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At least 145 records · Page 8Linked to original sources
PubMed1987

Clonal evolution of t(14;18) follicular lymphomas demonstrated by immunoglobulin genes and the 18q21 major breakpoint region.

A 2.8-kilobase major breakpoint region on chromosome segment 18q21 is the site of most t(14;18) translocations typical of human follicular lymphomas. Breaks are focused at the 5' end of joining (JH) regions of immunoglobulin (Ig) on chromosome 14, indicating that the translocation occurs at a pre-B-cell stage during attempted heavy (H) chain joining. A new gene from 18q21 (Bcl-2) is placed in the H chain locus creating a unique, translocation-specific JH;18q21 rearrangement that presumably represents a transformation event. In addition, normal Ig gene joining occurs in a H before light (L) chain and K before lambda cascade, creating ordered clonal markers. These serial markers were examined to determine if variations in Ig gene patterns during the natural history of lymphomas represent the emergence of truly separate neoplasms or heterogeneity of a single neoplasm. We examined 45 serial biopsies from 16 B follicular lymphoma patients; six cases showed variation in Ig gene patterns over time. Seven individuals had a detectable JH;18q21 rearrangement present, and it remained unchanged over 5-10 years. Further rearrangements of H chain genes occurred on the normal chromosome 14 within evolving subclones of the original tumor. Lambda L chains also underwent additional rearrangements in two instances, while K gene patterns remained unchanged. All variations in the normal H and L chain genes were 2 degrees rearrangements occurring at a mature B-cell stage following the initial successful rearrangement of a H and L chain. In contrast the t(14;18) breakpoint was conserved in each individual, indicating that evolving neoplastic subpopulations arose from a common clonal progenitor cell.

Alleles↗
PubMed2005

DNA macrorestriction analysis of nontypeable group B streptococcal isolates: clonal evolution of nontypeable and type V isolates.

Group B streptococci (GBS) are serotyped according to capsular polysaccharide (CPS) type (Ia to VIII); an isolate is classified as nontypeable (NT) if no detectable CPS is found. Surface-localized protein antigens (alpha, beta, R1, and R4) serve as additional markers to classify GBS isolates, which is particularly useful since NT isolates often express one or more of these proteins. To compare genetic resemblance among isolates with similar protein profiles, we studied 58 NT isolates digested with the SmaI macrorestriction enzyme prior to pulsed-field gel electrophoresis (PFGE). Of these 58, 15.5% expressed alpha only, 20.7% expressed alpha+beta, 15.5% expressed R4, and 25.8% expressed R1,R4, while 22.4% of the isolates expressed no detectable proteins. The largest PFGE profile group, with 48% of the isolates, was group 4, composed primarily of isolates that expressed R1,R4 or no proteins. The second most common profiles were 3 and 32, each with 13.8% of the isolates. Since NT isolates in profile group 4 were highly related to type V isolates, as demonstrated by PFGE profiles, we investigated 45 type V isolates. Two-thirds of the type V isolates within profile group 4 were classified into subgroup 4a, compared to 28.2% of 39 NT isolates. Only 11% of the V/R1,R4 isolates were identical to the prototype group 4 profile, in contrast to 75% of the NT/R1,R4 isolates. A shift of type V isolates into profile 4 subgroups may be indicative of a genetic change over time. PFGE is a valuable approach for comparison of GBS isolate relatedness and for monitoring of NT and typeable GBS isolates for potential clonal divergence.

Bacterial Typing Techniques↗
PubMed2000

TCR v(beta) repertoire restriction and lack of CDR3 conservation implicate TCR-superantigen interactions in promoting the clonal evolution of murine thymic lymphomas.

Thymic lymphoma development is a multistage process in which genetic and epigenetic events cooperate in the emergence of a malignant clone. The notion that signaling via TCR-ligand interactions plays a role in promoting the expansion of developing neoplastic clones is a matter of debate. To investigate this issue, we determined the TCR V(beta) repertoire of thymic lymphomas induced in AKR/J mice by either endogenous retroviruses or the carcinogen, N-methyl-N-nitrosourea (MNU). Both spontaneous and MNU-induced lymphomas displayed restricted V(beta) repertoires. However, whereas V(beta)6, V(beta)8 and V(beta)9 were expressed by a greater than expected frequency of MNU-induced lymphomas, V(beta)8, V(beta)7, V(beta)13 and V(beta)14 were over-represented on spontaneous lymphomas. The dissimilar TCR V(beta) profiles indicate that different endogenous ligands promote neoplastic clonal expansion in untreated and MNU-treated mice. Although the nature of these ligands is not clear, the lack of conservation in TCR beta chain CDR3 regions among lymphomas that express the same V(beta) segment suggests that endogenous superantigens (SAG), as opposed to conventional peptide ligands, are likely to be involved in the selection process. The biased representation of lymphomas expressing V(beta)6-, V(beta)7- and V(beta)9-containing TCRs that recognize endogenous SAG is consistent with this hypothesis. The finding that Bcl-2 is expressed at high levels in spontaneous and MNU-induced lymphomas suggests that preneoplastic thymocytes may be resistant to SAG-induced clonal deletion. A working model is presented in which preneoplastic clones expressing TCRs that recognize endogenous SAG are selectively expanded as a consequence of sustained TCR-mediated signaling.

Animals↗
PubMed2000

Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung.

Comparative genomic hybridization (CGH) was applied to squamous cell carcinomas (SCC) of the lung to define chromosomal imbalances that are associated with the metastatic phenotype. In total, 64 lung SCC from 50 patients were investigated, 25 each with or without evidence of metastasis formation. The chromosomal imbalances summarized by a CGH histogram of the 50 cases revealed deletions most frequently on chromosomes 1p21-p31, 2q34-q36, 3p, 4p, 4q, 5q, 6q14-q24, 8p, 9p, 10q, 11p12-p14, 13q13-qter, 18q12-qter and 21q21. DNA over-representations were most pronounced for chromosomes 1q11-q25, 1q32-q41, 3q, 5p, 8q22-qter, 11q13, 12p, 17q21-q22, 17q24-q25, 19, 20q and 22q. In ten cases, paired samples of primaries and at least one metastasis were analysed. The comparison revealed a considerable chromosomal instability and genetic heterogeneity; however, the CGH pattern indicated a clonal relationship in each case. The difference in histograms from the metastatic and non-metastatic tumour groups was most useful in pinpointing chromosomal imbalances associated with the metastatic phenotype, indicating that the deletions at 3p12-p14, 3p21, 4p15-p16, 6q24-qter, 8p22-p23, 10q21-qter and 21q22, as well as the over-representations at 1q21-q25, 8q, 9q34, 14q12 and 15q12-q15, occurred significantly more often in the metastatic tumour group. The comparison of the paired samples confirmed these findings in individual cases and suggested distinct genetic changes, in particular the extension of small interstitial deletions, during tumour progression. Importantly, metastasis-associated lesions were frequently detectable in the primary tumour providing a method of identifying patients at risk for tumour dissemination. Individual profiles and histograms are accessible at our web site http://amba.charite.de/cgh.

Carcinoma, Squamous Cell↗
PubMed1994

Clonal evolution of malignant and non-malignant T cells carrying t(14;14) and t(X;14) in patients with ataxia telangiectasia.

People with ataxia telangiectasia (AT) are at a higher than normal risk of T cell leukaemia and often have either non-malignant or malignant T cells with chromosomal abnormalities, typically t(14;14), inversion 14 or more rarely t(X;14). This provides a chance to study the pre-leukaemic phase of the disease. T cells have been studied with either t(14;14)(q11;q32.1) or t(X;14)(q28;q11) from two AT sisters of which the latter developed T cell leukaemia. The telomeric breakpoint of the t(14;14) was cloned and found to occur at 14q32.1 where known tumour-associated breakpoints are located, but the patient remains asymptomatic for leukaemia. Analysis of T cell populations in both patients showed that the cells containing the translocation became oligoclonal with respect to T cell receptor beta rearrangement and complete T cell receptor beta clonality was only established in the patient with t(X;14) by onset of overt disease. Therefore in these chronic diseases, chromosomal translocations can precede T cell receptor rearrangement suggesting a role for these abnormalities as early events of malignant outgrowth.

Ataxia Telangiectasia↗
PubMed1995

Temperature gradient gel electrophoresis for analysis of clonal evolution in non-Hodgkin's lymphoma of the thyroid.

To analyze the transition of an autoimmune disease into a mucosa-associated lymphoid tissue-non-Hodgkin's lymphoma (MALT-NHL), we investigated a total of 27 cases of clinically diagnosed autoimmune thyroiditis with lymphoid hyperplasia. Three cases of thyroid hyperplasia served as controls. Monoclonal B cells were detected by studying rearrangement patterns of the hypervariable CDR III regions within the immunoglobulin heavy chain gene locus and the T-cell receptor gamma chain gene (TCRG). We used a seminested polymerase chain reaction (PCR) to demonstrate immunoglobulin rearrangements and a multiplex PCR for TCRG rearrangements. The PCR products were analyzed by temperature gradient gel electrophoresis to expand mixtures of homo- and hetero-duplices within heterogeneous populations of B cells. With this approach we found monoclonality in 14 of the 27 cases of Hashimoto's disease. In a reinvestigation we discovered additional histological and immunohistochemical features of MALT-NHL in 17 cases. The 14 cases of thyroiditis with clonally expanded B cells clearly demonstrate the transition from autoimmune disease to non-Hodgkin's lymphoma.

B-Lymphocytes↗
PubMed1998

Squamous change in bladder cancer and its relevance to understanding clonal evolution in development of bladder cancer.

Using conventional morphological assessment, squamous change in bladder epithelium has been observed in 73% of bilharzial associated squamous cancers but only 28% of pure transitional cancers. However, more detailed studies of patients with TCC suggest that the latter figure may be an underestimate, since in one series it was reported to be more than 50%. The most significant risk factor for development of squamous carcinoma in the bladder is chronic persistent bacterial cystitis, although in the areas of the world where bilharzia is endemic this infestation also increases the risk of both squamous bladder cancer and chronic bacterial cystitis. Although it is clear that carcinogens are involved as co-factors in transformation from squamous metaplasia to cancer, the fact that in Zimbabwe one author has observed that TCC is more frequent in whites than squamous cancer is in bilharzia infected blacks is evidence that other unidentified risk factors are involved. This is increasing evidence for involvement of HPV subtypes in cervix, oropharynx and lung cancer. As all three of these tumours are associated with squamous metaplasia, there could be a case for investigation of bladder squamous tumours for HPV involvement. This is particularly so given the observation of the "hit and run" type of transient infection in cattle that develop BPV associated tumours and the tenfold difference (30% vs 3%) in frequency of HPV detection in squamous skin tumours developing in immunosuppressed individuals compared with those arising spontaneously. With new technology for cytological screening techniques using dot ELISA and evidence of differences in TP53 mutations that support the involvement of nitrous oxide, it is clear that there is more to learn from study of this tumour type that may be of general interest in understanding the clonal development of cancer.

Animals↗
PubMed1996

Acquired homozygosity (isodisomy) of chromosome 3 during clonal evolution of a uveal melanoma: association with morphologic heterogeneity.

Cytogenetic investigation of untreated uveal melanoma has shown that the most frequent abnormality is monosomy 3, which occurs in approximately 60% of cases. One of our cases showed distinct pigmented and nonpigmented areas at gross dissection; representative tissue was collected separately from each area, cultured, and harvested using standard cytogenetic techniques. On histologic examination, the pigmented area was found to be composed of small epithelioid cells, whereas the nonpigmented area contained large, pleomorphic epithelioid cells. The karyotype of the pigmented tumor revealed monosomy 3, whereas the nonpigmented tumor showed two apparently normal chromosomes 3. Our purpose in the present study was to investigate the two tumor areas by molecular techniques to determine whether the karyotype of the nonpigmented tumor evolved directly from the pigmented tumor with duplication of the remaining chromosome 3 or whether the two sublines evolved in a divergent fashion from a common precursor stemline. DNA was extracted from normal lymphocytes and separately from both areas of the tumor. The DNA was analyzed using the polymerase chain reaction for polymorphic dinucleotide and tetranucleotide repeat sequences on chromosome 3. Both pigmented and nonpigmented areas of the tumor showed loss of heterozygosity at all informative loci on chromosome 3 that were tested. These results support our hypothesis that an abnormality on chromosome 3 plays a central role in the molecular pathogenesis of uveal melanoma and that some melanomas develop acquired homozygosity (isodisomy) by loss and duplication of the remaining, presumably abnormal, chromosome 3.

Aged↗
PubMed1986

Clonal evolution of T-cell chronic lymphocytic leukaemia in a patient with ataxia telangiectasia.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder in which patients show an unusual predisposition to malignant disease, including T-cell chronic lymphocytic leukaemia. We report here the steady growth over 5 years of a complex, cytogenetically abnormal clone of T lymphocytes in an A-T patient who was subsequently found to have an OKT3/OKT8 chronic lymphocytic leukaemia. The tumour cells at diagnosis had clearly evolved from a pre-existing, cytogenetically abnormal T-cell clone which contained an inv(14) chromosomal inversion alone.

Ataxia Telangiectasia↗
PubMed1987

Mast cell disease followed by leukemia with clonal evolution.

A 29-yr old woman developed urticaria pigmentosa which subsequently progressed through systemic mastocytosis to Philadelphia chromosome negative (Ph neg) chronic myelogenous leukemia (CML) with t(8;17). Further cytogenetic evolution occurred at the time of transformation to the aggressive phase of the disease. Unlike Ph-positive CML, chromosome number 9 was not involved, nor was the breakpoint cluster region located at band 22q11. This clearly separates this case from other Ph-negative CML patients who do have involvement of 9q34 or the breakpoint cluster region. Since this is the first case of its type to be reported with cytogenetic abnormalities, the clinical relevance of the unique chromosomal rearrangement t(8;17)(p11;q25) in the setting of systemic mastocytosis is unclear. Additional cases need to be reported to determine if this genetic rearrangement is a nonrandom marker of leukemia evolving in a setting of malignant mast cell disease.

Adult↗
PubMed1983

Cytogenetic evidence of clonal evolution in a case of hemopoietic dysplasia with a 5q- chromosome.

A 70-year-old Japanese male with hemopoietic dysplasia is described. Cytogenetic investigation revealed an abnormal karyotype, 46,XY,del(5)(q13q33), in all metaphases examined at the time of diagnosis. Eight months later, a newly appearing abnormal hyperdiploid karyotype, 47,XY,5q-, +21, was observed in 74% of the cells analyzed, which was associated with evolution of the disease when a pathologic diagnosis of a myeloproliferative disorder was made.

Aged↗
PubMed1990

Analysis of inferred cytogenetic clonal evolution in a metastatic human ovarian carcinoma.

Cytogenetic analyses of solid tumors are hampered both by the difficulties in preparing high-quality banded metaphases and the high degree of karyotypic heterogeneity. Three specimens were obtained from a single patient with serous carcinoma for karyotyping and compared to determine whether the tumor was multifocal or metastatic. All three specimens were hypodiploid, sharing marker chromosomes, thus indicating metastasis. To simplify comparison between the specimens, a diagram of the inferred cytogenetic evolution of the cells analysed was developed. This method afforded a simple means of comparing the different tumor sites in a single patient and might also be applied to sequential samples from patients.

Chromosome Aberrations↗