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PubMed2006

Molecular biology of Barrett's cancer.

Oesophageal adenocarcinoma (OA) remains one of the more deadly forms of gastro-intestinal cancer with a mortality rate exceeding 90%. The incidence of OA remains unabated and has a reported fivefold increase since 1970 [Pera M, Cameron AJ, Trastek VF, Carpenter HA & Zinsmeister AR. Increasing incidence of adenocarcinoma of the esophagus and esophagogastric junction. Gastroenterology 1993; 104(2): 510-513]. Gastro-oesophageal reflux disease and its sequelae, Barrett's oesophagus, is one of the principle risk factors in the development of OA, with a 30-fold increased risk in Barrett's patients compared with the general population [Tytgat GNJ. Does endoscopic surveillance in esophageal columnar metaplasia (Barrett's-Esophagus) have any real value. Endoscopy 1995; 27(1): 19-26]. OA is thought to be a microcosm of evolution, developing sequentially along the metaplasia-dysplasia-adenocarcinoma sequence. Progression is attributed to a series of genetic and epigenetic events that ultimately allow for clonal selection of Barrett's cells via subversion of intrinsic control mechanisms regulating cellular proliferation and/or apoptosis. This review will describe the current suppositions of the mechanisms behind the selection and subsequent expansion of Barrett's clones, and focus on some of the principle hallmarks associated with this transition.

Adenocarcinoma↗
PubMed1994

Tracing paternal ancestry in mice, using the Y-linked, sex-determining locus, Sry.

The molecular evolution of mammalian Y-linked DNA sequences is of special interest because of their unique mode of inheritance: most Y-linked sequences are clonally inherited from father to son. Here we investigate the use of Y-linked sequences for phylogenetic inference. We describe a comparative analysis of a 515-bp region from the male sex-determining locus, Sry, in 22 murine rodents (subfamily Murinae, family Muridae), including representatives from nine species of Mus, and from two additional murine genera--Mastomys and Hylomyscus. Percent sequence divergence was < 0.01% for comparisons between populations within a species and was 0.19%-8.16% for comparisons between species. Our phylogenetic analysis of 12 murine taxa resulted in a single most-parsimonius tree that is highly concordant with phylogenies based on mitochondrial DNA and allozymes. A total evidence tree based on the combined data from Sry, mitochondrial DNA, and allozymes supports (1) the monophyly of the subgenus Mus, (2) its division into a Palearctic group (M. musculus, M. domesticus, M. spicilegus, M. Macedonicus, and M. spretus) and an Oriental group (M. cookii++, M. cervicolor, and M. caroli), and (3) sister-group relationships between M. spicilegus and M. macedonicus and between M. cookii and M. cervicolor. We argue that Y-chromosome DNA sequences represent a valuable new source of characters for phylogenetic inference.

Animals↗
PubMed1976

[Triple Philadelphia chromosome during blastic crisis of a chronic myelocytic leukemia].

The blastic phase of a Ph1-positive chronic myeloid leukemia (CML) is often characterized by hyperdiploidy and sometimes by the presence of a double Ph1, suggesting a pattern of clonal evoluation. In the case reported here, the caryotype at the time of diagnosis in 1970 was 46, XY, Ph1. In 1975, after a blastic evolution followed by a drug-induced hematologic remission, cytogenetic studies revealed a chromosomal mosaic: 47, XY, 2 Ph1 and 51, XY, 3 Ph1, 3 C, the clone with 3 Ph1 representing approximately 20% of the mitotic cells. Furthermore, with the Giemsa banding technique, it was possible to identify the 3 supplementary C chromosomes of the 51 chromosomes clone, as being an 8, a 9 and 9 q + respectively. This observation illustrates the succession of chromosomal anomalies occurring during the evolution of CML with, in this case, the unusual appearance of a clone with 3 Ph1.

Adult↗
PubMed1985

Determinants of deoxyadenosine toxicity in hybrids between human T- and B- lymphoblasts as a model for the development of drug resistance in T-cell acute lymphoblastic leukemia.

Cultured human T-lymphoblastoid cell lines are more sensitive than B-cell lines to 2'-deoxyadenosine in the presence of 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase. This difference is related to the greater efficiency with which T-lymphoblasts accumulate cytotoxic levels of dATP derived from the adenosine deaminase substrate 2'-deoxyadenosine (dAdo). Previous work has shown that differences in dATP accumulation by cultured T- and B-lymphoblastoid cell lines cannot be explained by large differences in the levels of dAdo-phosphorylating or dAdo nucleotide (dAXP)-degrading activities in cytoplasmic extracts of these cells, although it has been proposed that intact B-cell lines may catabolize intracellular dAXP more rapidly than do T-cell lines. To further examine the determinants of dAdo sensitivity in T- and B-lymphoblasts, we have studied dAdo and dAXP metabolism in the human T- and B-cell lines CEM and WI-L2 and in hybrids generated by fusion of these cell lines. The hybrid nature of the fusion products was established by nutritional studies and by analyses of cellular surface antigens, DNA content, and enzymatic activities. We found that WI-L2 X CEM hybrids and another T X B hybrid derived from fusion of the SB human B-cell line with CEM were 30- to 40-fold less sensitive to dAdo and about 10-fold less sensitive to the dAdo analogue 9-beta-D-arabinofuranosyladenine than was CEM, or about as resistant as were their B-cell parental lines. Our studies confirm that CEM avidly accumulates dAXP from dAdo but does not catabolize intracellular dAXP. In contrast, WI-L2, SB, and WI-L2 X CEM and SB X CEM hybrids rapidly degraded intracellular dAXP, which limited their ability to undergo dAXP pool expansion. Expression of dAXP catabolic activity in T X B hybrids behaved as a dominant mechanism, conferring resistance to dAdo- and dAdo-related nucleosides to T X B hybrids. It has been postulated that cell fusion may play a role in the progression of tumors and contribute to diversity among the cells that compose clonal tumors. We have speculated that fusion of a malignant T-lymphoblast with an activated B-cell might be a mechanism for the evolution of drug resistance in acute T-cell leukemia.

Adenine Nucleotides↗
PubMed1982

Glucocorticoid regulation of the mouse metallothionein I gene is selectively lost following amplification of the gene.

The mouse metallothionein I (MT-I) gene is regulated by both heavy metals and glucocorticoid hormones. We selected cadmium-resistant variants of the mouse sarcoma cell line, S180, in which the metallothionein I gene has been amplified 10-fold and found that the amplified genes are regulated by cadmium in a manner identical with that observed for the original MT-I gene in unselected S180 cells. However, the amplified metallothionein I genes appear to be essentially nonresponsive to glucocorticoids even though at least 18 kilobases of DNA flanking the 5' side of the metallothionein I gene are amplified in these cells. The same result has been observed in nine clonal lines derived from the cadmium-resistant (CdR) population. The implications of this result both for models of steroid hormone action and for gene evolution are discussed.

Animals↗
PubMed2000

Molecular evolution and intratumor heterogeneity by topographic compartments in muscle-invasive transitional cell carcinoma of the urinary bladder.

Superficial transitional cell carcinomas (TCC) of the urinary bladder have been shown to be monoclonal. However, no combined study of clonality and tumor suppressor genes (TSG) is available to date for muscle-invasive TCC. Forty-four muscle-invasive TCC of the urinary bladder selected from women were included in this study. Tumor cells located above and below the muscularis mucosa zone were systematically microdissected and used for DNA extraction. Hha-I digested and undigested samples were used to study the methylation pattern of androgen receptor alleles and undigested samples were used for microsatellite analysis of TSG (TP53, RB1, WT1, and NF1). Both loss of heterozygosity (LOH) and single nucleotide polymorphism (SNP) analyses were performed using optimized denaturing gradient gel electrophoresis. The expression of p53, pRB, and p21WAF1 was assessed by immunohistochemistry. Appropriate controls were run in every case. All except two TCC showed a monoclonal pattern with the same allele inactivated in both compartments. Microsatellite analysis of TSG revealed the same LOH/SNP pattern in both tumor compartments in 30 cases (involving more than 1 TSG locus in 8) and genetic heterogeneity in 14 cases. From the latter group, 9 cases expressed more genetic changes in the deep compartment (involving TP53 gene in all cases, WT1 gene in 2, and NF1 in 1), whereas in 4 cases the superficial compartment showed more genetic changes (three involving NF1 and one involving both RB and TP53). No statistical difference in the immunoexpression was detected, although it tended to be higher in the superficial compartment than in the deep compartment. These concordant data in polymorphic DNA regions indicate that bladder-muscle-invasive TCC are monoclonal proliferations with homogeneous tumor cell selection. Heterogeneous tumor cell selection by topography defined two different genetic compartments: superficial, NF1-defective, and deep, TP53-defective. No differences in the immunohistochemical expression were observed, precluding a more extensive clinical application.

Base Sequence↗
PubMed2002

Horizontal gene transfer in microbial genome evolution.

Horizontal gene transfer is the collective name for processes that permit the exchange of DNA among organisms of different species. Only recently has it been recognized as a significant contribution to inter-organismal gene exchange. Traditionally, it was thought that microorganisms evolved clonally, passing genes from mother to daughter cells with little or no exchange of DNA among diverse species. Studies of microbial genomes, however, have shown that genomes contain genes that are closely related to a number of different prokaryotes, sometimes to phylogenetically very distantly related ones. (Doolittle et al., 1990, J. Mol. Evol. 31, 383-388; Karlin et al., 1997, J. Bacteriol. 179, 3899-3913; Karlin et al., 1998, Annu. Rev. Genet. 32, 185-225; Lawrence and Ochman, 1998, Proc. Natl. Acad. Sci. USA 95, 9413-9417; Rivera et al., 1998, Proc. Natl. Acad. Sci. USA 95, 6239-6244; Campbell, 2000, Theor. Popul. Biol. 57 71-77; Doolittle, 2000, Sci. Am. 282, 90-95; Ochman and Jones, 2000, Embo. J. 19, 6637-6643; Boucher et al. 2001, Curr. Opin., Microbiol. 4, 285-289; Wang et al., 2001, Mol. Biol. Evol. 18, 792-800). Whereas prokaryotic and eukaryotic evolution was once reconstructed from a single 16S ribosomal RNA (rRNA) gene, the analysis of complete genomes is beginning to yield a different picture of microbial evolution, one that is wrought with the lateral movement of genes across vast phylogenetic distances. (Lane et al., 1988, Methods Enzymol. 167, 138-144; Lake and Rivera, 1996, Proc. Natl. Acad. Sci. USA 91, 2880-2881; Lake et al., 1999, Science 283, 2027-2028).

Archaea↗
PubMed1992

Ph-negative and bcr-negative atypical chronic myelogenous leukemia: biological features and clinical outcome.

We report the clinical, hematologic, cytogenetic, and molecular characteristics of 13 patients with Philadelphia-negative (Ph-), bcr-negative atypical chronic myelogenous leukemia (CML). In the majority of cases, the phenotypic features at presentation resembled those of typical CML. However, these patients presented with a higher median age, lower median hemoglobin levels, and lower leukocyte and platelet counts than patients with Ph-positive CML. Cytogenetic analysis showed an abnormal karyotype in only one case. Southern blot investigation, using probes exploring the entire M-bcr region, demonstrated the absence of genomic bcr-abl rearrangements. The assessment of clonality in five patients (study of X-methylation patterns in females heterozygous at the DXS255 locus) indicated the proliferation of a monoclonal cell population. Disease evolution was mostly characterized by bone marrow failure, extramedullary infiltrates, and poor response to chemotherapy, without evidence of overt acute transformation. Our observations suggest that some hematologic and clinical features and the modalities of disease progression are presently the most helpful factors in distinguishing these bcr/abl-negative patients from those with typical bcr+CML. The differences existing also with chronic myelomonocytic leukemia (CMMoL), allow the consideration of ph-/bcr- CML as a separate entity, the nature of which remains to be elucidated.

Cytogenetics↗
PubMed1994

Nonrandom chromosomal abnormalities in bovine lymphoma.

Despite detailed knowledge of the genetic map of the bovine leukemia virus (BLV), the mechanism whereby BLV infection results in transformation and B-lineage restriction of tumors is poorly understood. The aim of this study was to gain new insight into pathogenetic mechanisms of BLV-induced tumorigenesis by determining the karyotypes of BLV-associated lymphomas in cattle. Metaphases in cells from lymphoid tumors from 20 mature dairy cows were banded and analyzed after short-term, unstimulated culture. Nineteen out of twenty cases exhibited clonal abnormalities, 17 cases were hyperdiploid, and 16 cases had extremely complex chromosomal changes. Recurrent chromosomal anomalies were identified and there was clear evidence for the evolution of increasing chromosomal instability in 12 cases. The most common abnormalities were the acquisition of additional small chromosomes (23-29); trisomy of chromosomes 5 and 7, and Robertsonian translocations and isochromosome rearrangements involving chromosomes 10, 12, 23, and 26. Monosomy X, trisomy X, and translocations involving the X chromosome were also detected. Chromosomes 2, 3, 4, 6, 8, 9, 11, 13, 14, 19, and 21 were infrequently involved in either structural or numerical changes. Structural rearrangements of chromosomes 10, 12, 23, and 26 may reflect primary abnormalities occurring relatively early in transformation, whereas trisomy 5 may be an extremely common secondary abnormality. While comparison of these findings with the current bovine gene map raises intriguing possibilities for pathogenetic mechanisms, further studies are needed before hypothetical mechanisms linking chromosomal abnormalities with BLV-induced transformation can be made.

Animals↗
PubMedDate not supplied

Grasshopper, a long terminal repeat (LTR) retroelement in the phytopathogenic fungus Magnaporthe grisea.

The fungal phytopathogen Magnaporthe grisea parasitizes a wide variety of gramineous hosts. In the course of investigating the genetic relationship between pathogen genotype and host specificity we identified a retroelement that is present in some strains of M. grisea that infect finger millet and goosegrass (members of the plant genus Eleusine). The element, designated grasshopper (grh), is present in multiple copies and dispersed throughout the genome. DNA sequence analysis showed that grasshopper contains 198 base pair direct, long terminal repeats (LTRs) with features characteristic of retroviral and retrotransposon LTRs. Within the element we identified an open reading frame with sequences homologous to the reverse transcriptase, RNaseH, and integrase domains of retroelement pol genes. Comparison of the open reading frame with sequences from other retroelements showed that grh is related to the gypsy family of retrotransposons. Comparisons of the distribution of the grasshopper element with other dispersed repeated DNA sequences in M. grisea indicated that grasshopper was present in a broadly dispersed subgroup of Eleusine pathogens, suggesting that the element was acquired subsequent to the evolution of this host-specific form. We present arguments that the amplification of different retroelements within populations of M. grisea is a consequence of the clonal organization of the fungal populations.

Amino Acid Sequence↗
PubMed1996

[Chronic myeloid leukemia. Karyotype changes].

Chronic Myeloid Leukemia (CML) is a clonal disease of bone marrow, citogenetically characterized by the presence of the Philadelphia chromosome (Ph). Additional anomalies in the Ph cromosome have been found during the evolution of CML. This paper will show evidence of cytogenetic abnormalities during the evolution of CML in this region, and its correlation with clinical evolution. 55 samples of bone marrow, 81.3% (45/55) in chronic phase (CP), 12.7% (7/55) in an accelerated phase (AP), and 5.4% (3/55) in blastic phase (BP) were received. In 12/45 patients in CP the karyotype was repeated at least once a year during the evolution of their illness. 9/12 presented the Ph chromosome as a single anomaly at the moment of diagnosis; the other 3 presented a distinct anomaly. 4/9 presented additional abnormalities moving to the stages AP or BP between 4-8 months after initial discovery. 7/10 patients referred in AP or BP presented additional abnormalities in the Ph chromosome. It is evident that the chromosome study of each patient with CML must be carried out at least once a year in order to detect chromosomal abnormalities in addition to the Ph chromosome. Thus, a greater therapeutic control of the disease is possible.

Adult↗
PubMed2006

Bottlenecks and broomsticks: the molecular evolution of Mycobacterium bovis.

Mycobacterium bovis is the cause of tuberculosis in cattle and is a member of the Mycobacterium tuberculosis complex. In contrast to many other pathogenic bacterial species, there is little evidence for the transfer and recombination of genes between cells. The clonality of this group of organisms indicates that the population structure is dominated by reductions in diversity, caused either by population bottlenecks or selective sweeps as entire chromosomes become fixed in the population. We describe how these forces have shaped not only the phylogeny of this group but also, at a very local level, the population structure of Mycobacterium bovis in the British Isles. We also discuss the practical implications of applying this knowledge to understanding the spread of infection and the development of improved vaccines and diagnostic tests.

Animals↗
PubMed1993

High-grade transformation of chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma. Genotypic confirmation of clonal identity.

The abrupt appearance of a high-grade tumor in patients with low-grade malignant lymphoma usually is associated with an accelerated clinical disease course. The high-grade lymphoma may take a variety of histologic forms and often, but not always, represents evolution of the original low-grade disease, as shown by immunophenotypic or immunogenotypic studies. The authors describe the transformation of a variety of low-grade B-cell neoplasms to high-grade tumors in four patients. The initial diagnoses included chronic lymphocytic leukemia and mantle cell lymphoma in one patient each and low-grade follicular lymphoma in two patients. The high-grade tumors were classified as lymphoblastic lymphoma in one patient and small noncleaved cell lymphoma in two patients. The high-grade component manifests primarily in the peripheral blood as circulating blast-like cells consistent with large-cell lymphoma in the remaining patient. In each case, immunophenotypic studies showed identical monoclonal surface immunoglobulin expression on the low- and high-grade tumors. Immunoglobulin heavy chain gene and kappa light chain gene studies showed identical clonally rearranged bands in paired samples from three of the four patients, a finding indicative of clonal identity. Unexpectedly, dissimilar immunoglobulin light and heavy chain gene rearrangements were detected in the paired samples from one patient with previously diagnosed follicular lymphoma, making the relationship of the two tumors from this patient uncertain; however, additional Southern blot analysis of the bcl-2 gene showed identical rearrangements in both lesions. Furthermore, polymerase chain reaction across the t(14;18) major breakpoint region in both tumors amplified nucleotide fragments of identical size, confirming the clonal identity of the low- and high-grade lymphomas despite the divergent immunoglobulin gene studies. These studies show that low-grade malignant lymphomas of small lymphocytic, mantle cell, or follicular small cleaved cell types may assume high-grade morphologic characteristics, that this change is the result of transformation of the preexisting low-grade malignant neoplasm, and that this progression, like typical Richter's syndrome, is associated with a dramatically accelerated clinical course. In addition, these studies confirm previous reports that disparate immunoglobulin light and heavy chain gene rearrangements are not necessarily an indicator of different cellular origins, and additional genotypic studies occasionally may be required to show the clonal identity of the cell population involved in these morphologic transformations.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2001

Exploring the evolution of diversity in pathogen populations.

Pathogen biodiversity is an under-exploited source of inference regarding disease processes and the evolution of pathogens and pathogenesis. In addition, the structure of pathogen populations, especially for diverse organisms such as the meningococcus, has implications for public health interventions including vaccination and antibiotic use. The predominant paradigm for interpreting bacterial diversity has been the clonal population structure, which has been modified by the incorporation of the effects of horizontal genetic exchange. Multilocus models of variable antigens, which explore the effects of immune selection, provide alternative explanations for structured diversity in pathogen populations.

Antigenic Variation↗
PubMed1991

Consecutive chromosomal studies in patients with myelodysplastic syndrome (MDS). Czechoslovak MDS Cooperative Group.

In order to detect a possible relationship between clonal chromosomal abnormalities acquired during the course of the disease and its prognosis in patients with myelodysplastic syndrome (MDS) the authors have performed consecutive analyses in 77 patients with this disease. They were part of the large series of 209 patients cytogenetically examined during the last ten years. According to the cytogenetic findings we have distinguished three groups: 1) sixteen patients who has a normal karyotype in bone marrow cells at the beginning of the investigation and this finding remained unchanged during the course of the disease. Three of them progressed into acute leukemia (AL) without any detectable change in the chromosomal complement of the bone marrow cells; 2) twenty-five patients who had at the beginning of the study, different pathological chromosomal clones in bone marrow cells. There was no chromosomal evolution detectable during the disease; eight of them progressed into acute leukemia; 3) thirty-six patients who had either normal or pathological chromosomal findings at the first examination and in whom further clonal abnormalities had developed during the course of the disease. Twelve of them progressed into acute leukemia. Two to nine cytogenetic examinations were successfully performed with a mean of three studies per patient. The results confirmed strictly individual development of chromosomal abnormalities during the course of the disease, with an unfavorable prognosis for the patients with complex chromosomal changes. Three patients with del 7q had very poor prognosis with rapid progression of the disease. Two cases with the same acquired abnormalities (del 20q, +8, -22) transformed into acute leukemia within the period of 36 months from the onset of the disease.

Acute Disease↗
PubMed1997

Analysis of clonality of lymphocytic leukemia and lymphoma by T-cell receptor gene rearrangement.

OBJECTIVE: To analyse the relationship between the number of T-cell receptor (TCR) gamma gene rearrangement and clonality of malignant cells in lymphocytic leukemia and lymphoma. METHODS: The TCR gamma gene characteristics of 73 cases of lymphocytic leukemia and lymphoma and other diseases that had presented 1 or 2 prominent bands of amplified TCR gamma VI subgroups-J1/2 gene rearrangement (GR) were detected by polymerase chain reaction-restriction enzymes (PCR-RE), heteroduplex formation (HDF), DNA sequencing and single-strand conformational polymorphism (SSCP). RESULTS: Thirty-four percent patients had 2 of TCR gamma GR (biallelic rearrangement); twenty-six percent had 1 of TCR gamma GR; fifty-four percent of acute lymphocytic leukemia's and nineteen percent of non-Hodgkin's lymphomas (NHL) had 2 of TCR gamma GR. HDF could rapidly confirm more than 1 of alleles while more alleles were difficult to be recognized by restriction analysis. Sense and antisense strands of heteroduplex were composed of 2 of TCR gamma GR respectively. By combining HDF method, oligoclonalities in three patients (2 acute lympholytic leukemia and 1 myelodysplastil syndrome and clone evolution in one NHL were found. CONCLUSIONS: The fact that many patients had 2 of TCR GR means that complications of two neoplastic clones can be affirmed only if more than 2 of TCR GR are found. HDF can be used to detect the clonality, oligoclonality and polyclonality of lymphoid cells in lymphocytic leukemia and lymphoma by analysis of the difference of gene segments. HDF is a reliable method for the clone evolution research of lymphoid malignancies in progression.

Base Sequence↗
PubMed1992

The evolution of the amplified adenylate deaminase 2 domains in Chinese hamster cells suggests the sequential operation of different mechanisms of DNA amplification.

Fluorescent in situ hybridization was used to localize the adenylate deaminase 2 (AMPD2) genes and flanking sequences on the chromosomes of the Chinese hamster line GMA32 and to study the distribution of additional copies of these genetic sequences in amplified mutants selected at several early stages of the amplification process. The synteny of AMPD2 genes and MDR1 genes, located on chromosomes 1, was demonstrated; in GMA32 the existence of a rearrangement positioning the two AMPD2 genes at different distances from the telomeres was disclosed. Using this structural marker, we showed that the amplified copies distribute along only one of the chromosomes 1. Their organization in different cells of clonal mutant populations at a very early stage of amplification was extremely heterogeneous; classes of organization could be recognized however. Their quantitative distribution at this stage and in cells which went through 10 more division cycles suggests an evolution pathway common to the mutant clones under study: as a rule, tandems of few units of identical and very large size (47 Mb) appear to be the first detected product of amplification; this organization is progressively overtaken by structures with more units of reduced and irregular size, while, in a growing number of cells, clusters of much shorter units can be observed. The nature of segregative amplification mechanisms operating in these processes and the possible involvement of replicative ones are discussed.

AMP Deaminase↗