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This paper describes an expert system for interpreting the standard notation used to represent human chromosomal abnormalities, namely, the International System for Human Cytogenetic Nomenclature. Written in Prolog, this program is very powerful, easy to maintain, and portable. The system can be used as a front end to any database that employs cytogenetic notation, such as a patient registry.
Karyotypes of 107 cases with adult T-cell leukemia/lymphoma (58 male, 49 female; 81 acute or lymphoma type, 26 chronic or smoldering type) were reviewed by a panel of cytogeneticists and were correlated with the subtypes of the disease. Clonal chromosome abnormalities were found in 103 (96%) cases, of which four had hypotetraploidy. Of 184 numerical abnormalities in the remaining 99 cases with near- or pseudodiploidy, trisomies for chromosomes 3 (21% of cases), 7 (10%), and 21 (9%), monosomy for X chromosome (38%) in the female, and loss of a Y chromosome (17%) in the male were more frequent than expected (P less than 0.01). Of 373 structural abnormalities in all the 103 aneuploid cases, translocations involving 14q32 (28%) or 14q11 (14%) and deletion of 6q (23%) were most frequent, followed by deletion of 10p (9%), 3q (8%), 5q, 9q, and 13q (7% each), and 1p and 7p (6% each). The proportion of cases with aneuploid clones (with greater than or less than 46 chromosomes), the average numbers per case of both numerical and structural abnormalities, and marker chromosomes were larger in the aggressive acute or lymphoma type than in the nonaggressive chronic or smoldering type (P less than 0.01). The combination of rearrangement in 14q32 and monosomy X (seven cases) or deletion of 10p (six cases), and that of trisomy 3 and deletion in 6q21 (six cases), occurred only in the acute or lymphoma type and may be associated with the aggressiveness in adult T-cell leukemia/lymphoma.
A study was undertaken to determine the relationship between chromosome composition and embryo development. Bovine cumulus-oocyte complexes were matured in vitro and exposed to semen from one of three different bulls, one of which was a 1/29 Robertsonian translocation carrier. There were no significant differences among the three bulls in their sperm penetration or in the cleavage or developmental rates of resulting embryos, which were subjected to chromosome analysis on Day 2 (40-44 h postinsemination [hpi]) and Day 5 (120-124 hpi) of development. No difference was detectable in the growth rates of embryos of different chromosomal composition on Day 2. On Day 5, a total of 343 embryos were obtained from all three bulls, of which 158 embryos could be karyotyped and assessed for cell numbers. Cell numbers for the Day 5 embryos showed that the mean numbers for the individual chromosome compositions (least-squares means +/- SEM) were 7.9 +/- 6.0 for haploids, 7.9 +/- 6.0 for haploids, 7.9 +/- 6.0 for polyploids, 16.8 +/- 4.3 for aneuploids, 23.4 +/- 4.0 for mixoploids, and 30.0 +/- 1.7 for diploids, indicating a significant reduction in the growth rate of embryos with chromosomal abnormalities (p < 0.001). It was concluded that development rates (as evidenced by cell numbers) were slowest in haploid and polyploid embryos, intermediate in aneuploid embryos, and fastest in mixoploid and diploid embryos.
During recent years a considerable improvement in diagnostic techniques has enabled cytogeneticists to find more and smaller chromosomal aberrations. However, accurate clinical knowledge about rare chromosome disorders is frequently lacking, mostly due to a significant decline in publishable cases. On the other hand, there is an increasing demand from parents and physicians for reliable information. In order to improve the quality and the quantity of data available, we designed a new database named the European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA) at http://www.ecaruca.net. This Internet-database contains cytogenetic and clinical data of patients with rare chromosome abnormalities, including microscopically visible aberrations, as well as microdeletions and -duplications. Cases with certain breakpoints collected in the Zurich Cytogenetic Database were transferred to ECARUCA. The advantages of ECARUCA compared to existing sources are that ECARUCA is interactive, dynamic and has long-term possibilities to store cytogenetic, molecular and clinical data. Professionals can login to submit new cases and perform searches in the database through the Internet. Currently the database contains 1500 unique chromosomal aberrations from almost 4000 patients. A frequent submission of new data ensures the up-to-date quality of the collection. Individual parent accounts allow parents to inform the ECARUCA team about the follow-up of their child. The ECARUCA database provides health care workers with accurate information on clinical aspects of rare chromosome disorders. Additionally, detailed correlations between chromosome aberrations and their phenotypes are of invaluable help in localising genes for mental retardation and congenital anomalies.
Adenocarcinoma of the pancreas is the fifth most common cause of cancer deaths in the United States, yet few cytogenetic studies of this tumor have been reported. We analyzed 26 primary tumors to identify which chromosome abnormalities occur most frequently in this neoplasm. One carcinoma was well differentiated and mucin producing, 18 were moderately well differentiated, and seven were poorly differentiated. Only normal karyotypes were obtained from nine carcinomas. The remaining 17 carcinomas frequently had normal metaphase cells in addition to simple to highly complex karyotypes. The modal chromosome number in 20 carcinomas was diploid or near-diploid; four carcinomas had both a major near-diploid and near-triploid or near-tetraploid component, and two were near-tetraploid. Numerical abnormalities included loss of whole copies of chromosomes 6, 17, and 18, and gains of chromosome 20. Structural abnormalities were frequent, with 1p, 2p, 3p, 4q, 6q, 7q, 11q, and 17p recurrently involved. Results of this study were combined with karyotypes of 19 other primary adenocarcinomas of the pancreas reported in the literature. The combined data involving 117 breakpoints suggest that careful analysis of chromosome 20, proximal 1q, 6q, proximal 8p, and proximal 17p could be productive in defining genes involved in adenocarcinoma of the pancreas.
De novo aberrations in chromosome structure represent important categories of paternally transmitted genetic damage. Unlike numerical abnormalities, the majority of de novo structural aberrations among human offspring are of paternal origin. We report the development of a three-color fluorescence in situ hybridization (FISH) assay (CT8) to detect mouse sperm carrying structural and numerical chromosomal abnormalities. The CT8 assay uses DNA probes for the centromeric and telomeric regions of chromosome 2, and a probe for the subcentromeric region of chromosome 8. The CT8 assay was used to measure the frequencies of sperm carrying certain structural aberrations involving chromosome 2 (del2ter, dup2ter, del2cen, dup2cen), disomy 2, disomy 8, and sperm diploidy. Analysis of approximately 80,000 sperm from eight B6C3F1 mice revealed an average baseline frequency of 2.5 per 10,000 sperm carrying partial duplications and deletions of chromosome 2. Extrapolated to the entire haploid genome, approximately 0.4% of mouse sperm are estimated to carry structural chromosomal aberrations, which is more than fivefold lower than the spontaneous frequencies of sperm with chromosome structural aberrations in man. We validated the CT8 assay by comparing the frequencies of abnormal segregants in sperm of T(2;14) translocation carriers detected by this assay against those detected by chromosome painting cytogenetic analysis of meiosis II spermatocytes. The CT8 sperm FISH assay is a promising method for detecting structural chromosome aberrations in mouse sperm with widespread applications in genetics, physiology, and genetic toxicology.
Little is known about the role of chromosomal abnormalities in the widely used models of rat mammary carcinogenesis. In this study, we cytogenetically analyzed nitrosomethylurea-induced rat mammary adenocarcinomas at different time points of development. As tools to study more advanced stages of malignant progression, we also analyzed the cytogenetic progression of tumors transplanted into younger syngeneic hosts, and of tumors that did not regress or that developed after host ovariectomy. Our results indicate that rat mammary adenocarcinomas appear to start development as diploid lesions with cytogenetically "normal" karyotypes. However, upon progression, tumors showed coexistence of normal diploid clones with abnormal clones bearing specific abnormalities affecting mainly chromosomes 1 and 15. Almost every ovary-independent tumor presented stem lines with specific nonrandom chromosomal abnormalities. Numerical chromosomal abnormalities such as specific trisomies started to develop mainly after subsequent in vivo transplantations. The abnormalities affecting chromosome 1 observed in many tumors were: (a) interstitial deletions and breakpoints for translocation in region 1q22; and (b) partial or complete overrepresentation of chromosome 1 in the form of direct duplication of region 1q22q43 or as trisomy 1. Interestingly, Harvey-ras-1 gene maps to rat chromosome 1, and by Southern analysis we observed that 4 of 8 primary tumors and 6 of 9 ovary-independent tumors showed considerable loss of Harvey-ras-1 signal indicating probable allele loss. However, analyses of some tumor transplants in more advanced stages of progression showed, paradoxically, an increased copy number of the Harvey-ras-1 oncogene coinciding with the presence of the direct duplication observed in chromosome 1 or with trisomy 1 as possible mechanisms for gene amplification. Interestingly, rat chromosome 1 is the homologue to human chromosome 11, and in numerous cases of human breast cancer loss of heterozygosity of several genes in chromosome 11p15.5 has been reported. Some of the rat chromosome 1 abnormalities observed may be equivalent to those affecting 11p15 in human tumors. We also observed 8 tumors with abnormalities affecting chromosome 15. At least 3 genes of interest in breast cancer have been previously mapped to that rat chromosome. The similarities observed with human breast cancer may point to common mechanisms of tumor progression in both species.
The LS/BL lymphosarcoma was induced by radiation in a C57BL/10 mouse in 1963 and was converted to ascites form in the first mouse transfer generation. In the course of cultivation in vivo the modal number of chromosomes dropped from the initial value 42-41 to 39 (73%). Cytogenetic characterization of the LS/BL tumor was carried out, using G-banding technique. Chromosome abnormalities were consistent in the cell line and involved chromosomes Nos. 3, 6, 12, 13, 16, and X. The most frequent abnormality was the presence of three markers and trisomy of chromosome No. 16.
Structural rearrangements in the long arm of chromosome 3, del(3)(q12q25) and t(3;5)(q21-25;q31-33), were observed in bone marrow cells from 2 patients with myeloid neoplastic disorders (myelodysplastic syndrome and acute myeloid leukaemia) and acute febrile neutrophil dermatosis (Sweet's syndrome). 3 of the 4 patients with leukaemia-associated Sweet's syndrome and acquired chromosome abnormalities known from the literature also had 3q changes, in 2 involving band 3q21.
Most studies of cytogenetic abnormalities in leukemia patients have focused on structural chromosomal rearrangements. Less attention has been paid to the role of single numerical abnormalities in the complex mechanisms of leukemia pathogenesis. We therefore studied 11 cases of acute lymphoblastic leukemia (ALL) with trisomy 21 as the sole chromosomal abnormality, representing 1.8% of 601 completely banded cases of ALL seen during a 10-year period. Bone marrow cells from all but one of these cases also had normal karyotypes, representing 8 to 77% of the completely analyzed metaphases. Each of the five cases tested lacked evidence of trisomy 21 mosaicism of constitutional origin in peripheral blood samples. The presenting features of these five girls and six boys were heterogeneous but tended to reflect lower-risk ALL: median age, 3.3 years (range 1-18 years), median leukocyte count, 11.6 x 10(9)/l (range 1.8-82 x 10(9)/l), white race, and a B-cell precursor immunophenotype. Complete remissions were readily induced in all 11 patients. With follow-up ranging from 1+ months to 6.4+ years, the only relapses have been extramedullary (testis and central nervous system) in two patients, both of whom have since achieved second remissions of greater than 76 and greater than 65 months. Trisomy 21 as the sole chromosomal abnormality in childhood ALL appears related to favorable presenting risk features and may represent a good prognosis subset within the group of patients with 47-50 chromosomes.
OBJECTIVE: To learn about parental decisions to abort or continue a pregnancy after prenatal diagnosis of chromosomal abnormalities among the population in Uruguay. METHODS: Between 1982 and 2003, 14 656 amniocentesis and 2740 chorionic villus samplings were performed in a referral Genetic Unit. Chromosomal anomalies were found in 376 cases (2.16%) and included Down syndrome, aneuploidies in which a severe prognosis was expected, sex chromosome aneuploidy and aneuploidies with a low risk of an abnormal clinical phenotype. The couples that received abnormal results were contacted by phone and asked if they had continued or interrupted the pregnancy after the diagnosis and genetic counseling. RESULTS: We contacted 207 couples (55%). When confronted with Down syndrome or an aneuploidy in which a severe prognosis was expected, 89% and 96% of patients, respectively, decided to terminate the pregnancy. When confronted with sex chromosome aneuploidy or aneuploidies with a low risk of an abnormal clinical phenotype, 79% and 90% of patients, respectively, decided to continue the pregnancy. CONCLUSIONS: The present study shows that when faced with an anomaly such as Down syndrome and aneuploidies in which a severe prognosis was expected, most of the couples decided to terminate the pregnancy, although TOP is not legally available in Uruguay.
We report the finding of clonal chromosome abnormalities in short-term cultures from 44 squamous cell carcinomas of the head and neck region. Eleven tumors had gain or loss of the Y chromosome, sometimes one clone with +Y and another with -Y, as the sole anomaly, whereas the remaining 33 all carried structural rearrangements and usually were cytogenetically complex with multiple aberrations. The chromosomal bands most frequently involved were, in decreasing order of frequency, 8p11-q11, 1p11-q11, 3p11-q11, 11q13, 13p11-q11, 1p13, 5p11-q11, 7p11-q11, 15p11-q11, and 14p11-q11. Almost one-half of the breakpoints were located in centromeric or juxtacentromeric bands. Recurrent aberrations included i(8q), i(5p), i(1q), del(3)(p11-12), del(5)(p11), t(1;1)(p13;q25), and der(14;15)(q10;q10). To see whether the karyotypic features of head and neck squamous cell carcinoma differ depending on exact tumor site, we added to the present series our previously published 23 karyotypically abnormal head and neck squamous cell carcinomas that had been cultured in the same way as the tumors of the present series. In the ensuing correlation analysis, tumors of the oral cavity and oropharynx and hypopharynx were found to share many features: highly complex karyotypes were frequent, often containing isochromosomes such as i(8q) and i(5p), and also rearrangements of 11q13 (often as homogeneously staining regions) and loss of genetic material from the short arms of chromosomes 3, 13, 14, and 15 were repeatedly seen. Laryngeal carcinomas, on the other hand, often had simple karyotypic changes.
OBJECTIVE: To review evidence regarding the effects of male age on germinal and heritable chromosomal abnormalities using available human and rodent studies and to evaluate possible underlying mechanisms. DESIGN: Review of English language-published research using MEDLINE database, excluding case reports and anecdotal data. RESULT(S): There was little evidence from offspring or germ cell studies for a generalized male age effect on autosomal aneuploidy, except in rodents. Sex chromosomal nondisjunction increased with age in both human and rodent male germ cells. Both human and rodent data showed age-related increases in the number of sperm with chromosomal breaks and fragments and suggest that postmeiotic cells are particularly vulnerable to the effects of aging. Translocation frequencies increased with age in murine spermatocytes, at rates comparable to mouse and human somatic cells. Age-related mechanisms of induction may include accumulation of environmental damage, reduced efficiency of DNA repair, increased genomic instability, genetic factors, hormonal influences, suppressed apoptosis, or decreased effectiveness of antioxidants and micronutrients. CONCLUSION(S): The weight of evidence suggests that the increasing trend toward fathering at older ages may have significant effects on the viability and genetic health of human pregnancies and offspring, primarily as a result of structural chromosomal aberrations in sperm.
To investigate the interrelationship among morphology, immunology and clinical features in adult acute myeloid leukemia cases with 11q23 chromosome abnormalities, 210 newly diagnosed AML patients were retrospectively analyzed by cell morphology, immunophenotyping, G-banding or R-bamding analysis and clinical features. The results showed that 13 cases were found with 11q23 rearrangements or deletion (the incidence rate was 6.19%.), totally 84.6% showed the involvement with the monocytic lineage. Immunophenotyping tests indicated that AML cases with 11q23 abnormalities usually expressed the marker molecules of hematopoietic stem or progenitor cells, monocytic lineage cells, such as CD34, CD117, CD14, CD15 and CD11b. The complete remission rate of the cases with 11q23 abnormalities was comparable to that of the cases with normal karyotype (P = 0.075), but the median disease-free survival in the former was significantly lower than that in the latter (P < 0.001). It is concluded that the category AML with 11q23 abnormalities accounts for 6.19% of all the newly diagnosed AML cases, that seems to be closely associated with monocytic differentiation blocking with a dismal prognosis.
The biologic significance of clonal karyotypic abnormalities in human neoplasms is becoming better understood, but the significance of rare chromosomal aberrations is uncertain. Useful, yet arbitrary, cytogenetic definitions of a clone have been established and cases with a frequency of chromosome aberrations less than the accepted convention are explained by random loss, karyotypic instability/evolution, or other technical artifact. Are non-clonal chromosomal abnormalities that may predict future clinically significant clones being ignored? A brief case report is presented raising two such issues in the same myelodysplastic patient. This child had monosomy 7 and, later, trisomy 8, as well as increased numerical/structural aberrations seeming to predict relapse. Preliminary data from the Southwestern Oncology group is also presented. Non-clonal data should be included, when appropriate, in the clinical report.
Tetrasomy 8 is a relatively rare chromosomal abnormality in hematological disorders, and is mostly associated with myeloid malignancies and poor prognosis. In a number of cases, tetrasomy 8 has been reported as an accompanying anomaly with other chromosomal changes. In this report, we describe a 14-year-old girl with acute megakaryoblastic leukemia associated with tetrasomy 8 (primary) and trisomy 6, 19 and 20. She died 6 months after diagnosis, suggesting a relatively poor prognosis for AML with tetrasomy 8. To the best of our knowledge, this is the first report of a tetrasomy 8 abnormality associated with subtype FAB M7. Interestingly, this abnormality has not been previously reported in childhood AML patients.
Fibroblasts from New Zealand Black mouse fetuses manifest increased frequency of chromosomal breaks and interchanges after exposure to ultraviolet radiation when compared with cells from BABL/c fetuses. This chromosomal instability is similar to what has been reported in cells from patients with xeroderma pigmentosum and may be related to the chromosomally abnormal clones and malignancy previously reported in adult New Zealand Black mice.
New Zealand Black (NZB) mice, an inbred strain characterized by immunological dysfunction and lymphoreticular malignancy, also develop populations of aneuploid spleen cells. In detailed cytogenetic analyses performed on 10 NZBs, the chromosomally abnormal cells were found to be clonally related within each mouse. Moreover, the karyotypic changes observed were highly non-random, usually involving the 15 (10/10 mice), 2 (8/10 mice), 16 or 17 (9/10 mice), and sex (6/10 mice) chromosomes. These observations suggest an important relationship between chromosomal alterations and tumorigenesis in NZB mice and emphasize the role of chromosome 15 in murine abnormal lymphoreticular proliferations.