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PubMed1993

Molecular diagnosis of lymphocytic infiltrates of the skin.

BACKGROUND: Advances in our understanding of the molecular genetics of lymphocyte antigen receptors (B-cell immunoglobulin and T-cell antigen receptor), have led to the application of molecular biologic techniques to molecularly characterize lymphocytic infiltrates of the skin. Molecular diagnosis refers to the application of these techniques as a diagnostic aid in the clinicopathologic evaluation of cutaneous lymphocytic infiltrates. OBSERVATION: Molecular studies have clinical application in the determination of lineage and detection of retroviruses in cutaneous lymphoid neoplasms, distinguishing between lymphoproliferative and reactive infiltrates, and staging and monitoring response to therapy in cutaneous T-cell lymphoma. Southern blot analysis of immunoglobulin and T-cell antigen receptor gene rearrangements may fail to aid the clinician in establishing a diagnosis of a cutaneous malignancy due to the limits of detection sensitivity in minimally infiltrated lesions (eg, parapsoriasis and patch-stage mycosis fungoides) or the still uncertain prognostic significance of clonality in benign cutaneous diseases (eg, follicular mucinosis, pityriasis lichenoides et varioliformis acuta, lymphomatoid papulosis, and cutaneous lymphoid hyperplasia). CONCLUSIONS: Molecular studies have enormous research value, providing new means to explore the pathogenesis and clonal evolution of lymphoproliferative skin diseases. Presently, however, they have limited applications as an independent diagnostic tool. As our understanding of the clinical and biologic significance of the molecular detection of clonal lymphocyte populations in the skin expands and as the application of polymerase chain reaction amplification provides us with greater detection sensitivity and specificity, the clinical utility of molecular diagnosis of lymphocytic infiltrates of the skin will be enhanced.

Antibodies, Monoclonal↗

PubMed1990

Chromosome evolution and high-resolution analysis of leucocytes, bone marrow, and tumor cells of retinoblastoma patients.

High-resolution cytogenetics were applied to leucocytes, bone marrow, and tumors of 8 retinoblastoma (Rb) patients in search of microdeletions or subtle rearrangements and in order to determine clonal evolution. Four of 9 tumors (Rb1, Rb6.1, Rb6.2, and Rb8) showed a deletion in the characteristic region on 13q while 2 others (Rb3 and Rb4) were hemizygous for chromosome 13 in approximately one-third of the cells. Our study presents a particularly high incidence of chromosome 13 anomalies as compared to the previously published data. Furthermore, comparison of karyotypes of 3 significant cases (Rb1, Rb6, and Rb8) allows the reconstruction of the necessary steps in the evolution of retinoblastoma. It also shows the need for a double mutation in tumor development, both in hereditary and non-hereditary cases. High-resolution chromosome analysis of retinoblastoma patients provides a rare opportunity to study the succession of events necessary for tumor development.

Bone Marrow↗

PubMed2025

Spatial-Temporal Diversity of Extrachromosomal DNA Shapes Urothelial Carcinoma Evolution and Tumor-Immune Microenvironment.

Extrachromosomal DNA (ecDNA) presents a promising target for cancer therapy; however, its spatial-temporal diversity and influence on tumor evolution and the immune microenvironment remain largely unclear. We apply computational methods to analyze ecDNA from whole-genome sequencing data of 595 urothelial carcinoma (UC) patients. We demonstrate that ecDNA drives clonal evolution through structural rearrangements during malignant transformation and recurrence of UC. This supports a model wherein tumors evolve via the selective expansion of ecDNA-bearing cells. Through multi-regional sampling of tumors, we demonstrate that ecDNA contributes to the evolution of multifocality and increased intratumoral heterogeneity. EcDNA is present in 36% of UC tumors and correlates with an immunosuppressive phenotype and poor prognosis. Single-cell RNA sequencing analyses reveal that ecDNA+ malignant cells exhibit diminished expression of major histocompatibility complex class I molecules, enabling them to evade T-cell immunity. Finally, we show that sequencing of urinary sediment-derived DNA has excellent specificity in detecting ecDNA.

Journal Article↗

PubMed1987

Gene rearrangements as markers of clonal variation and minimal residual disease in acute lymphoblastic leukemia.

Immunoglobulin (Ig) heavy (H) and light (L) chain gene rearrangements were used as molecular markers of clonal evolution and minimal residual disease in B cell precursor acute lymphoblastic leukemia (ALL). All leukemic episodes within individual patients shared at least one identical Ig rearrangement and thus arose from a common clonal progenitor cell. Nine of 11 patients displayed completely identical patterns between leukemic episodes, while two of 11 patients demonstrated genetic progression between diagnosis and relapse as evidenced by additional rearrangements. These genetic changes marked the emergence of leukemic subclones. Ig gene rearrangements were also used as sensitive markers to identify clonal cell populations in ALL patients following induction or reinduction therapy and to search for residual bone marrow disease in patients in clinical remission or with isolated extramedullary relapse. DNA rearrangements provide tumor-specific markers to follow the genetic variation of ALL and may facilitate the early detection of recurrent disease.

B-Lymphocytes↗

PubMed1994

Chance and selection in the evolution of barley mildew.

Populations of the barley powdery mildew fungus are genetically very diverse. However, when a new resistance gene is introduced into barley to control mildew, the population of the pathogen may respond by rapid growth of a few virulent clones. These phases of rapid clonal evolution cause radical changes in the frequencies of mildew genotypes.

Biological Evolution↗

PubMed1992

Myelodysplastic syndromes in childhood: a population based study of nine cases.

Nine cases of de novo myelodysplastic syndromes (MDS) in childhood from a population based study are presented. The annual incidence of MDS was 3.4/1,000,000 in children less than 15 years old, corresponding to 8.7% of all haematological malignancies in childhood. Two patients had Down's syndrome. None of the remaining patients had constitutional anomalies. All patients were classified according to the FAB classification. Five patients presented with refractory anaemia (RA), only one of these did not progress, one showed clonal evolution, and the remaining three patients all progressed to refractory anaemia with excess of blasts (RAEB). Three patients presented with RAEB. Two progressed to overt leukaemia. The last patient was classified as chronic myelomonocytic leukaemia (CMML). Clonal cytogenetic abnormalities were detected in five patients, in three of them as monosomy 7. Five patients have died; two of progressive disease, two of infections, and one of haemorrhage, two of the latter three patients died during therapy induced cytopenia. Of the four patients still alive, one patient showed a complete remission after cyclosporine and later immunoglobulin therapy, one patient is a long-term survivor after allogeneic bone marrow transplantation, and one patient apparently obtained a spontaneous remission several months after chemotherapy.

Adolescent↗

PubMed1979

In vitro granulopoiesis in oligoblastic leukaemia: prognostic value, characterization and serial cloning of bone marrow colony and cluster forming cells in agar culture.

The colony and cluster forming capacity of bone marrow cells (BM CFC and CluFC) in agar culture, was studied from 20 oligoblastic patients. 13 patients had a leukemic growth pattern and 12 of these died within one year after diagnosis. 7 patients had no leukemic growth and 4 are alive 16 to 90 months after diagnosis. Both the determination of the proportion of abnormally light buoyant density of CFC and CluFC and the study of their suiciding index were used to characterize more precisely the leukemic or nonleukemic status of patients. Because of the small number of patients involved in the later preliminary study, the prognostic significance cannot be valuated. Serial studies of individual patients showed different types of evolution in the growth pattern of BM CFC and CluFC. Either the increase of BM CFC and CluFC paralleled that of the myeloblasts, or there was a change in the growth pattern before AML transformation suggesting clonal evolution.

Aged↗

PubMed1995

Twenty-three cases of acute lymphoblastic leukemia with translocation t(4;11)(q21;q23): the implication of additional chromosomal aberrations.

The translocation t(4;11)(q21;q23) is one of the most common specific chromosomal aberrations in acute lymphoblastic leukemia (ALL), occurring in 2% of childhood and in 5-6% of adult cases. Especially in adults, the t(4;11) is associated with a poor prognosis. In order to determine the significance of clonal chromosome aberrations that occur in addition to t(4;11), we studied the karyotypes and clinical courses of 23 patients with acute lymphoblastic leukemia and a translocation t(4;11)(q21;q23). Additional clonal chromosome aberrations were found in ten patients. An isochromosome i(7)(q10) and a trisomy 6 were observed most frequently as secondary anomalies. Clonal evolution was detected in four of six patients analyzed at diagnosis as well as at relapse. With treatment carried out according to modern risk-adapted therapy protocols, no difference in outcome was observed between patients with clonal chromosome aberrations in addition to t(4;11) at diagnosis and those without.

Adolescent↗

PubMed1980

C-group chromosome abnormalities in bone marrow cells of three children with dyshematopoiesis of unknown origin.

Clinical and cytogenetic findings in three children with dyshaematopoiesis and bone marrow aneuploidy are described. Monosomy 7 was found in immature cells of one 10-year-old boy with myelofibrosis following a 3 years evolution of severe thrombocytopenia and anaemia. Trisomy 8 was found in 80% of the bone marrow metaphases of a 5 1/2-year-old girl with aplastic anaemia and Australia antigen positivity. During a 3 year observation period the number of cells with trisomy 8 regressed and eventually disappeared. Improvement of her clinical condition is present but still limited. Trisomy 8 was also found in all bone marrow cells of an 8-year-old girl with an undefined myeloproliferative disorder. Her disease was apparently related to collagen-vascular disorders like periarteritis or other necrotizing angiitis and presented with periods of exacerbation and periods of chronic evolution. Periods of exacerbation were accompanied by excessive myeloid proliferation. Repeated bone marrow cytogenetic analysis during the acute and chronic phases showed trisomy 8 in all the metaphases analysed. During the last episode of acute illness, further clonal evolution was observed, characterized by a translocation (8;17).

Anemia, Aplastic↗

PubMed2000

Hodgkin/Reed-Sternberg cells and Hodgkin's disease in patients with B-cell chronic lymphocytic leukaemia: an immunohistological, molecular and clinical study of four cases suggesting a heterogeneous pathogenetic background.

We report the immunohistological, molecular and clinical findings in four patients affected by B-cell chronic lymphocytic leukaemia (CLL) who developed "Richter's syndrome with Hodgkin's disease (HD) features" or "CLL with Hodgkin's transformation", all characterised by the presence of typical Hodgkin/Reed-Sternberg (H/RS) cells in lymph node biopsies. In three cases the nodal involvement by CLL was demonstrated both by the presence of a predominant background of CD5/CD19/CD23+ small lymphocytes and an IgH monoclonal rearrangement revealed by PCR analysis. Conversely, in the remaining case there was neither immunohistological nor molecular evidence of lymph node involvement by CLL. In all four cases H/RS cells were Epstein-Barr virus (EBV) latent membrane protein (LMP-1) positive. These findings suggest that the presence of H/RS cells in the first three patients, who had CLL/HD nodal involvement, might be related to transformation or clonal evolution of CLL cells in H/RS cells, which is in keeping with use of the term "CLL with Hodgkin's transformation". In the fourth case a de novo HD may be postulated, representing a second malignancy presumably not clonally related to CLL. In all cases a key pathogenetic role of EBV is suggested by the expression of LMP-1 in H/RS cells. Our findings indicate that the presence of typical H/RS cells in lymph node biopsies in CLL patients may reflect a heterogeneous pathogenetic background. The different clinico-pathologic settings should be taken into consideration because of their possible implications for patients' treatment and prognosis.

Aged↗

PubMed1992

Epstein-Barr virus-associated anaplastic large cell lymphoma in renal transplant patients.

A novel association, Epstein-Barr virus-positive Ki-1+/CD30+ anaplastic large cell non-Hodgkin's lymphoma of B-cell phenotype in immunosuppressed renal transplant recipients is reported. Case 1 involved an aggressive clinical evolution, whereas case 2 followed a more "benign" clinical course. Both lymphomas were Epstein-Barr virus-positive as assessed by in situ hybridization, Southern blot, polymerase chain reaction, and immunohistochemical analysis. Both lymphomas contained a single clonal Epstein-Barr virus terminal-repeat fragment. In case 1, clonality was confirmed by the detection of bi-allelic immunoglobulin (Ig) heavy chain gene rearrangement. Case 2 showed germline Ig genes at presentation and oligoclonal Ig heavy chain gene rearrangements at relapse. These results are consistent with the notion that anaplastic large cell lymphoma might arise in a B cell transformed by Epstein-Barr virus at a very early stage, before Ig gene rearrangement. The latter may occur later in the course of clonal evolution, thus permitting investigators to trace intermediate and late stages within a process of multistep lymphomagenesis and/or tumor progression.

Adolescent↗

PubMed1985

Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications.

The myelodysplastic syndromes represent a preleukaemic state in which a clonal abnormality of haemopoietic stem cell is characterised by a variety of phenotypic manifestations with varying degrees of ineffective haemopoiesis. This state probably develops as a sequence of events in which the earliest stages may be difficult to detect by conventional pathological techniques. The process is characterised by genetic changes leading to abnormal control of cell proliferation and differentiation. Expansion of an abnormal clone may be related to independence from normal growth factors, insensitivity to normal inhibitory factors, suppression of normal clonal growth, or changes in the immunological or nutritional condition of the host. The haematological picture is of peripheral blood cytopenias: a cellular bone marrow, and functional abnormalities of erythroid, myeloid, and megakaryocytic cells. In most cases marrow cells have an abnormal DNA content, often with disturbances of the cell cycle: an abnormal karyotype is common in premalignant clones. Growth abnormalities of erythroid or granulocyte-macrophage progenitors are common in marrow cultures, and lineage specific surface membrane markers indicate aberrations of differentiation. Progression of the disorder may occur through clonal expansion or through clonal evolution with a greater degree of malignancy. Current attempts to influence abnormal growth and differentiation have had only limited success. Clinical recognition of the syndrome depends on an acute awareness of the signs combined with the identification of clonal and functional abnormalities.

Anemia, Refractory, with Excess of Blasts↗

PubMed1986

Phenotypic changes in large cell transformation of small cell lymphoid malignancies.

Large cell transformation of two cases of chronic lymphocytic leukemia and two cases of small lymphocytic lymphoma were studied. Changes in surface immunoglobulins were observed in two cases. In one case, there was a change from IgM to IgG. In another case, the large cells bore kappa light chains whereas the small cells had lambda light chains. Surface antigens other than immunoglobulin might also differ. All three small cell malignancies tested, but none of the large cell tumors, expressed the antigen T1 (Leu 1). The antigens HLA-DR, Leu 14, B1, and BA1 were expressed by both the small and large cell malignancies with one exception. The staining intensity might, however, change on transformation. The common acute lymphocytic leukemia antigen was not detected on any of the tumors studied and the expression of BA2 was variable. Surface marker studies cannot confidently distinguish between large cell lymphomas resulting from clonal evolution and those arising de novo. More definitive studies such as analyzing the idiotypic determinants on and amino acid sequences of the heavy and light chains or analyses of immunoglobulin gene rearrangements are necessary to confirm or exclude the same clonal origin in such cases.

Adult↗

PubMed1996

Amyloid tumors of the lung--an immunocytoma?

Amyloid tumors are nodular amyloid depositions usually limited to one organ, which often develop without a known cause. In most cases they may be observed as being situated in the lung, the larynx, the skin, the urinary bladder and in the region of the orbita, and are restricted to these organs. In the present study, we report on two cases of pulmonal amyloid tumors which after immunohistochemical investigation revealed a clonal evolution of light chain restricted plasma cells and lymphocytes corresponding to a localized primary extranodal lymphoplasmacytic immunocytoma, with only few vital tumor cells among abundant tumor-shaped amyloid. Additionally, using polymerase chain reaction (PCR) to investigate IgH gene rearrangement, clonality of the tumor cells could be demonstrated in both cases.

Aged↗

PubMed1984

Clonal analysis of stable chromosome rearrangements in Bloom's syndrome fibroblasts.

In situ cytogenetic analysis was performed on colonies derived from single cells of cultured skin fibroblast-like strains from two patients with Bloom's syndrome (GM 1492 and GM 2520). Metaphases in all of the colonies displayed structural chromosome rearrangements. Among 212 metaphases from 24 colonies of GM 1492, only 16% were pseudodiploid, and there was a high incidence of de novo rearrangements within individual colonies. There were two "families" of 16 and five colonies, respectively, each containing identical or related aneusomies, and these could be arranged into pedigrees showing clonal evolution. The heterochromatic region of chromosome #1 and the telomeric regions of chromosome arms 2q, 3q, 4p, and 11q were most frequently involved in the rearrangements. In contrast, strain GM 2520 showed less intraclonal variation, was primarily pseudodiploid, and displayed only three clonal types, one of which had extensive subclonal variation (19 of 24 clones). A remarkable finding in GM 2520 was that, in some clones, extra copies of specific chromosome segments were present as translocations. These results caution against the use of strain GM 1492 as a prototype Bloom's syndrome strain for cell biological studies.

Bloom Syndrome↗

PubMed1990

Use of oligonucleotide probes directed against T cell antigen receptor gamma delta variable-(diversity)-joining junctional sequences as a general method for detecting minimal residual disease in acute lymphoblastic leukemias.

To provide a sensitive and generally applicable method to detect clonal cells in acute lymphoblastic leukemias (ALL), we have designed a new strategy based on the polymerase chain reaction (PCR) amplification of the T cell receptor gamma delta gene rearrangements found in most T and B lineage ALLs. PCR allows rapid sequencing of variable-(diversity)-joining (V-[D]-J) junctions from tumor DNA and construction of anti-junctional oligonucleotides (AJOs) used as probes to detect clonal cells in the same patient. We have defined oligonucleotides suitable for all T cell receptor (TCR) rearrangements involving functional V gamma segments. Oligonucleotides corresponding to preferential TCR delta rearrangements in T and B lineage ALLs were also used. By analysis of the nucleotide sequence of 52 V gamma-V gamma junctions from 30 cases of B and T ALLs, we demonstrate that V-J junctional sequences are clone specific in both lineages and at all stages of differentiation examined despite the frequent presence of the recently described P nucleotides. Experiments performed with TCR gamma delta AJOs on DNA from tumor cells and polyclonal T cells show that AJOs can be used to differentiate clonal cells from polyclonal T cells, distinguish between different T cell clones, and detect residual clonal populations at 10(-4)/10(-5) dilution. AJOs were also used to detect residual disease in samples from patients in clinical and morphological complete remission. Finally, rearrangement patterns were studied by classical Southern analysis in selected cases at both presentation and subsequent relapse showing absence of clonal evolution in most cases. V-(D)-J nucleotide sequences of rearrangements with an identical pattern of rearrangement at presentation and relapse were identical in all cases analyzed. We therefore describe a new, specific, and clinically useful strategy for the detection of minor clonal populations applicable in the majority of cases of ALL.

Alleles↗

PubMed1985

Karyotypic evolution in multiple myeloma.

A patient with IgG kappa multiple myeloma was studied cytogenetically prior to therapy and was found to have a clone of 55,XX cells. After treatment leading to a clinical response, the patient relapsed with a clone of 57,XX cells, which were derivatives of the original neoplastic cell line. This is the first case of demonstrated clonal evolution of myeloma in a patient studied prior to chemotherapy.

Aged↗

PubMed1995

Large-cell transformation following detection of minimal residual disease in cutaneous T-cell lymphoma: molecular and in situ analysis of a single neoplastic T-cell clone expressing the identical T-cell receptor.

PURPOSE: One of the unique characteristics of cutaneous T-cell lymphoma (CTCL) is its ability to undergo cytologic transformation in which the malignant T cells develop the morphologic appearance of a large-cell lymphoma. Reported to occur in up to 20% of advanced cases, large-cell transformation (LCT) is associated with an aggressive clinical course. Little is known about the risk factors or the molecular mechanisms of LCT. Before current immunohistochemical and molecular techniques, it was not possible to determine if LCT represented changes of the initial neoplastic T-cell clone or, in fact, was a distinct second malignancy. The goal of this study was to define the clonal evolution of LCT in CTCL. PATIENTS AND METHODS: Polymerase chain reaction (PCR) amplification of T-cell receptor-beta (TCR-beta) gene rearrangements and immunohistochemistry with monoclonal antibodies to TCR-V beta regions were used as markers of T-cell clonality to analyze the skin and peripheral blood of a patient with CTCL and LCT. RESULTS: We first detected the presence of minimal residual disease (MRD) in a CTCL patient with a complete clinical response to biologic response modifiers (BRMs). When clinical relapse occurred and demonstrated LCT, TCR-beta-PCR and in situ immunohistochemistry with a specific TCR-V beta monoclonal antibody identified a single neoplastic T-cell clone that expressed the identical TCR as the original clone. CONCLUSION: Our results confirm a common clonal origin for CTCL and LCT. We also provide evidence of MRD in CTCL by molecular analysis, implying that residual malignant cells maintain a potential for clinical relapse and possibly LCT. The role of MRD detection remains to be defined in the clinical assessment of CTCL. LCT in CTCL provides a unique model to investigate the molecular events that underlie terminal-stage tumor progression.

Amino Acid Sequence↗