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PubMed1995

Karyotypic evolution in CLL: identification of a new sub-group of patients with deletions of 11q and advanced or progressive disease.

Chronic lymphatic leukaemia (CLL) is the most common leukaemia and is characterized by long-term survival. Previous studies have shown that karyotypic abnormalities are relatively stable and that certain abnormalities may be associated with a poor prognosis. In a prospective 5-year study of 45 patients with typical CLL, sequential karyotypic studies were undertaken every 6-12 months. Clonal karyotypic abnormalities were identified in 62% of patients, either at diagnosis or during the study period with 38% (17/45) exhibiting clonal evolution. In patients with no clinical disease progression, 13q abnormalities were most commonly detected compared with 11q deletions in patients with progressive disease. Karyotypic evolution was significantly associated with progressive disease (12/16, 75% vs 5/29, 17%; P < 0.001, chi2). Thus, karyotypic evolution is not uncommon in CLL, is usually associated with disease progression and deletions of 11q are the commonest detected abnormalities.

Adult↗
PubMed1999

[Molecular therapy in malignant tumors].

Gene therapy encompasses deliberate alteration of the genetic material of cancer cells. Somatic-cell therapy involves the administration to cancer patients of living cells that have been genetically manipulated or processed to change their biological characteristics. Gene therapy of cancer, although much hyped, is still in its very early infancy. Current approaches to delivering genes into cells include physico-chemical methods, viral vectors and direct DNA injection. None of these strategies is in any way perfect and their efficacy leaves much to be desired. Based on the somatic mutation theory of carcinogenesis, it would be attractive to repair genetic alterations responsible for neoplastic transformation and clonal evolution of cancer cells. Attempts have been made to replace inactivated tumour suppressor genes in cancer cells through intact wild type gene copies, or to suppress the leukaemogenic effects of chromosomal fusion genes in leukaemia through antisense oligonucleotides. One of the snags of these concepts is that cancer cells harbour several if not myriads of mutated genes, and clonal tumour heterogeneity seems to be the rule rather than the exception. It is at present impossible to repair all gene mutations in cancer lesions of a given patient if such were to be the aim of therapy. Nevertheless, some interesting clinical data have been reported. These include the local injection via bronchoscopy of p53 wild type gene copies into p53-deficient lung cancer lesions and other tumours. Somatic-cell therapy includes a considerable spectrum of interventions. Tumour cells may be transduced with genes which upon their expression will render the tumour cells more immunogenic. Tumour-infiltrating lymphocytes may be harvested, transduced with a gene of interest and re-injected. Since they recognise tumours specifically, they will serve as vehicles to carry therapeutic genes into cancer lesions where the gene product can exert an anti-cancer effect. Such attempts might increase the immunogenicity of tumours considerably. Examples are the transduction of tumour-infiltrating lymphocytes with a gene for tumour necrosis factor alpha or the transduction of tumour cells with the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic renal cell carcinoma. Protocols on gene therapy and somatic-cell therapy seem to be a worthy goal of cancer research. However, it seems unlikely that gene therapy will provide magic anti-cancer bullets in the near future or the definitive cancer cure, although this is often promised in the media. Careful clinical and laboratory research will pave the way towards stepwise improvement of cancer patient care.

Genetic Therapy↗
PubMed1990

Chromosomal evolution and tumor progression in a myxoid liposarcoma.

A myxoid liposarcoma showed macroscopic, histologic, and cytogenetic heterogeneity. In one of three myxoid nodules and in the surrounding lipoma-like tumor tissue, the translocation t(12;16)(q13;p11), known to be specific for myxoid liposarcoma, was found as the sole chromosomal abnormality. In the other two nodules, additional rearrangements involving chromosomes 1, 12, and 16 were found. These aberrations were probably secondary to the primary t(12;16), and are cytogenetic evidence of clonal evolution. The complex chromosome aberrations were present in those tumor parts that had more malignant histology, indicating that the acquisition of secondary chromosomal aberrations parallels the histologic manifestations of tumor progression.

Chromosome Aberrations↗
PubMed1984

Cell population analysis of a heterogeneous blast cell crisis of chronic myelogenous leukemia.

A case of Philadelphia negative chronic myelogenous leukemia (CML) is described with the following features: 1) initial lymphoid blast crisis; followed by 2) a heterogeneous blast crisis including myeloid, monocytic, and lymphoid elements that could be distinguished by morphological, cytochemical, ultrastructural methods and by immunologic markers; and 3) clonal evolution as shown by methylcellulose cultures and ultrastructural studies with emergence of a relatively drug resistant subclone of leukemic cells. Determination of surface antigen phenotype in CML blast crisis thus provides clinically useful information for the structuring of treatment protocols. This study also confirms previous studies that lymphoid blast crisis of CML can occur in Ph'-cases and that the Philadelphia chromosome is probably a clonal marker only and its presence is not directly related to the subsequent clinical course of the disease.

Cells, Cultured↗
PubMed1998

Nonrandom numerical chromosome abnormalities in basal cell carcinomas.

Clonal chromosome abnormalities were found in 22 of 23 short-term cultured basal cell carcinomas (BCC) of the skin. The karyotypic abnormalities were nonrandom and in several cases included evidence of clonal evolution. Especially in cultures showing an epithelial growth pattern, simple numerical changes, most commonly +18, +9, +20, +7, and +5, predominated and presumably constitute pathogenetically important aberrations present in the neoplastic parenchyma. Also, several structural rearrangements of chromosome arm 9q were seen, which may be of particular interest against the background that a gene for familial BCC (Gorlin syndrome), the PTCH gene, maps to this region. Finally, most of the clonal aberrations detected in predominantly fibroblast-like cultures are likely to reflect changes acquired by cells of the tumor stroma, which raises the question whether mutations also of this tumor component may play a pathogenetic role in BCC development.

Adult↗
PubMed1999

Field cancerization, clonality, and epithelial stem cells: the spread of mutated clones in epithelial sheets.

There has been considerable debate about the origin of human tumours, whether they arise from a single cell and are clonal populations or whether there needs to be some sort of co-operativity between cells for the neoplastic process to begin. Current theories subscribe to the clonal view, where a series of mutations in one cell begins a process of selection and clonal evolution leading to the development of the malignant phenotype. This review approaches this problem by asking how mutated clones, once established, spread through tissues before becoming overtly invasive. While there is substantial evidence in favour of independent origins of each tumour from a unique mutated clone, there are instances where such clones expand and remain cohesive, often involving a large area of tissue. The main example is the movement of mutated clonal crypts through the colorectal epithelium, by the process of crypt fission. In passing, the clonal architecture of early, pre-invasive lesions is examined, often with some surprising results.

Animals↗
PubMed1993

Chromosome aberrations in tenosynovial giant cell tumors and nontumorous synovial tissue.

Five tenosynovial giant cell tumors--4 pigmented villonodular synovitis (PVNS) and 1 nodular tenosynovitis (NTS)--were investigated cytogenetically. Clonal chromosome aberrations were detected in 3 of them. One PVNS had t(7;16)(q22;q24) as the sole anomaly, whereas 1 PVNS and the NTS displayed aberrations suggesting clonal evolution: t(1;19)(p11;p12)/t(1;19), +12 and ins(5;1)(q31p34)/ins(5;1),t(2;4)(p23;q21), respectively. Including our 3 cases, a total of 6 tenosynovial giant cell tumors with karyotypic changes have been reported. Apart from 2 PVNS with trisomies 5 and 7, and 2 NTS with rearrangement of chromosome band 1p13, no recurrent chromosome change has been detected. Although the detection of clonal, acquired chromosome abnormalities has formerly generally been accepted as sufficient to conclude that a lesion is neoplastic, the interpretation of the pathogenetic significance of the karyotypic aberrations in synovial tumors is obscured by the fact that we have also detected comparable aberrations in obviously nonneoplastic synovial tissue. One of 2 lesions from patients with hemorrhagic synovitis carried a clonal del(13)(q12q21), and 2 of 4 synovectomy samples from patients with rheumatoid arthritis displayed -Y and -Y together with +7. The available cytogenetic data therefore cannot be used to resolve the controversy as to whether tenosynovial giant cell tumors are truly neoplastic or only reactive, inflammatory proliferations.

Adult↗
PubMed1998

Cytogenetic analysis of colorectal adenomas: karyotypic comparisons of synchronous tumors.

The phenotypic progression of colorectal tumors is driven by their step-by-step acquisition of genomic alterations. These pathogenetically important mutations are at the same time markers of tumor clonality. The aim of this study was to describe the clonal relation among synchronous colorectal adenomas. Twenty-four colorectal adenomas from 11 patients were subjected to chromosome banding analysis. Clonal chromosome abnormalities were found in 20 tumors. Recurrent structural rearrangements involved chromosomes 1, 13, 17, and 18. The most common numerical changes were gain of chromosomes 7, 13, 20, and 3 and loss of chromosome 18. Eight adenomas had subclones as evidence of clonal evolution. Similar clones in separate polyps were seen in tumors from 6 patients; these adenomas were always located in the same part of the large bowel. In 2 patients, both with one rectal adenoma and one adenoma in the colon, no karyotypic similarity between the lesions was found. Our findings indicate that whereas close, but macroscopically distinct, synchronous colorectal adenomas usually have a common pathway of progression, perhaps even the same clonal origin, large bowel adenomas at a considerable distance from one another exhibit karyotypic differences, indicating that they arise independently.

Adenoma↗
PubMed1997

Properties of intraepithelial neoplasia relevant to cancer chemoprevention and to the development of surrogate end points for clinical trials.

Cancer chemoprevention is defined as the prevention of cancer by the administration of diet supplements or drugs. A drug discovery effort should therefore focus on finding agents that will avert the process of intraepithelial neoplasia which precedes invasive cancer. Over 30 agents developed by the chemoprevention program at the National Cancer Institute are being tested against intraepithelial neoplasia of many organ sites in more than 80 clinical trials. Two basic mechanisms underlie the onset and development of intraepithelial neoplasia. First is the development of the two precursor lesions of chronic diffuse epithelial hyperplasia and genomic instability, the latter being produced by "mutator" mutations in genes responsible for genomic stability, by gene copy amplification or loss from DNA breakage-fusion-anaphase-bridge cycles, by unequal sister chromatid exchange, and by accumulation of double minutes. Second is the development of multicentric intraepithelial neoplastic lesions which independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (i) the development of better technology for early diagnosis, (ii) the development of multiple agents that block intralesional proliferation at steps along the signal pathway of mitotic signal transduction and along the signal pathway of synthesis of daughter cell components, (iii) the development of nontoxic anti-inflammatory agents, anitoxidants, antimutagens, and proapoptotics, (iv) the avoidance of "clonal escape" through use of drug combinations, and (v) the use of computer-assisted quantitative image analysis to assay modulation of surrogate end points in chemoprevention clinical trials.

Anticarcinogenic Agents↗
PubMed1997

Properties of intraepithelial neoplasia relevant to the development of cancer chemopreventive agents.

Cancer chemoprevention is concerned with the development of drugs or diet supplements that will avert the onset or stop the progression of the intraepithelial neoplasia which precedes invasive cancer. Two basic processes underlie the onset and development of intraepithelial neoplasia. First is genomic instability (often associated with chronic diffuse epithelial hyperplasia), which is the increased production of genomic structural variants due to unrepaired DNA breaks with secondary formation of abnormal structures, including "mutator" mutations in genes responsible for genomic stability, gene copy amplification or loss from DNA breakage-fusion-anaphase bridge cycles, unequal sister chromatid exchange, and accumulation of double minutes. Second is the development within an epithelium having genomic instability of multicentric neoplastic lesions that independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (1) early diagnosis and treatment of genomic instability before the appearance of intraepithelial neoplasia, i.e., during the "predysplastic" or "premorphologic" phase, (2) development of multiple agents that block intralesional proliferation at steps along the "command" pathways of mitotic signal transduction and along the "execute" pathways of synthesis of daughter cell components, (3) development of nontoxic antiinflammatory agents, antioxidants, antimutagens, and proapoptotics, (4) avoidance of "clonal escape" through use of drug combinations, and (5) use of computer-assisted quantitative image analysis to assay modulation of surrogate endpoints in chemoprevention clinical trials.

Carcinoma in Situ↗
PubMed2026

Grade progression and high-grade transformation in neuroendocrine neoplasms.

Epithelial neuroendocrine neoplasms (NENs) comprise a biologically diverse group of malignancies that span a wide spectrum of differentiation, proliferative activity, and clinical behavior. Contemporary classifications distinguish well-differentiated neuroendocrine tumors (NETs) from poorly differentiated neuroendocrine carcinomas (NECs). However, growing longitudinal data indicate that a subset of NETs may undergo temporal evolution characterized by rising Ki-67, increasing morphologic atypia, and acquisition of genomic alterations classically associated with NEC, particularly TP53 and, less commonly, RB1 inactivation. These phenomena, referred to as grade progression and high-grade transformation, can result in tumors with NEC-like behavior despite retention of a NET molecular backbone, creating diagnostic and therapeutic ambiguity. In this review, we synthesize recent evidence on the molecular, morphologic, and clinical features of gastroenteropancreatic NET grade progression and transformation, highlight the role of clonal evolution and treatment-associated selection pressure, and discuss implications for imaging, biopsy strategy, molecular profiling, and therapy selection.

Humans↗
PubMed1981

Heterogeneous blast cell crises in Philadelphia negative chronic granulocytic leukaemia.

A case of Philadelphia negative chronic granulocytic leukaemia (Ph1-CGL) is described showing features only previously demonstrated in Ph1+ disease. These features include: (1) lymphoid blast crisis, determined by morphology and immunological marker analysis; (2) dual blast cell populations that can be distinguished both morphologically and by immunological markers; (3) clonal evolution, as shown by the emergence of chromosome markers and in one of the cell lines a change in membrane phenotype. These changes were apparently associated with the emergence of a relatively drug resistant subclone of leukaemic cells. This study demonstrates that the lymphoid blast crisis of CGL, and its sequelae, can occur in Ph1- cases. It is similar in respect to morphology, enzyme, and membrane markers and responsiveness to vincristine and prednisolone therapy to the lymphoid blast crisis seen in Ph1+ CGL. This suggests that the Philadelphia chromosome is a clonal marker only, and its presence is not directly related to the subsequent clinical course of the disease.

Bone Marrow↗
PubMed2003

Trisomy 13 in a patient with common acute lymphoblastic leukemia: description of a case and review of the literature.

Trisomy 13 occurring as a single cytogenetic abnormality has been associated with undifferentiated or biphenotypic acute leukemias and with an adverse prognostic outcome. We describe for the first time a case of B-cell common acute lymphoblastic leukemia (ALL) with trisomy 13 at diagnosis in an 18-year-old boy. The leukemic cells did not express myelocytic or T-cell associated antigens and no molecular abnormalities were detected. Following treatment, according to the GIMEMA ALL 0496 protocol, the patient achieved a brief (2 months) complete remission. At relapse, cytogenetic analysis showed karyotypic evolution that included two novel subclones carrying a del(6q), a del(7q), and an add(17q) in association with trisomy 13. In addition, immunophenotypic analysis revealed the coexpression of the CD33 and CD7 antigens on common ALL blasts, in accordance with other reported cases that displayed a predominant biphenotypic leukemia profile. The patient failed to obtain a second remission and died soon after due to infective complications. This report indicates that trisomy 13 can be found also in B-lineage ALL and underlines that this cytogenetic abnormality may identify a subgroup of male patients with clonal evolution potential and an adverse clinical outcome.

Adolescent↗
PubMed1993

The cytogenetic scenario of chronic myeloid leukemia.

The Philadelphia chromosome (Ph), i.e., the reciprocal translocation t(9;22)(q34;q11), is found with great specificity in bone marrow cells from patients with chronic myeloid leukemia (CML). Variant Ph-producing translocations, seen in 5-10% of all patients, are all complex and involve the same molecular rearrangement as the regular t(9;22). Patients with classic and variant Ph-producing translocations are clinically and hematologically identical, and as a group differ from Ph-negative CML patients. In all patient groups, the occurrence of additional chromosome changes is an ominous sign indicating that disease progression is imminent. The chromosome changes occurring in excess of the Ph in CML are clearly nonrandom and two pathways of cytogenetic evolution may be distinguished. Major route changes comprise trisomy 8, i(17q), trisomy 19, and an extra Ph; totally, 71% of Ph-positive CML patients have at least one of these four major route changes. Six minor route changes, including five numerical abnormalities (-7, -17, +17, +21, and -Y) but also one structural aberration, t(3;21) (q26;q22), have been identified. At least one of these changes is found in 15% of all Ph-positive CML cases. Altogether, the four major route aberrations and the six minor route changes are present as part of the clonal evolution in 86% of CML with cytogenetic abnormalities in addition to the Ph chromosome.

Blast Crisis↗
PubMed1982

Evolution of Sézary syndrome in the course of hairy cell leukemia.

A patient with a history of "leukemia" for 19 yr and documented hairy cell (HC) leukemia for 10 yr developed mycosis fungoides and the Sézary syndrome. The manifestations of both diseases were diagnostic on clinical and pathologic grounds. Ultrastructural, immunohistochemical, and surface marker techniques proved the HC to have phenotypic characteristics of the T-helper subset of lymphocytes to which the Sézary cells (SC) also belonged. Both types of cells contained tartrate-resistant acid phosphatase. HC did not infiltrate the skin. SC did not contain ribosome lamellar complexes. Because of otherwise overlapping morphology and the apparent replacement of HC by SC, it is likely that the Sézary cells constituted a genetic variant of the original neoplastic clone represented by the hairy cells. Since the biologic and therapeutic implications of such clonal evolution may be important, subtle phenotypic changes should be looked for repeatedly in patients with these diseases.

Aged↗
PubMed2003

Genetic evolution of alpha fetoprotein producing gastric cancer.

BACKGROUND: Alpha fetoprotein (AFP) producing gastric cancer is an unusual form of aggressive adenocarcinoma with a complex histological picture, including enteroblastic and hepatoid differentiation. AIMS: To investigate the genetic events underlying the phenotypic diversity in AFP producing gastric cancer and the ability of these tumours to produce AFP ectopically. METHODS: Multiple foci from 19 AFP producing gastric adenocarcinomas were microdissected and loss of heterozygosity (LOH) analysis was performed with a panel of microsatellite markers on nine chromosomal arms. RESULTS: For informative cases, LOH was most frequently detected on 17p (100%), followed by 13q (88%), 3p (87%), 5q and 9p (80%), 11q (70%), 18q (58%), 16q (53%), and 8p (50%). The average fractional allelic loss was 0.72. LOH was detected either homogeneously throughout the microdissected foci, or only in some parts of the neoplastic foci for each case. Heterogeneous patterns of LOH indicated genetic progression and/or divergence in clonal evolution. Furthermore, in six cases with heterogeneous LOH of 13q, 13q LOH was restricted to immunohistochemically AFP positive neoplastic foci. CONCLUSION: AFP-GC arises as an aggressive clone with extensive LOH and high fractional allelic loss. The presence of heterogeneous patterns of LOH suggested that the AFP producing carcinoma foci might evolve through genetic progression and/or genetic divergence. Silencing of the crucial gene on 13q may be involved in the acquisition of the AFP producing phenotype.

Adult↗
PubMed1992

Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin.

One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in "remission," ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in "remission." Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during "remission." Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.

Adult↗
PubMed1993

Overrepresentation of chromosome 12p sequences and karyotypic evolution in i(12p)-negative testicular germ-cell tumors revealed by fluorescence in situ hybridization.

Human testicular germ-cell tumors (TGCTs) comprise a heterogeneous group of solid neoplasms. These tumors are characterized by the presence of a highly specific chromosomal abnormality, i.e., an isochromosome of the short arm of chromosome 12. At present, this i(12p) chromosome is found in more than 80% of TGCTs. Isochromosome 12p has also been observed in some ovarian and extragonadal germ cell tumors. In the remaining so-called i(12p)-negative TGCTs other abnormalities involving chromosome 12, mainly 12p, can be found. In order to establish whether 12p abnormalities other than i(12p) are a common phenomenon in TGCTs, a panel of 11 i(12p)-negative tumors was investigated using multicolor fluorescence in situ hybridization. All TGCTs examined appeared to contain chromosomal abnormalities involving 12p, resulting in a distinct overrepresentation of short arm sequences. In addition, indications were obtained for a clonal evolution in one of the tumors. Our data suggest that the occurrence of 12p abnormalities is a common phenomenon in i(12p)-negative TGCTs and that these abnormalities, analogous to i(12p), may contribute to the process of tumor development.

Chromosome Aberrations↗