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PubMed1994

p53 mutations in Barrett's adenocarcinoma and high-grade dysplasia.

BACKGROUND/AIMS: Allelic losses of chromosome 17p and overexpression of p53 protein have been reported in Barrett's adenocarcinomas. This study aimed to determine the stage in which p53 mutations arise in neoplastic progression in Barrett's esophagus and their relationship to the clonal evolution of cancer. METHODS: Fourteen patients with high-grade dysplasia, adenocarcinoma, or both arising in Barrett's esophagus were evaluated. Flow cytometric cell sorting was used to obtain purified populations of neoplastic cells for analysis of p53 mutations. DNA was extracted, and exons 5 through 9 of the p53 gene were amplified by polymerase chain reaction. Amplified DNA was sequenced and analyzed by automated sequencing. RESULTS: Nine of the 14 patients had p53 mutations. Six of the 9 patients had regions of high-grade dysplasia that could be evaluated; all 6 had p53 mutations in high-grade dysplasia. In 3 patients, the same p53 mutations were found in both high-grade dysplasia and adenocarcinoma. All 14 patients had aneuploidy. In 4 patients, diploid cell populations could also be evaluated for p53 mutations; 3 of the 4 patients had p53 mutations in diploid cell populations. In 2 patients, the same p53 mutation was found in multiple aneuploid cell populations within a cancer. CONCLUSIONS: p53 mutations occur frequently in Barrett's adenocarcinomas. They develop in diploid cell populations. The same p53 mutations are then found in aneuploid cell populations in high-grade dysplasia, in cancer, and in multiple aneuploid cell populations in cancer.

Adenocarcinoma↗

PubMed1994

Epstein-Barr virus-associated primary malignant lymphomas of the pleural cavity occurring in longstanding pleural chronic inflammation.

Primary pleural non-Hodgkin's lymphomas (NHLs) have been described mostly in Japan and occasionally in western countries. We report three cases occurring in nonimmunocompromised patients demonstrating close similarities to the Japanese cases. These lymphomas occurred more than 20 years after thoracoplasty for the treatment of pleural or pulmonary tuberculosis. They were all high grade lymphomas of B phenotype (two immunoblastic with plasmocytoid differentiation and one immunoblastic with anaplastic large cells). In situ hybridization (ISH) detected small nuclear RNAs encoded by Epstein-Barr virus (EBERs) in most lymphomatous cells in all cases. This suggests a link between primary pleural lymphoma and the longstanding chronic inflammation, which could favor a clonal evolution of Epstein-Barr virus (EBV)-infected B cells through the production of growth factors or immunosuppressive cytokines produced by inflammatory cells.

Aged↗

PubMed1987

Multiple chromosome abnormalities in a drug resistant TdT positive B-cell leukemia.

A 17-year old caucasian male presented with B-cell acute leukemia which proved aggressive and refractory to treatment. Cytogenic investigation showed a single clone with a complex karyotype 49,XY,del(2)(p13),+4,del(4)(p11),-6,+i(6)(p),+7,+8, t(8;14), (q24;q32),del(17)(p11). This includes the Burkitt's translocation and a deletion at the site of the immunoglobulin kappa light chain gene. Clonal evolution included tetraploidy, duplication of the derived chromosomes and, terminally, trisomy 1q. Immunological investigation revealed a monoclonal population of B-cell blasts, expressing the kappa light chain, and with an extremely rare combination of SIg and TdT positivity. Immunoglobulin gene rearrangement confirmed monoclonalility. Tetraploidy of the clone and del(17)(p11) have been previously described only in a cell line or at end stage disease in B-ALL. It is suggested that the chromosomal abnormalities present at diagnosis were directly related to the refractory nature of this leukemia.

Acute Disease↗

PubMed1992

Structural alterations of the p53 gene in human leukemias.

We have investigated alterations of the p53 gene in human leukemias by polymerase chain reaction-mediated restriction fragment length polymorphism analysis. This method detects the codon 72 polymorphism of the p53 gene, allowing identification of loss of heterozygosity (LOH) of the p53 gene. In this study, at least two specimens were obtained from each patient to compare the allele status at different points of clinical course. Of 21 cases examined 7 were heterozygous at this polymorphic site and were evaluable for LOH study. Only one patient of Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) lost the heterozygosity in the specimen of her last relapse. Leukemic cells from her repeated relapses including the last one revealed to have the clonally rearranged immunoglobulin H chain gene of the same size, indicating that alteration of the p53 gene in this patient might account for the lethal relapse as a clonal evolution event. Northern-blot analysis of the p53 gene showed that one case of CD7(+) ALL had altered p53 mRNA. Overall, it is demonstrated that alterations of the p53 gene might be involved in the pathogenesis or progression of at least some human leukemias, although the alterations in leukemias seemed to be not as frequent as in solid tumors.

Base Sequence↗

PubMed1992

Chromosomal deletions in the myelodysplastic syndrome.

Karyotypic abnormalities in primary myelodysplastic syndrome (P-MDS) are less frequent than in secondary myelodysplasia. A review of the literature involving over 3000 reported cases, shows the incidence of karyotypically abnormal clones at presentation in nearly 48% of cases. Approximately 50% of the abnormalities comprise of deletions of chromosomes 5, 7, 11, 12, 13 and 20. Localisation of a number of haemopoietic growth factors and their receptors to the deleted segments of the chromosomes, has invoked considerable interest in the molecular pathology of the interstitial deletions and their consequent role in the multistep pathogenesis of MDS. Present evidence suggests chromosome abnormalities are a later event in the multistep painogenesis, and it is suggested their occurrence may be restricted to a restricted myeloid progenitor cell, although the initial event(s) occur at the common lymphoid-myeloid progenitor. Much has been gleaned from the dominant modes of leukaemogenesis, such as the occurrence of missense mutations at specific positions of RAS and FMS mutations. It is suggested that a similar enquiry into the mechanisms of chromosomal deletions in P-MDS is required in order to delineate the role of these abnormalities in the clonal evolution of this group of diseases.

Chromosome Aberrations↗

PubMed1995

Mutations of the p53 gene in myelodysplastic syndrome and overt leukemia.

We analysed p53 mutations in 24 patients with myelodysplastic syndrome (MDS) and overt acute myeloid leukaemia after a period of MDS, using polymerase chain reaction-single strand conformation polymorphism analysis. In exons 5 to 8, mobility shifts were detected in five of the 24 patients. Sequence analysis was subsequently performed, and four missense mutations (16.7%) and one silent nucleotide substitution were identified. Patients harbouring mutations were characterized as having advanced disease. Loss of the wild type allele was observed in three of the four patients with missense mutations. No mobility shifts of the N-ras or FMS gene were detected in these four patients. We next analysed the correlation of the p53 mutations with the progression of MDS in three patients. The mutation was accompanied by the progression in two of the three patients. These findings suggest that mutations of the p53 gene are associated with progression in some cases of MDS, while being compatible with stable disease or clonal evolution in others.

Base Sequence↗

PubMed1995

Complex hypodiploidy in acute myeloid leukaemia: a United Kingdom Cancer Cytogenetics Group study.

Forty cases of acute myeloid leukaemia with 41 hypodiploid clones were investigated in a collaborative study. Cases with -5, -7, -X or -Y either alone or in association with an established translocation were excluded. Karyotypes were reviewed in all cases and bone marrow or blood morphology was reviewed in 22 cases. Twenty-six cases were very complex (more than five abnormal chromosomes), 14 cases were complex (two to five abnormal chromosomes) and only one case was simple (one abnormal chromosome). Chromosomes 5, 7, 17 and 18 were involved in a significantly greater number of cases than expected. Only five cases had normal chromosomes 5 and 7. Chromosomes 10, X and Y were involved in significantly fewer cases than expected. Ten cases had ring chromosomes and 18 showed clonal evolution. Patients were aged between 19 and 90, median 61 years. Evidence of myelodysplasia was found on morphological review in 18/22 cases, and on clinical features in a further five cases. There was a high proportion of cases with FAB M6, 'erythroleukaemia' (9/31 cases). Only 4/16 patients treated with cytotoxic therapy achieved remission. Median survival was 2.5 months (35 patients). Survival was slightly better for patients with normal chromosomes 5 and 7, and for those with simpler karyotypes, but this was not statistically significant. This study confirms the association between hypodiploidy, complex karyotype, abnormalities of chromosomes 5 and 7 and a poor prognosis.

Adult↗

PubMed1982

Abnormalities of chromosome No. 17 in myeloproliferative disorders.

In routine analyses, abnormalities of chromosome No. 17 were found in the bone marrow cells of 28 patients with Ph1-positive and three patients with Ph1-negative chronic myeloid leukemia (CML), 4 patients with acute nonlymphocytic leukemia (ANLL), and 4 patients with preleukemia. With three exceptions, all patients were in the blastic (CML) or the terminal phase. In 28 patients, the aberrant chromosome No. 17 arose by clonal evolution from the karyotype found at diagnosis or before the terminal phase. The abnormalities encountered were an isochromosome for the long arm, i(17q), (26 cases), translocations involving No. 17 (12 cases), trisomy 17 (three cases), and ring 17 (one case). In 35 patients, there was an unbalanced structural aberration of at least one of the No. 17 chromosomes. In every case (35/35), detailed analysis of the structurally abnormal No. 17 revealed loss of the distal part of the short arm (or possibly most of the short arm). Gain of the long arm (or at least its proximal part) was also common, but not invariably present (26/35). It is suggested that loss of 17p is a highly nonrandom event related to blastic crisis in CML and the terminal phase in other myeloid leukemias.

Acute Disease↗

PubMed1982

Karyotypic findings in a colonic villous adenoma.

Chromosomes from a patient with a villous adenoma of the colon were examined in detail with fluorescent banding. Of the cells analyzed, 73% had a modal chromosomal number of 48-52. The karyotypic findings show clonal evolution, an additional chromosome #8 being the most frequent abnormality, suggesting that this may be the primary chromosomal change, but other changes such as loss of a Y chromosome and the presence of marker chromosome #1 with duplication of the long arm also were observed. Previous cytogenetic data on large-bowel tumors is summarized. We hypothesize that this chromosomal evidence suggests that tubular adenoma, villous adenoma, and adenocarcinoma may be interrelated steps of a growth disorder.

Adenoma↗

PubMed1983

Chromosome 1q+ in erythroid and granulocyte-monocyte precursors in a patient with essential thrombocythemia.

A 55-year-old man with essential thrombocythemia had multiplication of bands q21 to q32 of chromosome 1 in all studied mitoses from bone marrow, from unstimulated blood, and from erythroid and granulocyte-monocyte colonies grown in vitro. The multiplication was in the form of triplication in 16 out of 20 mitoses from the marrow and in 4 of 6 mitoses from the blood; the rest showed a duplication of this region. All 20 mitoses from erythroid and granulocyte-monocyte colonies showed the abnormality in the form of duplication. These findings indicate most probably a clonal evolution, the triplication having arisen in the clone with the duplication. This may be associated with early leukemic transformation. The detection of the 1q+ aberration in two different types of hematopoietic colonies indicates the involvement of multipotent stem cells in at least this patient with essential thrombocythemia.

Adult↗

PubMed1983

Development of dysmyelopoietic syndrome in a hairy cell leukemia patient treated with chlorambucil: cytogenetic and morphologic evaluation.

A splenectomized patient with hairy cell leukemia (HCL) who had received chemotherapy with a low-dose alkylating agent for 2 years developed dysmyelopoietic syndrome (DMPS), the first such case to be described. A portion of his marrow remained chronically involved with HCL, but the remainder evolved from being morphologically and karyotypically normal to involvement with DMPS, with cells having a bizarre karyotype. Three of four metaphase cells had consistent abnormalities, with a missing chromosome No. 5, structural rearrangements resulting in deletion of part of the long arm of chromosome No. 7, deletion of 2q, and a small ring chromosome; upon further clonal evolution, a translocation between chromosomes No. 12 and 15 and deletion of the long arm of chromosome No. 19 were seen. We therefore add HCL patients to the growing list of those at risk of developing a secondary hematologic malignant disease possibly due to cytotoxic therapy for their primary disorder.

Bone Marrow↗

PubMed1983

Serial cytogenetic study of a human glioma cell line.

Chromosome studies were performed on a human glioma cell line. Nineteen passages were studied, and a heterogeneous chromosome complement with variable modal numbers was found. The main range varied from tetraploidy to triploidy. The presence of identical markers (9p-, 11p+, an increase in the copies of chromosome No. 7) in different passages suggests a clonal evolution.

Brain Neoplasms↗

PubMed1984

Ph1-positive acute leukemia with a 17q;21q translocation.

Chromosome studies on the neoplastic cells of an adult patient with poorly differentiated acute leukemia revealed two Ph1-positive subpopulations, with and without a 17q;21q (q22;q22) translocation. The breakpoints appeared to be the same as in the 8;21 and 15;17 translocations of acute mytelogenous leukemia (AML) and acute promyelocytic leukemia (APL), emphasizing the significance of rearrangements involving these sites in the pathogenesis of acute leukemia. Terminally, there was clonal evolution, with the new predominant subline having an additional translocation, 1q;19q, resulting in trisomy for most of 1q and, apparently, additional selective advantage.

Adult↗

PubMed1985

Cytogenetic findings in childhood acute lymphoblastic leukemia.

Chromosome studies were performed on the bone marrow cells of 42 children with newly diagnosed acute lymphoblastic leukemia (ALL). All the children were subsequently treated with the same protocol. Chromosomal abnormalities were found in 25 patients, i.e., in 59.5% of the cases. Hyperdiploidy was observed in 21.4% hypodiploidy in 14.3%, and pseudodiploidy in 23.8% of the children. The most frequent structural aberrations were translocations, which were found in half of the patients with abnormal karyotypes. Chromosomes #5, #6, #7, #9, #14, #17, and #21 were involved in different types of changes most frequently. Because these findings correspond with observations published by others, they can be regarded as evidence of nonrandom involvement of these chromosomes in rearrangements in ALL. Special attention should be also paid to the deletion of 6q, which seems to be relatively common in ALL. In 12 cases, clonal evolution of karyotypic changes was observed.

Adolescent↗

PubMed1985

Burkitt cell acute lymphoblastic leukemia with partial expression of T-cell markers and subclonal chromosome abnormalities in a man with acquired immunodeficiency syndrome.

A 45-year-old white male, bisexual, with a 2-year history of acquired immunodeficiency syndrome (AIDS) prodrome, developed a Burkitt cell-like acute lymphoblastic leukemia (ALL). Marker studies of marrow blasts show an unusual and possibly unique pattern, in that an unequivocal monoclonal B cell leukemia, having K-IgM with HLA-DR and B cell subset antigen (BA-1) expression, was superimposed with a mature suppressor T cell marker profile (pan-T, mature T, and suppressor/cytotoxic T antigens). The leukemic blasts were totally negative for terminal deoxynucleotidyl transferase (TdT), human T cell leukemia-lymphoma virus (HTLV) p19 antigen, and other immunoglobulin isotypes. Chromosome analysis of marrow cells disclosed that 70% of the cells had 47,XY, + 12,t(8;14)(q24;q32) chromosome complement, and 30% of the cells had a 47,XY, + 12,dup1q + (q22-31),t(8;14)(q24;q32). The consistent finding of the specific chromosome rearrangement (8/14 translocation) in all abnormal cells suggests that the cells were derived from a common precursor. With regard to the partial T cell marker expression, the significance of these markers in B cell leukemia is unclear, as is their relation to the additional chromosome abnormalities that apparently developed in the process of clonal evolution.

Acquired Immunodeficiency Syndrome↗

PubMed1986

Chromosome abnormalities in meningiomas.

Cytogenetic analyses of eight meningiomas grown in culture for 1 week are reported. Normal karyotypes were found in three cases and hypodiploidy in the remaining five. In the five hypodiploid meningiomas, one chromosome #22 was missing in four cases, and one case exhibited a 22q- deletion. In four of these five cases, chromosome #14 was either lost or altered. Chromosome #1 was lost or altered in three, and chromosome #6 in two. These findings lend further support for the association of total or partial loss of chromosome #22 in meningiomas and suggest the involvement of other chromosomes in the clonal evolution of these tumors.

Aged↗

PubMed1987

Duplication of Ph and of 9q+ chromosomes during the blastic transformation of a CML case.

We describe the blastic transformation of a case of chronic myelocytic leukemia in which, among other abnormalities, one extra Philadelphia and one extra 9q+ were observed. Molecular studies and analysis of the clonal evolution of the karyotype led to the interpretation of such an unusual finding as the result of nondisjunction, rather than of a double t(9;22) translocation.

Adult↗

PubMed1987

Distinct chromosome abnormalities in ataxia telangiectasia with chronic T-cell lymphocytic leukemia.

We report chromosomal studies of a 27-year-old male patient with ataxia telangiectasia who developed a chronic T-cell lymphocytic leukemia. The leukemic cells grew spontaneously although a better yield of metaphases could be obtained after PHA stimulation. Chromosome analysis revealed a hypodiploid leukemic clone (44 chromosomes) and a single remaining normal metaphase. An isochromosome 8q was detected in a subclone at an early analysis, which was lost during clonal evolution. At the time of the last analysis, 6 months before the patient died, the diploid metaphases disappeared completely. The karyotype of the final chromosome study showed a monoclonal condition with the following abnormalities: 44,X,-Y,4q-,6p-,14q-,19p+,20q+,-20,22q-. Loss of the Y chromosome was limited to the leukemic cells. Comparing our data with the chromosome abnormalities reported in the literature, breakpoints at band 14q11-12 (location of the gene for the alpha chain of the T-cell receptor), loss of a normal chromosome #20, as well as structural abnormalities of the remaining chromosome 20p seem to be nonrandom in T-CLL arising in patients with ataxia telangiectasia. A Philadelphia-like marker that seems to be a peculiar feature of the case described here, however, resembles a small marker chromosome qualified as unidentifiable in a similar case of T-CLL reported in the literature.

Adult↗