Identical cytogenetic clones and clonal evolution in pediatric monozygotic twins with acute myeloid leukemia: presymptomatic disease detection by interphase fluorescence in situ hybridization and review of the literature.

PURPOSE: Observation of identical acquired genetic changes in infant monozygotic (MZG) twins with acute leukemia has provided strong evidence for in utero twin-twin transfusion as the cause of concordance. Documentation of similar phenomenon in older MZG twins offers insight into the latency period for leukemia and may provide the opportunity for presymptomatic disease detection in one twin. DESIGN: The literature describing leukemia in MZG twins is reviewed and the results of classical and molecular cytogenetic studies of one pair of MZG twins at 3 and 4 years with acute nonlymphocytic leukemia-FAB type M1 are reported. RESULTS: The twins studied had cytogenetically identical neoplastic clones with identical clonal evolution. Retrospective fluorescence in situ hybridization studies demonstrated the presence of the abnormal clone in the asymptomatic twin at the time of bone marrow transplant of the first twin. CONCLUSIONS: These observations support in utero twin-twin transfer as the origin of leukemic clones in pediatric and infant leukemia, demonstrate that clonal evolution of a leukemic clone may occur years before onset of overt disease, and indicate that knowledge of acquired genetic change(s) in one twin may provide markers to assess disease in the asymptomatic twin.

t(4;19)(q35;q13.1): a recurrent change in primitive mesenchymal tumors?

We report an apparently balanced t(4;19)(q35;q13.1) as the sole cytogenetic change in a highly malignant extraskeletal sarcoma in a 12-year-old-boy. Tumor cells were negative for all immunocytochemical markers except vimentin and neuron-specific enolase. Electron microscopy indicated chondroblastic differentiation. The tumor was categorized as a malignant sarcoma with differentiation toward extraskeletal mesenchymal chondrosarcoma. Reports of a similar translocation in an embryonal rhabdomyosarcoma (RMS) and in a dedifferentiated sarcoma with both rhabdomyosarcomatous and osteosarcomatous elements suggest that this translocation can arise in a primitive mesenchymal stem cell that can differentiate along at least these three pathways.

Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: a collaborative study.

Among 179,663 prenatal diagnosis cases collected from ten institutions and two publications, 555 (0.3 per cent) were diagnosed as having chromosome mosaicism. Of these, 57 (10.3 per cent) were mosaic for an autosomal structural abnormality, 28 (5 per cent) for a sex chromosome structural abnormality, and 85 (15.3 per cent) were mosaic for a marker chromosome. Ninety-five cases of prenatally diagnosed mosaicism with a structural abnormality in an autosome and a normal cell line, and with a known phenotypic outcome, were collected for karyotype-phenotype correlations through our collaboration (40 cases), a prior survey (26 cases), and published reports (29 cases). They included 13 balanced reciprocal translocations, one unbalanced reciprocal translocation, four balanced Robertsonian translocations, four unbalanced Robertsonian translocations, four inversions, 17 deletions, three ring chromosomes, 19 i(20q), seven +i(12p), six other isochromosomes, and 17 partial trisomies resulting from a duplication or other rearrangement. All cases mosaic for a balanced structural rearrangement resulted in a normal phenotype. All cases of 46/46,i(20q) resulted in normal liveborns. Five of seven cases with 46/47,+i(12p) had an abnormal phenotype compatible with Killian-Pallister syndrome. The overall risk for an abnormal outcome for a mosaic case with an unbalanced structural abnormality, excluding 46/46,i(20q) and 46/47,+i(12p), is 40.4 per cent. In the same category, the study also suggested a correlation between the percentage of abnormal cells and an abnormal phenotype. For mosaicism involving a terminal deletion, the possibility of a familial fragile site should be considered.

Cardiac myxoma characterized by clonal telomeric association.

We report on the cytogenetic analysis of a case of cardiac myxoma of the "syndrome myxoma" type, in which clonal telomeric associations between chromosomes 13 and 15, as well as nonclonal telomeric associations between chromosomes 12 and 17 and between chromosome 2 and an unidentified chromosome were observed. Nonclonal structural abnormalities were also present. This is the second reported case of cytogenetic abnormalities of syndrome cardiac myxoma, and the fourth case in which telomeric associations have been described.

The use of giant cell tumor conditioned media in cytogenetic studies of hematologic malignancies.

The use of conditioned media produced from solid tumor cell lines has been beneficial in the study of hematologic malignancies. Conditioned media from giant cell tumors (GCT), human lung adenocarcinoma, and human bladder carcinoma express growth factors that have been used to stimulate growth of bone marrow cells and improve the quality of the preparations. It has been reported that addition of Lu-CSF1-conditioned media from a lung adenocarcinoma cell line masks abnormalities in cases of acute leukemia [1.] Because we routinely use GCT-CM in bone marrow and leukemic blood cultures for chromosome analysis in our lab, we investigated this potential effect on our case analysis. We have performed a serial study of a 100 cases of hematologic malignancies received for analysis in our lab to determine the effect of the addition of GCT-CM to our culture media with respect to 1) mitotic index, 2) quality of preparation, and 3) differential selection of either chromosomally normal or abnormal cell lines. Our results indicate that the mitotic index and quality of metaphases is enhanced with the addition of GCT media and that there is no difference in the rate of abnormality detection with or without the addition of GCT media.

Prenatal diagnosis and outcomes of five cases of mosaicism for an isochromosome of 20q.

Five cases of mosaicism for an isochromosome of 20q have been detected from a total of 50,000 cases analysed for prenatal diagnosis by amniocentesis. Karyotypes were designated mos 46,X-/46,X-,i(20q). In all cases, the abnormal cell line was detected in more than one primary culture, thus fulfilling the criterion for true (level III) mosaicism. Indications for prenatal diagnosis were parental anxiety (two cases), low maternal serum alpha-fetoprotein (AFP) (two cases), and high maternal serum AFP (one case). Level II ultrasounds on all five fetuses were normal, and the abnormal cell line was never detected in fetal blood and/or cord blood. All five pregnancies were continued and had normal outcomes, with birth weights ranging from 2.4 to 3.8 kg. The development of all five children has been normal, with the oldest child in the study now 4 years of age. We suggest that the abnormal cell line in each case was of extrafetal origin, and that this may be one of the more common examples of this phenomenon, occurring in approximately 1/10,000 prenatal diagnoses. Mosaicism i(20q) may have been missed in the past because of the higher resolution necessary to detect this subtle change.

Sensitivity of chromosomal mosaicism detection by different tissue culture methods.

In the field of prenatal cytogenetic diagnosis, two tissue culture methodologies are currently in use: the flask method, which examines mixed populations of cells, and the in situ method, which examines distinct colonies of cells. These two methods provide inherently different levels of sensitivity which can be made comparable by adjusting the number of cells examined depending on the methodology used and the number of colonies formed per ml of specimen. Assuming that there are 2 colonies per ml of amniotic fluid in a 20 ml specimen, in order to detect 10, 20, and 30 per cent mosaicism with 95 per cent confidence, 29, 14, and 9 colonies should be examined respectively by the in situ method. Similarly, 50, 17, and 10 cells must be analysed by the flask method.

Translocation 1;7 in four cases of myeloid disorders.

A der(1)t(1;7)(p11;p11) was observed in bone marrow chromosome analyses of four patients with myeloproliferative disorders. Three patients had developed secondary leukemias or preleukemias following chemotherapeutic exposure, and one patient was diagnosed with M4 de novo.

Fetal proteins in ataxia-telangiectasia.

Ataxia-telangiectasia (AT) is a genetic disorder of unknown pathogenesis, with primary effects on the immune and nervous systems. The presence of a fetal-like thymus and elevated alpha-fetoprotein (alpha FP) levels in patients with AT suggests that suppressed mesodermal development may be a factor in the development of this disease. We investigated this hypothesis by using electrophoretic and quantitative analyses to test for the presence of other fetal proteins in mesodermal tissues. With the exceptions of alpha FP and carcinoembryonic antigen, all other proteins assessed in these patients were present at levels or in isozymic patterns characteristic of a normal, nonfetal state.

Responses of natural wildlife populations to air pollution.

Deer mice (Peromyscus californicus) trapped in areas of Los Angeles with high ambient air pollution are significantly more resistant to ozone (6.6 ppm for 12 h) than are mice trapped from areas with low ambient pollution (56 versus 0% survival, respectively). Laboratory-born progeny of these mice show similar response patterns, indicating a genetic basis to this resistance. Young mice (less than 1 yr of age) are more sensitive than older mice (15 versus 44% survival, respectively). Sensitivity is also affected by degree of inbreeding; progeny of full-sib crosses are more sensitive than randomly bred deer mice. The data suggest that deer mice are more resistant to ozone toxicity than are commercially bred laboratory mice and rats.

Polymorphism at the glucosephosphate isomerase locus in the dog.

A polymorphism of the enzyme glucosephosphate isomerase (GPI) in canine red blood cells is reported. This polymorphism was detected by horizontal starch gel electrophoresis utilizing a tris-EDTA-borate buffer system of pH 8.0. Four out of 92 dogs examined appeared to be heterozygous at this locus.