Karyotypic changes in phyllodes tumors of the breast

Cytogenetic analysis of short-term cultures of five phyllodes tumors of the breast-classified as benign (one tumor), borderline malignant (two tumors removed from the same breast in 1991 and 1993), and malignant (two tumors)--revealed clonal changes with simple structural abnormalities in the benign tumor, the borderline malignant tumors, and one malignant tumor in which benign areas and areas of borderline malignancy were also present. In contrast, the malignant tumor without admixed borderline malignant or benign areas had a complex karyotype. The karyotype of the benign phyllodes tumor was 46,XX,del(12)(p11p12)/46,XX,t(8;18)(p11;p11)/46,XX. The first borderline malignant phyllodes tumor had t(3;20)(p21;q13) as the sole abnormality. When the tumor recurred, this was no longer the only clone detected and the tumor karyotype was now 46,XX,t(3;20)(p21;q13)/46,XX,t(9;10)(p22;q22)/46,XX,t(1;8) (p34;q24)/46,XX,del(11)(q22-23)/46,XX. The malignant/borderline malignant/benign tumor had t(1;6)(p34;p22) as the sole clonal abnormality. Finally, the karyotype of the malignant phyllodes tumor which contained no benign or borderline malignant areas was 42,XX,der(1)t(1;4)(q21;q21),der(3)t(3;17)(q29;q21), -4,i(8)(q10), -10, -13,i(13)(q10),der(14)t(1;14)(q21;p11),der(14)t(4;14) (p12;p11), -17/80-90,idemx2, +del(1)(q12), +i(1)(p10), +dic(5;5)(p14;p14), +i(6)(p10), +del(7)(p11), +dup(7)(q11q36), +i(15)(q10),inc/46,XX. The findings indicate some cytogenetic similarities between benign/borderline malignant phyllodes tumors and fibroadenomas of the breast, presumably reflecting similar pathogenetic mechanisms in the two types of mixed-lineage tumors.     

Hearing aid effect in older females

We report the use of dual-colour chromosome painting to determine the exact nature of certain chromosome rearrangements observed in the pig (Sus scrofa domestica). The chromosomal abnormalities were detected by GTG- and RBG-banding techniques. The initially proposed interpretations were: (1) rcp(6;13)(p1.5;q4.1); (2) rcp(11;16)(p1.4;q1.4); (3) rcp(6;16)(p1.1;q1.1); (4) rcp(13;17)(q4.1;q1.1); (5) rcp(6;14)(q2.7;q2.1); (6) rcp(3;5)(p1.3;q2.3); (7) rcp(2; 14)(q1.3;q2.7); (8) rcp(15;17)(q1.3;q2.1). Hybridizations were carried out with biotin- and digoxigenin-labelled probes obtained by priming authorizing random mismatches polymerase chain reaction (PARM-PCR) amplification of porcine flow-sorted chromosomes. In some cases, i.e. (1), (4), (5), (6), (7) and (8), the fluorescence in situ hybridization (FISH) results allowed confirmation of the interpretations proposed with classical cytogenetic methods. Chromosome painting proved the reciprocity of the translocation in cases (1), (6) and (8), whereas modifications of the formula were proposed for case (2). Primed in situ DNA labelling (PRINS) experiments have also been carried out in case (3) using a primer specific for the centromeres of acrocentric chromosomes (first experiment) or a primer specific for the centromeres of a subset of meta- and submetacentric chromosomes including chromosome 6 (second experiment). It allowed us to demonstrate that the breakpoints occurred in the centromeric region of chromosome 16 and in the p. arm of chromosome 6, just above the centromere.     

Homozygosity for pericentric inversions of chromosome 9. Prenatal diagnosis of two cases

The finding of homozygosity for a pericentric inversion of chromosome 9 [inv(9)] is rare, and previously has not been reported at prenatal diagnosis. We describe two unrelated cases of homozygosity for inv(9) identified in amniocytes. In each case, both parents were heterozygotes for the inv(9); 46,XX,inv(9)(p11q13) and 46,XY,inv(9) (p11q13). Case 1 resulted in a normal term infant who at age 5 years was phenotypically and developmentally normal. Case 2 was referred for severe intrauterine growth retardation (IUGR) and oligohydramnios, and subsequently expired in utero. Even though inv(9) is a normal chromosome variant with a frequency of 1 to 3% in the general population, the finding of homozygosity for inv(9) and IUGR in this fetus suggested the possibility of uniparental disomy (UPD). Molecular studies confirmed the presence of both parental inv(9) chromosomes, excluding the possibility of chromosome 9 UPD as the cause of IUGR in this fetus. Presumably, inv(9) homozygosity results from the high frequency of inv(9) heterozygosity, and is a normal variant. However, until the effects of UPD for chromosome 9 are established, parental karyo types and, where appropriate, molecular studies should be performed to exclude UPD. In addition, more reports of inv(9) homozygosity detected prenatally are needed to assess its frequency and outcome.     

Constitutional mosaicism for a chromosome 9 inversion resulting in recombinant aneusomy in an offspring

We report on a case of constitutional mosaicism for a large pericentric inversion of chromosome 9 in a man whose daughter had recombinant aneusomy resulting in partial 9q duplication and partial 9p deletion. At age 6 months, the girl was evaluated because of congenital anomalies [corrected] and developmental delay. Chromosomal analysis on this infant showed a derivative chromosome 9 which was later determined to be a recombinant chromosome with trisomy of 9q34.1-->qter and monosomy of pter-->9p24. Chromosomal analysis in her father showed the presence of two cell lines; 75% of lymphocytes had a 46,XY pattern, and 25% had a 46,XY,inv(9)(p24q34.1) karyotype. The infant's physical findings represent a composite of the reported cases of both trisomy 9q34.1-->qter and monosomy pter-->9p24. The infant's father was phenotypically and cognitively normal. This case broadens the spectrum of reported cases of mosaicism for an autosomal structural rearrangement generating unbalanced gametes, and further supports the tenet that constitutional mosaicism has clinical relevance for genetic counseling.     

Are duodenal ulcer seasonal fluctuations paralleled by seasonal changes in 24-hour gastric acidity and Helicobacter pylori infection?

Short-term cultures from two histologically benign chemodectomas, one from the carotid body and one from the vagal nerve, were analyzed cytogenetically. The former had a small abnormal clone with the karyotype 46,XX,t(3;19)(q21;q13),t(12;15) (p13;q12-14), whereas the majority of the cells from the latter tumor displayed two related abnormal clones: 46,XY,i(I)(q10)/ 46,iderm,add(2)(q37). The findings add to the evidence that chemodectomas are heterogeneous neoplasms and suggest that the heterogeneity may possibly be associated with the site of origin.     

N-ras mutation in acute myeloid leukemia: incidence, prognostic significance and value as a marker of minimal residual disease

The combined use of qualitative and quantitative analysis of 11p13 polymorphic markers together with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to 11p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in the family: an insertion of brand 11p13-p14 carrying the genes for predisposition to Wilms' tumor, WT1, and for aniridia, AN2, into the long arm of chromosome 11 in 11q13-q14. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del(11)(p13). Two of these women gave birth to children carrying a deleted chromosome 11, most likely resulting from the loss of the 11p13 band inserted in 11q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide variation in clinical expression. One child, with the karyotype 46,XY, del(11)(p13p14), presented the full-blown WAGR syndrome with aniridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del(11)(p13), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WT1 gene can result in similar genital and kidney abnormalities.     

A case with dicentric translocation between chromosome 9 and 18: confirmation by fluorescent in situ hybridization on metaphase spread

A female child with dicentric translocation between chromosome 9 and chromosome 18 presented non-specific minor anomalies with laryngomalacia. Chromosomal analyses were performed by the G-banding method and a fluorescence in situ hybridization (FISH) technique with a specific probe for the centromeric region of chromosome 18 and the painting probe for the chromosomes 9 and 18. Her full karyotype was confirmed as 45,XX,tdic(9;18)(p24;p11). This is the first case of dicentric translocation between chromosomes 9 and 18. The FISH technique is an important tool in chromosome diagnostics.     

Cytogenetic profile of lymphoma of follicle mantle lineage: correlation with clinicobiologic features

Conventional chromosome analysis (CCA) and interphase fluorescence in situ hybridization (FISH) was performed in 42 patients with mantle-cell lymphoma (MCL), with BCL1 rearrangement. The t(11;14)(q13;q32) or 11q abnormalities were detected by CCA in 34 cases, 20 of which had additional aberrations. A normal karyotype was observed in 8 cases. Probes detecting the chromosome aberrations that were observed in at least 3 cases by CCA, ie, +12, 13q14 deletion, and 17p deletion, were used for interphase FISH analysis. FISH detected total or partial +12, 13q14 deletion and 17p- in 28.5%, 52.4%, and 26% of the cases, respectively. The presence of these anomalies was not a function of karyotype complexity. Based on the results of CCA/FISH, three groups of increasing karyotype complexity were recognized: group 1, including 11 patients without detectable aberrations in addition to BCL1 rearrangement; group 2, including 14 patients with 1 to 2 additional anomalies; and group 3, including 17 patients with three or more additional anomalies. Clinical parameters associated with shorter survival were male sex (P =.006) and primary lymph-node involvement compared with primary bone marrow involvement (P =.015). Trisomy 12 was the only single cytogenetic parameter predictive of a poor prognosis (P =.006) and the best prognostic indicator was the derived measure of karyotype complexity (P <.0001), which maintained statistical significance in multivariate analysis (P<.0001). We arrived at the following conclusions: 13q14 deletion occurs at a high incidence in MCL; 17p deletion and total/partial +12 are relatively frequent events in MCL, the latter aberration being associated with a shorter survival; and the degree of karyotype complexity has a strong impact on prognosis in this neoplasia.     

Intrachromosomal triplication of 15q11-q13

A 7 year old girl with intrachromosomal triplication 46,XX,-15,+der(15)(pter-->q13::q13-->q11::q11-->qter) resulting in tetrasomy of 15q11-q13 is reported. Fluorescence in situ hybridisation confirmed that the tetrasomic region included the entire segment normally deleted in Prader-Willi and Angelman syndrome patients, and breakpoints were similar to those reported in two tandem duplications of 15q11-q13. The middle repeat was inverted, suggesting a possible origin through an inverted duplication intermediate. Microsatellite analysis showed that the rearrangement was of maternal origin and involved both maternal homologues. Clinical findings included multiple minor anomalies (a fistula over the glabella, epicanthic folds, downward slanting palpebral fissures, ptosis of the upper lids, strabismus, a broad and bulbous tip of the nose, and small hands and feet), motor and mental retardation, a seizure disorder, and limited verbal abilities. In addition, immunological examination disclosed a selective immunodeficiency. The overall phenotype did not clearly resemble that of cases with tetrasomy 15pter-q13 associated with an extra inv dup(15)(pter-->q13:q13-->pter) chromosome. The latter aberration causes more severe mental deficit and intractable seizures, but less marked phenotypic alterations, although some overlap in mild facial dysmorphic features is present. A number of features common to Angelman syndrome were also observed in the patient.     

Partial trisomy 16q-

A 5-month-old female was found with a 16q- trisomy; her mother was the carrier of a balanced translocation 46,XX,t(15p+;16q-)(15p12;16q11). This is the first report in the literature of a liveborn with this chromosome abnormality.     

Unbalanced t(3;12) in a case of juvenile myelomonocytic leukemia (JMML) results in partial trisomy of 3q as defined by FISH

Juvenile myelomonocytic leukemia (JMML) is a rare disorder of early childhood, to which no recurrent chromosome rearrangement has been yet associated. We report a case where leukemic cells harbored a 46,XX,der(12)t(3;12) (q21 approximately 22;p13.33) karyotype, resulting in partial trisomy of 3q. The origin of chromosome material translocated to chromosome 12 was assessed by chromosome painting using a whole chromosome 3-specific probe. The breakpoint regions were defined by FISH using YAC probes from 3q and 12p chromosomal regions. Interestingly, partial trisomy of 3q has been detected in a previously reported JMML case, consequent to the presence of a der(15)t(3;15)(q13.1;q26). The involvement of a similar chromosome 3 rearrangement in these two JMML cases suggests the hypothesis that either the resulting duplication of some gene/s on 3q or the loss of heterozygosity (LOH) of some gene/s on 3p may be involved in one of the steps leading to JMML. On the other hand, it cannot be ruled out that the relevant mutation in our case might be consequent to the particular breakpoints at bands 3q21 approximately 22 and 12p13.3, that may alter the structure and/or expression of the involved gene/s.     

A de nevo complex t(7;13;8) translocation with a deletion in the TRPS gene region

Molecular cytogenetic analyses have resolved the pathogenetic aberration of an 8-year-old girl with tricho-rhino-phalangeal syndrome type I (TRPS I), normal intelligence, and a karyotype originally described as 46,XX,t(8;13)(q24;q21). R- and Q-banding and high resolution R-banding analyses have also disclosed a seemingly mosaic abnormality of the distal short arm of chromosome 7 but have not fully characterized this abnormality. Combined primed in situ labelling and chromosome painting, and three-colour chromosome painting have revealed a complex, apparently balanced translocation t(7;13;8). Fluorescence in situ hybridization with yeast artificial chromosome and cosmid clones from 8q24.1 has shown an interstitial deletion of at least 3 Mb covering most of the TRPS I critical region.     

Chromosome aberrations in atypical chronic lymphocytic leukemia: a cytogenetic and interphase cytogenetic study

To define better the chromosomal profile of atypical chronic lymphocytic leukemia (aCLL), cytogenetic and interphase cytogenetic studies were performed in 43 cases, using mitogen-stimulated cultures and DNA probes detecting the two most frequently occurring aberrations in CLL, ie +12 and 13q14 deletions. All cases showed monoclonal CD5/CD19-positive lymphocytosis, with more than 10% large lymphocytes and/or prolymphocytes in peripheral blood smears and reactivity with FMC7, or bright expression of surface immunoglobulins in a fraction of the cases. Karyotype aberrations were detected in 27 of 43 cases (62.8%). Recurrent chromosome changes were +12 (nine cases), 13q14 aberrations (five cases), 11q anomalies (three cases), 6q21-q23 abnormalities and 4q anomalies with different breakpoints (two cases each). Additional chromosome changes were seen in four cases with +12, in three cases with 13q14 anomalies, in two cases with 11q anomalies, in one case with 6q and 4q anomalies. Trisomy 12 was associated with 13q14 anomalies in three cases, one of which also had an 11q abnormality; other associations, found in one case each, were: 13q14 deletion with a 6q anomaly, 11q anomaly with 13q- and 7q-, a 6q anomaly with 7q- and +12. Interphase cytogenetics confirmed the results of chromosome banding analysis and showed that six patients with normal karyotype or no mitosis in fact had concomitant +12 and 13q14 deletion in four cases and isolated +12 or 13q14 deletion in one case each, with a resultant 76% overall incidence of cytogenetic abnormalities. The presence of +12, 13q14 deletions, 11q, and 6q21-q23 anomalies in 19 cases was associated with a 2-month median interval between diagnosis and start of treatment, as compared with a 24-month median interval in 14 cases with normal karyotype or non-recurrent chromosome changes (P = 0.003). We conclude that aCLL is characterized by a relatively high incidence of chromosome anomalies, with recurrent chromosome changes, involving chromosomes 12, 13q14, 6q21q23, 11q, and, possibly, 4q. The presence of complex karyotypes, with concomitant abnormalities of 13q, +12, 6q, 11q, suggests that the development of sequential chromosome changes, rather than any single specific anomaly, may underlie leukemogenesis in this cytologic subset of CLL, partially accounting for the relatively aggressive clinical course.     

A female case of the HCG-producing ectopic pinealoma associated with precocious puberty

Report on a 5 year old girl with the caracteristic features of the partial trisomy of the short arm of a chromosome no.4: short stature, microcephaly, hydrocephaly, enophthalmus, bulbous nose, deep set malformed ears, hypertrichosis, brachydactyly, hypoplastic ribs, abnormal EEG, imbecility. Trisomy originated from a reciprocal translocation in the father (46, XY, rcp (4;11) (p 13; q23)). q23)).     

Abnormalities of 3q21 and 3q26 in myeloid malignancy: a United Kingdom Cancer Cytogenetic Group study

Cytogenetic and clinical details are presented for 66 patients with myeloid malignancy and chromosome abnormalities of 3q21 and/or 3q26 (3qabns). Bone marrow and/or peripheral blood morphology was assessed for 52 cases. 3qabns in Philadelphia negative (Ph-ve) and positive (Ph+ve) cases were inv(3)(q21q26), (21 Ph-ve, 6 Ph+ve); t(3;3)(q21;q26) (nine Ph-ve, four Ph+ve); and t(3;21)(q26;q22) (four Ph-ve, six Ph+ve). Ph-ve cases also had t(1;3)(p36;q21) (three cases), and t(3;5)(q21;q31)/(q21;q35)/(q26;q21) (five cases aged < 40 years). Three cases, aged < 30 years, had t(3;12)(q26;p13) which defines a new 3qabn subgroup. Monosomy 7 and/or 5q- accompanied inv(3) or t(3;3) in 17/30 cases. All cases had a myeloid malignancy (predominantly AML M1, M4 or M7), frequent trilineage myelodysplasia, and markedly abnormal megakaryopoiesis with micromegakaryocytes (< 30 microns). Thrombocytosis occurred in two cases only. Most Ph+ve cases were in myeloid blast crisis and in Ph+ve cases alone, micro-megakaryocytes were uniquely small (10 microns) in 7/11 cases. There were equal numbers of males and females. Seven secondary leukaemias were found in Ph-ve cases with inv(3), t(3;3), t(3;21), t(1;3) or del(3)(q21). Three cases with t(3;21) (one Ph+ve) were de novo AML or had de novo aplastic anaemia. Survival was rarely greater than 12 months from detection of the 3qabn.     

The use of amplified variable number of tandem repeats (VNTR) in the detection of chimerism following bone marrow transplantation. A comparison with restriction fragment length polymorphism (RFLP) by Southern blotting

A 49-year-old woman patient with atypical myelodysplastic syndrome (MDS) showing a der(3)t(3;12)(q21;p13), and der(12)t(3;12)(q21;p13)inv(3)(q21q26) as an acquired chromosomal abnormality in the bone marrow is described. The chromosomal breakpoints of the presented complex aberration with combination of the inv(3)(q21q26) and t(3;12)(q21;p13) were defined by fluorescence in situ hybridization (FISH) with yeast artificial chromosomes (YACs). The inv(3) is a relatively frequent chromosomal rearrangement in patients with myeloid malignancies and dysmegakaryopoiesis and t(3;12)(q26;p13) has also been reported as a recurrent abnormality in MDS and in blast crisis of chronic myelogenous leukemia (CML). Whereas the t(3;12), inv(3), and t(3;3) are associated with a very poor prognosis, our patient surprisingly had a mild clinical course.     

Prenatal diagnosis of ring chromosome 6 in a fetus with hydrocephalus

A patient with ring chromosome 6/monosomy 6 mosaicism is presented. At 25 weeks' gestation, ultrasound examination demonstrated fetal hydrocephalus. Amniocentesis was performed. The fetal karyotype was 45,XY,-6/ 45,XY,-6,+f/46,XY,r(6)(p25q27). Delivery of this male infant was by Caesarean section at 37 weeks' gestation. The karyotype in peripheral blood lymphocytes was 46,XY,r(6)(p25q27) with no indications of mosaicism. The infant had hydrocephalus which required treatment with a ventriculoperitoneal shunt at 22 days of age. He had no other obvious serious congenital anomalies. By 17 months he had developed microcephaly, seizures, severe bilateral hearing loss, and global development delay. This patient provides information regarding phenotypic variability of ring chromosome 6 and also reinforces the importance of offering amniocentesis if fetal hydrocephalus is detected as an isolated anomaly.     

Mechanisms explaining the onset, course and spontaneous resolution of gouty arthritis

Cytogenetic analysis of short-term cultures from three untreated and one recurrent ependymoma revealed clonal aberrations in three of the four tumors. A posterior fossa ependymoma from a 3-year-old male patient showed trisomy 11 as the sole clonal chromosome aberration. A recurrent spinal ependymoma from a 35-year-old male showed hypertriploid clones with abnormalities involving chromosomes 1p11,7q21, and 10p13. A 62-year-old male patient with a cerebellar ependymoma showed a hypodiploid stem-cell line with clonal structural aberrations of both the long and short arms of chromosome 1, an interstitial deletion of 2q, trisomy 7, and monosomy for chromosomes 11, 13, and 16. A 3-year-old female patient with posterior fossa ependymoma showed a normal 46,XX karyotype. Chromosome 1 aberrations appear to be the most consistent finding in this small series of tumors, with the net loss or rearrangement of chromosome 1 pter-->p22 material from two of the four tumors. These findings, in addition to a previously published case [1], suggest a possible role for genes on the short arm of chromosome 1 in the cytogenetic evaluation of ependymomas.     

Prenatal detection of short arm deletion and isochromosome 18 formation investigated by molecular techniques

A patient was referred for amniocentesis because of advanced maternal age and polyhydramnios. The fetal karyotype was a mosaic 46,XX,del(18)(p11.1)/46,XX,-18,+i(18q)de novo. The deletion appeared to encompass the whole short arm as evidenced by G banding and in situ hybridisation. However, telomere sequences were found on both ends of the deleted chromosome as well as the isochromosome. The normal 18 and the isochromosome showed more alphoid sequences than the del(18). Subsequent passages of the cell lines showed an increase in the frequency of the isochromosome from 20% to about 30%. Possible mechanisms are discussed.     

Chromosomes and causation of human cancer and leukemia. XLVIII. T-cell acute leukemia in ataxia telangiectasia

Cytogenetic and immunologic studies were performed on the cells of an 18-year-old female with ataxia telangiectasia (AT) associated with acute lymphocytic leukemia (ALL). At the onset of the leukemia 15.4% of peripheral blood cells stimulated with phytohemagglutinin (PHA) contained a tandem translocation of the long arm of chromosome #14, i.e., t(14;14). To ascertain if these karyotypically abnormal cells and the leukemic cells had a common lineage, chromosome analyses were performed on bone marrow cells. Examination of the marrow cells on the seven occasions when leukemic cells were present in the marrow, including times when they were predominant, showed only a normal karyotype without the presence of t(14;14). However, an abnormal clone, which had the karyotype 45,XX,-9,t(9;6)(q12;q13), was identified in the marrow cells on the last examination during the terminal phase of the leukemia. Immunologically, the ALL was classified as an atypical type which had characteristics in common with certain T-cell subsets. We suggest that the malignant cells did not originate from the preexisting cells with a tandem duplication of the 14q.