases, as well as in one case that displayed clonal numerical chromosome abnormalities only. The MIC2 antigen was expressed in 19 of 20 cases (95%), including all three cases lacking EWS rearrangement.(ABSTRACT TRUNCATED AT 250 WORDS)

12E7 Antigen↗

PubMed1993

Sporadic amplification of the MYC gene in human osteosarcomas.

The MYC proto-oncogene has been shown to be overexpressed in several types of sarcomas, including some osteosarcomas. In most cases, the overexpression is due to gene amplification. The total number of osteosarcoma patients studied, however, remains too small to derive any conclusions regarding the true prevalence and the possible clinical significance of MYC gene amplification. To address the issue more thoroughly, we studied 27 specimens from 25 patients with high-grade osteosarcoma (16 primary, 11 metastatic; 11 adult, 14 pediatric) for MYC gene alterations by Southern blot analysis. Two of 27 specimens (7%) showed MYC gene amplification: a primary fibrohistiocytic osteosarcoma of the femur in a 37-year-old man showed threefold amplification, and a primary Paget's osteosarcoma of the tibia in a 60-year-old man showed fourfold amplification. None of the specimens tested showed MYC gene rearrangement (zero of 27) or activating point mutations at the PvuII site in MYC exon-1 (zero of 26). Hence, the MYC gene is amplified in a subset of osteosarcomas. The possible clinical or biological significance of MYC gene amplification in osteosarcoma may warrant further investigation.

Adult↗

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

Variant t(8;14) translocations in non-Burkitt's non-Hodgkin's lymphomas.

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Adult↗

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↗