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PubMed1988

Clonal chromosomal abnormalities showing multiple-cell-lineage involvement in acute myeloid leukemia.

To determine whether one or more hematopoietic-cell lineages are involved in acute myeloid leukemia (AML), we designed a technique that simultaneously identifies a cell as malignant and determines its lineage. We used numerical clonal chromosomal abnormalities, which are readily detected, to indicate neoplasia, and monoclonal antibodies in an alkaline phosphatase-antialkaline phosphatase detection procedure to identify lineages as granulocytic-monocytic, erythrocytic, or megakaryocytic. Examination of bone marrow from 12 patients with AML showed metaphases of granulocytic-monocytic lineage with abnormal karyotypes in all patients. In seven patients, we also detected abnormal karyotypes in the erythrocytic or megakaryocytic lineage. In all four patients with monosomy 7, both granulocytic-monocytic and erythrocytic cells were affected. Two of four patients with trisomy 8 also had evidence of multiple-lineage involvement, but in two the erythrocytic lineage had normal karyotypes, suggesting an origin at a progenitor-cell stage committed to granulocytic-monocytic development. Multiple-lineage involvement was found in AML both arising de novo (four of five analyzable cases) and following another cancer (three of four analyzable cases). These data demonstrate multiple-lineage involvement in a high proportion of cases of AML and suggest that many cases originate from the multipotent hematopoietic cell or from an earlier progenitor cell.

Adult↗
PubMed1980

Frequency of chromosomal abnormalities in early embryos of the domestic sheep (Ovis aries).

Embryos or unfertilized eggs were collected 2 or 3 days post coitum from mature sheep of various breeds and crosses. The karyotypes of 89 of the 376 collected were established. There were 44 embryos with 2n = 54XX, 30 with 2n = 54XY;1 was a 2n/1n mouse; 4 had 2n + 1 chromosomes giving an incidence of trisomy of 4.7%; and 1 unfertilized egg had n = 28. The incidence of chromosomal abnormalities was 6%, and 1.3% of the eggs or embryos had a cracked zona pellucida.

Animals↗
PubMed1988

Cytogenetic study of chronic lymphocytic leukemia in ten Japanese patients with a case of the same chromosome abnormality both in T and B cells.

Peripheral blood lymphocytes from ten patients with chronic lymphocytic leukemia (CLL) stimulated with phytohemagglutinin (PHA), pokeweed mitogen (PWM), Epstein-Barr virus (EBV), and T-cell growth factor were studied cytogenetically. Eight of ten cases were clinically and immunologically B-cell CLL, and two cases were T-cell CLL. Chromosome analysis revealed that one patient, diagnosed as B-cell CLL, had a clonal abnormality in the leukemic cells. The abnormal karyotype was 46,XY,+3,-15,t(10;19)(q22;p13),t(11;14) (q13;q32),13q+,17q-. The frequencies of the abnormal cell stimulated with PHA, PWM, and EBV were 50%, 13%, and 100%, respectively. Finding the same clonal abnormality after stimulation with three different mitogens suggests that the factor responsible for the development of CLL might affect the stem cell common to T-cell and B-cell lymphocytes. In cells with this abnormal karyotype, chromosome 13q+ seems to have a homogeneous staining region. In the present series of B-cell CLL, no trisomy 12 known to be the specific chromosome abnormality was observed.

Adult↗
PubMed1990

An examination of respiratory distress and chromosomal abnormalities in the offspring of male mice treated with ethylnitrosourea.

A functional defect (respiratory distress), in addition to morphological defects, was induced in the offspring of male ICR mice treated with ethylnitrosourea (ENU) before mating. ENU (100 and 50 micrograms/g) was injected intraperitoneally into adult male ICR mice that were then mated with untreated females. After the cesarian operation on the 18th day of gestation, fetuses were resuscitated. In the apneic fetuses showing respiratory distress, the lung was collapsed and the ductus arteriosus was not closed. The incidence of fetuses showing respiratory distress was significantly increased with the high dose (100 micrograms/g) of ENU, and it was higher after spermatogonial exposure than after postmeiotic exposure. There was no linearity in the dose-response relationship at the lower dose (50 micrograms/g), as was the case with the specific-locus mutation. The frequency per microgram ENU of fetuses showing respiratory distress was 3.7 X 10(-4) for spermatogonial treatment (calculated at a dose of 100 micrograms/g), the value being about 10-20 times higher than that of ordinary mutations in mice. About half of the fetuses showing respiratory distress often had specific anomalies (dwarfism and gigantic thymus), but the remainder showed no morphological changes. Spermatogonial treatment produced a zero or very low incidence of translocations in the meiotic configurations of primary spermatocytes. G-band analysis of the affected F1 fetuses also revealed no visible chromosomal abnormalities (there could be small deletions or inversions) except that trisomy 19 was found in a dwarf fetus.

Abnormalities, Drug-Induced↗
PubMed2004

Multiple chromosomal abnormalities in human liver (pre)neoplasia.

BACKGROUND/AIMS: In human hepatocarcinogenesis the tumor precursor lesions and the sequence of genetic aberrations are not known. We therefore compared genetic alterations of different types of benign liver lesions to those of hepatocellular carcinoma. METHODS: By comparative genomic hybridisation (CGH) 40 cases, including cirrhotic liver (CL), focal nodular hyperplasia (FNHs), hepatocellular adenoma (HCAs), dysplastic nodules (DNs), primary hepatocellular carcinoma (HCCs), and hepatocellular metastases to the lung were studied. RESULTS: FNHs and HCAs exhibited few chromosomal abnormalities. Frequency and pattern of genetic alterations in DNs highly resembled those in HCCs: gains of DNA clustered in chromosome arms 1p/q, 7q, 15q, 16p, 17q, and 20q and losses were often found at 3p, 4q, 9p, and 11q. Aberrations on 1p, 6q, 8p/q, and 13q occurred almost exclusively in HCCs; the gain at 8q encompassed amplification of c-myc, as verified by fluorescence in situ hybridisation. CONCLUSIONS: The pattern of genetic alterations in HCCs resembled more the alterations found in DNs than in FNHs and HCAs, suggesting that DNs may be the actual tumor precursors. Furthermore, alterations at 4q, 9p, 11q, 16p, and 17q appear as early genetic events being crucial for hepatocarcinogenesis.

Adenoma, Liver Cell↗
PubMed1995

The relationship between secondary chromosomal abnormalities and blast transformation in chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a stem cell disorder which progresses from a chronic phase (CP) to an accelerated phase (AP), and/or a blast phase (BP) of myeloid (M) or lymphoid (L) phenotype. This progression is frequently preceded or accompanied by recurring secondary chromosomal abnormalities which are believed to play a role in the transformation. In order to investigate the relationship between the secondary change and the development of BP, we undertook a study using fluorescence in situ hybridization to determine in which cells the secondary abnormalities were present. We observed that in one case of L-BP, the secondary change (trisomy 8) appeared to be in a subclone that was different from the blast cells, as it was absent from the lymphoblasts but present in differentiating erythroid, monocytic and granulocytic cells. In two cases, the secondary change (trisomy 8, extra Ph) probably occurred prior to an acute transforming event as it was present in CP or AP predominantly in differentiated granulocytic or monocytic cells. In one case of M-BP, the secondary change (trisomy 8) probably occurred after the acute transformation, as it appeared in only a subset of the blasts. Lastly, in four cases of L-BP, the secondary change (monosomy 7, extra Ph or hyperdiploidy) was closely associated with the BP as it was present in all of the blasts. The findings indicate that some secondary abnormalities may be directly related to the development of BP and may provide clues to the identity of genes responsible for the acute phase transition. Other abnormalities occurring before, or after the acute transformation or in a different subclone from the acute phase blasts, may be more important for denoting genomic instability than for helping to understand the mechanism of blast transformation.

Adolescent↗
PubMed1990

Do chromosome abnormalities determine the type of acute leukemia that develops in CML?

Chronic myelogenous leukemia (CML) is characterized by two distinct phases--chronic and acute. Features of the chronic phase include proliferation and accumulation of mature myeloid cells and their progenitors; differentiation is seemingly intact. In contrast, the acute phase is characterized by impaired differentiation. Acute phase is heterogeneous--granulocytes, lymphocytes, megakaryocytes, and erythroid cells are involved singly or in combination. The t(9;22) translocation, which results in the Ph1 chromosome, is the hallmark of chronic phase CML. Transition to acute phase is often accompanied by additional chromosome abnormalities. Here we suggest that these additional abnormalities determine the phenotype of acute phase CML.

Chromosome Aberrations↗
PubMed2002

SEPTIN6, a human homologue to mouse Septin6, is fused to MLL in infant acute myeloid leukemia with complex chromosomal abnormalities involving 11q23 and Xq24.

t(X;11) is a recurrent translocation in pediatric acute myeloid leukemia (AML). We showed that the MLL gene on 11q23 was fused to the SEPTIN6 gene on Xq24, a human homologue to mouse Septin6, in three de novo infant AML with complex chromosomal abnormalities involving 11q23 and Xq22-24. SEPTIN6 consisted of at least 12 exons and was predicted to encode at least two types of proteins by alternative splicing. Expression of approximately 2.3-, 3.1-, and 4.6-kb SEPTIN6 transcripts was simultaneously detected in fetal lung, liver, and brain, in all of the adult tissues except brain, and in acute lymphoblastic leukemia and AML cell lines. However, the expression of an approximately 2.7-kb transcript was detected alone in fetal heart and adult brain. The SEPTIN6 protein is homologous to septin family members including CDCREL1 and AF17q25/MSF, which generate fusion products with MLL. The MLL-SEPTIN6 fusion proteins contain almost the entire septin protein, similar to MLL-CDCREL1 and MLL-AF17q25/MSF. Notably, all three of the patients were diagnosed with M1 or M2. Combined present results and literatures suggest that AML with the MLL-SEPTIN6 fusion gene is a subset of infant AML, which differentiate into the myeloid lineage, although AML with other MLL fusion genes is capable of differentiating into the myelomonocytic or monocytic lineage.

Adult↗
PubMed2002

Clinical implications of chromosomal abnormalities in gastric adenocarcinomas.

Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer-derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome-wide level. Eighty-four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24-qter (53%), 20q13-qter (48%), 1p32-p36 (42%), 22q12-qter (27%), 17p13-pter (24%), 16p13-pter (21%), 6p21-pter (19%), 20p12-pter (19%), 7p21-pter (18%), 3q28-qter (8%), and 13q13-q14 (8%), and losses at 18q12-qter (11%), 3p12 (8%), 3p25-pter (8%), 5q14-q23 (8%), and 9p21-p23 (5%), are associated with unique patient or tumor-related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy.

Adenocarcinoma↗
PubMed1975

[Cytogenetic studies of preinvasive lesions and invasive carcinomas of the cervix uteri. II. Structural chromosome abnormalities. Karyotype deviations (author's transl)].

An analysis of karyotypes was possible in 17 preinvasive lesions (3 dysplasias, 14 carcinomas in situ) and 15 invasive lesions of the cervix uteri (3 carcinomas in situ with microinvasion, 12 invasive squamos carcinomas - at least clinical stage I b). With regard to the structural chromosome abnormalities or karyotype deviations in this study the preinvasive lesions analysed could not be differentiated in principle as a group from the invasive lesions. The question of whether the dysplasia group would be different on further investigation with more cases and could be differentiated like the numerical deviations cannot yet be answered, because of the small numbers, only preinvasive lesions and invasive lesions could be studied comparatively as groups.

Adult↗
PubMed1998

Long-term disappearance of previous chromosomal abnormalities in myelodysplastic syndromes treated with low dose cytosine arabinoside and granulocyte/macrophage-colony stimulating factor.

Most therapies for elderly patients with myelodysplastic syndromes offer few short responses and little improvement in survival. We describe two patients who, after several cycles of low dose cytosine arabinoside and GM-CSF, achieved and maintained complete remission and became transfusion independent. Previous chromosomal abnormalities also disappeared and karyotype remains normal.

Aged↗
PubMed1991

Fetal obstructive uropathies. Importance of chromosomal abnormalities and associated anomalies to perinatal outcome.

The ultrasound records of 30 fetuses suspected of having an obstructive uropathy were reviewed retrospectively. A prenatal karyotype was obtained with amniocentesis on each patient. After delivery, neonatal urologic records, renal ultrasound reports and autopsy information were reviewed and compared to the ultrasound records and fetal karyotype results. Chromosomal defects were found in 23% of fetuses with a suspected obstructive fetal uropathy. In five patients the chromosomal abnormality was lethal and caused 45% of the perinatal deaths in this series. If a fetus with an obstructive uropathy was female, there was a significant likelihood of an extrarenal anomaly or a complex genitourinary tract malformation. Seventeen percent of patients with an obstructive uropathy had a coexistent extrarenal defect. A prenatal karyotype should be obtained if a fetal obstructive uropathy is suspected antenatally since lethal chromosomal defects are an important cause of perinatal death. A female karyotype may indicate a fetus at higher risk of extrarenal anomalies or complex genitourinary malformations.

Adult↗
PubMed2002

Clinical and biological implications of partial tandem duplication of the MLL gene in acute myeloid leukemia without chromosomal abnormalities at 11q23.

The clinical and biological features of acute myeloid leukemia (AML) with 11q23/MLL translocations are well known, but the characteristics of AML with partial tandem duplication of the MLL gene have not been explored comprehensively. In this study, MLL duplication was analyzed, in 81 AML patients without chromosomal abnormalities at 11q23, using Southern blotting, genomic DNA polymerase chain reaction (PCR), reverse-transcription PCR and complementary DNA sequencing. Nine patients showed partial tandem duplication of the MLL gene, including eight (12%) of the 68 with normal karyotype. Seven patients showed fusion of exon 6/exon 2 (e6/e2), one, combination of differentially spliced transcripts e7/e2 and e6/e2, and the remaining one, combination of e8/e2 and e7/e2. Among the patients with normal karyotype, children aged 1 to 15 showed a trend to higher frequency of MLL duplication than other patients (2/5 or 40% vs 6/62 or 10%, P = 0.102). The patients with tandem duplication of the MLL gene had a significantly higher incidence of CD11b expression on leukemic cells than did those without in the subgroup of patients with normal karyotype (75% vs 28%, P = 0.017). There were no significant differences in the expression of lymphoid antigens or other myeloid antigens between the two groups of patients. In adults, the patients with MLL duplication had a shorter median survival time than those without (4.5 months vs 12 months, P = 0.036). In conclusion, partial tandem duplication of the MLL gene is associated with increased expression of CD11b on leukemic blasts and implicates poor prognosis in adult AML patients. The higher frequency of MLL duplication in children older than 1 year, than in other age groups, needs to be confirmed by further studies.

Acute Disease↗
PubMed2000

Expression of pro-EPIL peptides encoded by the insulin-like 4 (INSL4) gene in chromosomally abnormal pregnancies.

The recent development of a specific immunoassay based on monoclonal antibodies directed to chain C and chain A of early placenta insulin-like peptide (EPIL) encoded by the INSL4 gene, has made it possible to demonstrate pro-EPIL peptide expression during normal pregnancy. In the present study, we report on the expression of pro-EPIL peptides in chromosomally abnormal pregnancies, namely trisomy 21 and 18. EPIL peptide levels were measured in amniotic fluid (AF) and maternal serum (MS) from pregnancies with trisomy 21 (n=16) or 18 (n=14) and compared to levels detected in AF and MS from 33 chromosomally normal pregnancies between 12 and 32 weeks of gestation. Pro-EPIL peptide levels were significantly higher in amniotic fluids from T21 than in AF from chromosomally normal pregnancies (mean pro-EPIL levels +/- SEM, 449+/-129.2 ng/mL vs 137+/-29.6 ng/mL, P = 0.0195), whereas there was only a trend towards an increase in pro-EPIL peptide levels in maternal serum. In a limited matched gestational age range (15 to 17 weeks), it was confirmed that pro-EPIL peptide levels were significantly higher in AF from T21 pregnancies (644.0+/-155.9 ng/mL, n = 11) than in AF from normal pregnancies (177.8+/-39.0 ng/mL, n = 12; P < 0.0001). Interestingly, the expression patterns of pro-EPIL peptides, human chorionic gonadotropin (hCG) and its free subunits were parallel in T21 pregnancies as recently observed in normal pregnancies. These results are in line with previous observations suggesting that the biosynthesis of both hCG and EPIL follows common regulation pathways.

Adult↗
PubMed2001

Cytogenetic findings in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Chromosomal abnormalities are associated with the polymorphous subtype and an aggressive clinical course.

We correlated bone marrow cytogenetic findings with morphologic and immunophenotypic data in 37 patients with lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM). Each LPL/WM case was classified as lymphoplasmacytoid (n = 18), lymphoplasmacytic (n = 10), or polymorphous (n = 9) using the Kiel criteria. Of 12 cases with chromosomal abnormalities, a single numeric abnormality was present in 4 and a complex karyotype in 8. The most common numeric abnormalities were and -8 in 3 cases each; the most common structural abnormality was del(6q) in 6 cases. Cytogenetic abnormalities were significantly less common in the lymphoplasmacytic and lymphoplasmacytoid groups (5/28 [18%]) compared with the polymorphous group (7/9 [78%]). Clinical follow-up was available for 28 patients for a median of 36 months. Six (67%) of 9 patients with aneuploid tumors, including 4 with polymorphous subtype, subsequently had clinical progression or developed high-grade lymphoma. In contrast, 4 (21%) of 19 patients with diploid tumors, including 1 of polymorphous type, developed clinical progression or high-grade lymphoma. We conclude that abnormal cytogenetic findings in LPL/WM correlate with the polymorphous subtype and poor prognosis.

Adult↗
PubMed1994

Swedish survey on extra structurally abnormal chromosomes in 39 105 consecutive prenatal diagnoses: prevalence and characterization by fluorescence in situ hybridization.

During 7 years (1985-1992), 39,105 consecutive prenatal diagnoses (34,908 amniocenteses and 4197 chorionic villus samples) were made at the five largest clinical genetic laboratories in Sweden. Thirty-one cases of extra structurally abnormal chromosomes (ESACs) were found, giving a total prevalence of 0.8 per 1000. Twelve ESACs were inherited, 14 were de novo and in five the parental origin was unknown. This gives an estimated prevalence of 0.3-0.4 per 1000 for familial and 0.4-0.5 per 1000 for de novo ESACs. Retrospectively, the ESACs were characterized by fluorescence in situ hybridization (FISH). In nine cases, no material was available for this analysis. In 21 of the remaining 22 cases, the chromosomal origin could be identified by FISH. Seventeen of these (81 per cent) were derived from the acrocentric chromosomes, of which 13 originated from chromosome 15 (62 per cent). The most common ESAC was the inv dup(15) (57 per cent). Two cases were derived from chromosome 22, one from chromosome 14, and one from either chromosome 13 or chromosome 21. The four remaining cases consisted to two i(18p)s and two small ring chromosomes derived from chromosomes 4 and 19, respectively.

Amniocentesis↗