The role of the Philadelphia translocation in chronic myeloid leukemia

During the last two decades evidence for a close association between the presence of specific chromosomal abnormalities and the occurrence of several types of cancers and leukemias has accumulated. The Philadelphia (Ph 1) translocation, present in about 90% of the patients with chronic myeloid leukemia (CML), is one of the most typical and best documented examples of such an aberration. Usually this translocation involves chromosome 9 and 22: t(9;22)(q34;q11). The translocation products are designated 9q+ and 22q-. Variant translocations involving an array of translocation sites different from 9 have been described as well, but chromosome 22 is always involved. So far, no clear indications were found for the possible role played by this highly specific chromosomal aberration in the etiology of CML. Moreover, results concerning the exact nature of the Ph1 translocation, obtained by different investigators using different techniques, appeared to be contradictory. In this thesis the application of somatic cell hybridization and gene segregation analyses to these questions has been described. Rodent cells (fibroblasts) were fused with human Ph1 positive leucocytes and, subsequently, hybrid cell 1 ines were isolated. These hybrids appeared to segregate human chromosomes, including the Ph1 translocation products. The segregation of genes, previously assigned to the regions of the chromosomal breakpoints, was studied together with the segregation of the relevant human (translocation) chromosomes. Several genes on chromosome 22 were found to be translocated to the 9q+ chromosome which confirmed, on a molecular level, the translocation of chromosome 22 materia] to chromosome 9. Another gene on chromosome 22 (immunoglobulin A 1 ight chain) stayed on the Ph1 chromosome (22q-). One gene on chromosome 9 (c-abl) appeared to be translocated to 22q-. This latter result provided unequivocal evidence for reciprocity of the Ph 1 translocation. No apparent differences in chromosomal breakpoints could be revealed in the different CML patients used for analysis and no evidence was found for loss of chromosomal material {genes) as a result of the Ph 1 translocation. The clonal origin of the Ph 1 translocation in CML was confirmed using a chromosome 9 encoded polymorphic enzyme (AKI)

Isolation of anonymous, polymorphic DNA fragments from human chromosome 22q12-qter

A series of 195 random chromosome 22-specific probes, equivalent to approximately 1% of the size of this chromosome, have been isolated from a chromosome 22-specific bacteriophage lambda genomic library. These probes were mapped to four different regions of chromosome 22 on a panel of five somatic cell hybrids. Restriction fragment length polymorphisms were detected by 28 of the probes mapping to 22q12-qter. Evolutionarily conserved sequences in human, mouse, and Chinese hamster DNA were detected by 12% of the isolated probes

A long-lasting, complete hematologic and cytogenetic remission of chronic myelogenous leukemia after treatment with busulfan alone

A 44-year-old man suffering from cytogenetically and molecularly proven Philadelphia translocation-positive chronic myelogenous leukemia in chronic phase was treated with busulfan for 18 months and studied during a follow-up period of 13 years. Hematologically and cytogenetically, he attained a continuing complete remission, although at one point (9.5 years) at least, after attaining complete remission molecular analysis indicated the presence of minimal residual disease

Fluorescence in situ hybridization-based approaches for detection of 12p overrepresentation, in particular i(12p), in cell lines of human testicular germ cell tumors of adults

Overrepresentation of the short arm of chromosome 12 is frequently detected in human testicular germ cell tumors of adolescents and adults (TGCT). This overrepresentation mostly results from the formation of an isochromosome i(12p). Whether the overrepresentation consistently involves the complete 12p arm including the centromere is still unclear. We studied five TGCT-derived cell line

Comparative genomic hybridization of germ cell tumors of the adult testis: Confirmation of karyotypic findings and identification of a 12p- amplicon

Comparative genomic hybridization (CGH) was carried out on 15 primary testicular germ cell tumors (TGCT) of adolescents and adults and two metastatic residual tumors after chemotherapeutic treatment. The results were compared with karyotypic data obtained form the same tumor specimens after direct harvesting of metaphases or short-term in vitro culture. Both techniques revealed that the most consistent abnormality in primary TGCT is gain of 12p-sequences. Although in most cases over-representation of the complete short arm was observed, CGH revealed a specific amplification of 12p11.1-p12.1 region in two independent primary tumors. In addition, loss of (parts of) chromosome 13 (always involving q31-qter), and gain of (parts of) chromosome 7 (mostly involving q11), (parts of) chromosome 8, and the X chromosome were detected in more than 25% of the tumors by this latter technique. Loss of 6q15-q21 in both re

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts

Localization of the xeroderma pigmentosum group B-correcting gene ERCC-3 to human chromosome 2q21.

The human excision-repair gene ERCC3 was cloned after DNA-mediated gene transfer to the uv-sensitive Chinese hamster ovary mutant cell line 27-1, a member of complementation group 3 of the excision-defective rodent cell lines. The ERCC3 gene specifically corrects the DNA repair defect of xeroderma pigmentosum (XP) complementation group B, which displays the clinical symptoms of XP as well as of another rare excision-repair disorder, Cockayne syndrome. The gene encodes a presumed DNA and chromatin binding helicase, involved in early steps of the excision-repair pathway. ERCC3 was previously assigned to human chromosome 2 (L.H. Thompson, A.V

Chromosomal localization of the human Thy-1 gene.

We have isolated the gene coding for human Thy-1. Introduction of this gene into HeLa cells by DNA-mediated transfer results in the expression of Thy-1 antigen on the cell surface. Chromosomal mapping of the Thy-1 gene by hybridization to metaphase chromosomes and Southern blots of DNA from hybrid cells indicate that the Thy-1 gene is located on the long arm of chromosome 11

Drug use, impaired driving and traffic accidents.

This literature review provides a comprehensive report on the relationship between drug use, impaired driving and traffic accidents. It covers methodological issues, presents results of prevalence surveys among drivers and provides an overview of findings from major international epidemiological surveys published since 1999. The report also gathers evidence from experimental and field studies of the relationship between drug use, driving impairment and traffic accidents Table of contents • Methodological issues in determining the relationship between drug consumption, impaired driving and traffic accidents • Prevalence of drugs in drivers • Effects and risks associated with drugs • Overall conclusio