Peter H. Fitzgerald

Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women

SummaryIn PHA-cultured lymphocytes, about 8% of metaphases from 32 women were aneuploid compared to 4% of metaphases from 35 men. A significant part of this aneuploidy was characterized by sex chromosome involvement: in women, the loss or gain of X chromosomes; in men, the gain of X chromosomes and the loss or gain of Y chromosomes. The incidence of this aneuploidy was positively age-related for both sexes. Premature division of the X-chromosome centromere was closely associated with X-chromosome aneuploidy in women and men, and appeared to be the mechanism of nondisjunction causing this aneuploidy. Premature centromere division (PCD) indicated a dysfunction of the X-chromosome centromere with aging, and this dysfunction was the basic cause of age-related aneuploidy. A similar mechanism of nondisjunction may operate for the Y chromosome of men, but could not be clearly demonstrated because of the low incidence of Y-chromosome aneuploidy.The balance of the aneuploidy was characterized by chromosome loss and the involvement of all chromosome groups. It was consistent with chromosome loss from metaphase cells damaged during preparation for cytogenetic examination.

Telomeric association of chromosomes in B-cell lymphoid leukemia

SummaryAbout 20% of leukemic bone marrow cells from each of two patients with B-cell lymphoid leukemias showed apparent translocations which appeared to be the result of telomeric association. In one patient, whole chromosomes were associated telomere to telomere in pairs; in the other patient, telomeres of whole chromosomes were associated with breakpoints located close to the proximal or distal ends of the heterochromatic band 1q12. Repeated base sequences, particularly (CA)n sequences, are believed to be the basis of telomere pairing, and likewise repeated base sequences of heterochromatin may explain the association of 1qh and telomeres. Telomeric association may be considered as a potential origin of new stable cytogenetic combinations that have a role in oncogene transposition and tumor etiology.

An abnormal chromosome in chronic lymphocytic leukaemia.

Lambo, T. A. (1956). Brit. med. J., 2, 1388. (1960). Ibid., 2, 1696. Laubscher, B. J. F. (1951). Sex, Custom, and Psychopathology. Routledge and Kegan Paul, London. McGeorge, J. (1942). Med. J. Aust., 1, 67. Mahi, Tigani El (1959). Africa: Social Change and Mental Health. W.H.O. Odegard, 0. (1932). Acta physiol. scand., Suppl. 4, p. 11. Read, C. S. (1936). Brit. med. J., 1, 631. Sainsbury, P. (1955). Suicide in London. Chapman, London. Stengel, E. (1950). Recent Progr. Psychiat., 2, 691. and Cook, N. G. (1954). J. forens. Med., 1, No. 5. Tooth, G. (1950). Studies in Mental Illness in the Gold Coast. Colonial Research Publ. No. 6. H.M.S.O., London. Wicksell, S. (1934). Svenska Forenigrens for Psykisk Halsovard Smaskrifter, No. 7. Quoted by Dahlgren (1945). Yap, P. M. (1958). J. ment. Sci., 104, 266.

A mechanism of X chromosome aneuploidy in lymphocytes of aging women

SummaryOne and sometimes both X chromosomes in cultured lymphocytes of women donors showed division of the centromere when the centromeres of other chromosomes were entire. This premature centromere division (PCD) was associated with evidence of nondisjunction of the X chromosome. On average, 2% of metaphases from 32 women donors showed PCD, but the incidence was 4 times greater in women over 59 years of age than in women under 40 years. Increased X chromosome aneuploidy was associated with the higher frequency of PCD in cultured lymphocytes from older women. PCD of the X chromosome is considered to be the mechanism of non-disjunction causing the previously described aneuploidy in cultured lymphocytes of aging women.

Nonrandom cytogenetic changes in New Zealand patients with acute myeloid leukemia

Bone marrow clones with abnormal chromosomes were observed in 56% of 66 patients with forms of acute myeloid leukemia [French-American-British (FAB) M1-M6]. Acute myeloblastic leukemia (AML, M1 and M2) was the most common form, and 65% of these patients showed chromosomal abnormalities compared with 41% of patients with acute myelomonocytic leukemia (AMMoL, M4). The recognized nonrandom chromosomal abnormalities found were trisomy 8, monosomy 5 or 7, trisomy 1q, t(6;9), t(8;21), t(15;17), and abnormalities in 17q. There was also a strong involvement of chromosome No. 11: Abnormalities were found in eight patients when their leukemia was diagnosed and in a further three patients during the course of karyotypic evolution. Six of these patients had AMMoL or AMoL. Complex or multiple clones were found in 37% of AML patients at diagnosis. Our AML patients had a reduced frequency of abnormalities in chromosome No. 5 or 7 and an increased frequency of abnormalities in chromosome No. 8 compared with studies reported in other countries (p = 0.01). This difference suggests that in New Zealand AML might be caused by factors different from those operating in more industrialized centers.

Stress experienced by physicians and nurses in the cancer ward.

This study examined occupational stress amongst medical staff on cancer wards. The sample consisted of 91 nurses and 57 physicians from 13 institutions in Bavaria, F.R.G. Strong associations emerged between specific, situational stressors and reported psychosomatic complaints. In particular, interpersonal difficulties, whether on or off the job, related to physical distress amongst nurses. For doctors, dissatifaction with the job and working conditions related to general malaise. Certain characteristics of the carer (sex, profession, age) and of the institutional environment (e.g. presence of trainees, size of institution) were also linked with stress and complaint levels.

Complex chromosomal translocations in the Philadelphia chromosome leukemias: Serial translocations or a concerted genomic rearrangement?☆

Joining of the BCR and ABL genes is an essential feature of the group of human leukemias characterized by the Philadelphia chromosome and there is recent evidence that the human BCR-ABL fusion gene induces leukemia in experimental animals. Joining of these two genes is the result of cytogenetic translocation, usually the t(9;22)(q34;q11), but sometimes of more complex translocations involving one or more chromosomes in addition to chromosomes 9 and 22. The leukemic cells of some patients carry the BCR-ABL fusion gene but have an apparently normal karyotype. Recent studies show that these cells conceal complex chromosome rearrangements. Because the BCR-ABL fusion gene appears to be the result of cytogenetic rearrangement in all cases of these leukemias, the causes and mechanism of chromosome rearrangement will be relevant to the development of leukemia in man. We examine mechanisms of chromosome rearrangement and propose that both simple and complex chromosome translocations result from a single, though sometimes complex, interchange event.

Evidence for the repeated primary non-disjunction of chromosome 21 as a result of premature centromere division (PCD)

SummaryA clinically normal 28-year-old woman had three conceptuses with trisomy 21 and one normal child. She showed minimal cytogenetic evidence of mosaicism: 4% of her blood cells and 6% of skin fibroblasts had trisomy 21. Also, 7% of her blood cells showed aneuploidy of the X chromosome which was associated with premature centromere division (PCD, X); 6% of fibroblasts showed trisomy 18, 10% of fibroblasts showed PCD,21, and 1% PCD, 18. It is unlikely that this woman is a constitutional mosaic for trisomies X, 18, and 21, all at low levels. We suggest that she has a predisposition to irregular centromere separation and that chromosomes X, 18, and 21 are most susceptible to its action.

Does multisomy of chromosome 1q confer a proliferative advantage in B-cell acute lymphoblastic leukemia?

Two patients fulfilled the clinical and hematologic criteria for B‐cell acute lymphoblastic leukemia: the malignant cells had L3 morphology, bore B‐cell markers, and carried the specific t(8;14) translocation. The leukemic cells of one patient were tetrasomic for lq, and those of the other patient showed several separate cell lines with complete or partial trisomy of lq. In the latter patient it appeared that a break close to the heterochromatin of lq produced an unstable chromosome end which formed associations with the telomeres of at least seven other chromosomes. It is suggested that multisomy of lq gives tumor cells a proliferative advantage and is secondary to the basic neoplastic event.

Clonal Origin of the Philadelphia Chromosome and Chronic Myeloid Leukaemia: Evidence from a Sex Chromosome Mosaic

Summary. A male patient aged 69 yr with chronic myeloid leukaemia was a constitutional XY/XXY sex chromosomal mosaic as indicated by a positive sex chromatin in neutrophils and cytogenetic studies of lymphocytes cultured with phytohaemagglutinin. He was of normal phenotype and intelligence. In a bone‐marrow aspirate taken when the patient was in the acute phase of leukaemia the 46, XY cell line carried the Ph1 chromosome, whereas the 47, XXY cell line did not. Two further cell lines were considered to have been derived by clonal evolution of the 46,XY,Ph1‐positive line, although one of them possessed ambiguous features. The results support a clonal origin of the Ph1 chromosome, and presumably also of chronic myeloid leukaemia. An interesting feature of the bone marrow was that the 46, XY, Ph1‐positive cell line had apparently replaced the normal 46, XY cells but not the 47, XXY cells.