Thyroid hemiagenesis

The translocation t(12;22)(p13;q11) has been consistently described in myeloid malignancies and shown to result from a fusion between the TEL and MN1 genes. Previously described deletions of 12p in acute lymphoblastic leukemias have been recently shown to harbor undetected translocations involving the TEL gene at 12p13. We document a case of an aggressive chronic B-cell leukemia whose cells had trisomy 12 and two unbalanced translocations involving 12p13, including a t(12;22)(p13;q11) as shown by conventional cytogenetics and fluorescence in situ hybridization (FISH). The 12p13 breakpoint of the t(12;22)(p13;q11) was telomeric to the TEL gene, and the second unbalanced translocation with breakpoint 12p13 resulted in the deletion of TEL. This case demonstrates that TEL gene deletions may be relevant in cases of mature B-lymphoproliferative diseases.     

Low frequency of TEL/AML1 in adult acute lymphoblastic leukemia

Translocation (12;21)(p13;q22) is a recently characterized aberration in acute lymphoblastic leukemia, and results in the fusion of the TEL and the AML1 genes. It is the most common translocation in pediatric acute lymphoblastic leukemia (ALL), occurring in about one third of the cases. To determine the frequency of TEL/AML1 in adult ALL, we studied 4 cases of T lineage ALL and 26 cases of B lineage ALL. Only one positive case was identified, giving a very low frequency of 3.3%. In this patient, TEL/AML1 was still detectable in complete hematologic remission. The apparent age predilection of t(12;21) warrants further investigations.     

Genetic alterations in the region of the p53 gene on human chromosome 17 in colorectal cancer]

Most colorectal tumors are characterized, among other genetic alterations, by allele loss of the genes located on the short arm of chromosome 17 (17p13.1), including the p53 suppressor gene. In ovarian and mammary-gland tumors, deletions of another candidate tumor-suppressor gene, located in the 17p13.3 chromosome region, were observed. We analyzed allele losses in the loci of the short arm of chromosome 17 (YNZ22, MCT35.1, and the p53 gene) in colorectal-cancer patients from the former Soviet Union. Tumors with cytogenetic alterations in 17p and/or with a detected loss of heterozygosity at the YNZ22 (D17S30) locus were examined for allele losses in the p53 gene using two polymorphic sites. Different methods revealed alterations on 17p in 24 (48%) out of 50 patients with colorectal carcinomas. In all tumors with an allele loss of the YNZ22 marker (15 out of 44 informative cases), which was detected by means of PCR, allele loss of the p53 gene was found (12 out of 15 informative cases). In 5 out of 13 tumors with cytogenetic alterations in 17p, allele loss of the p53 gene was found, with the YNZ22 marker being unaffected. In one of these tumors, the i(17q) marker was found, and in the remaining four tumors, 17p translocations were detected. In 4 out of 5 tumors with translocations affecting 17p, the t(17;20)(q21;p12) translocation was detected. The informativeness of the screening for 17p translocations, using PCR for the YNZ22 locus, and the reasons for discrepancy between the data of PCR and cytogenetic analyses are discussed.     

The heart of darkness--does public health medicine offer any solutions for the next millennium in Africa?

A novel and as yet unrecorded translocation, (1;2)(p34;p21-22), detected in a patient with acute myeloid leukemia (AML) is reported. The leukemia--in this case, AML-M4--showed a rapidly progressive fatal course despite an early transient response to aggressive chemotherapy. In this patient, the leukemic cells showed a novel balanced translocation, (1;2)(p34;p21-22), in most of the metaphases at the time of diagnosis and during subsequent relapse. Interferon-inducible double-stranded RNA-dependent protein kinase (ds RNA-PK) is located in the chromosome region, 2p21-22, that was involved in the translocation in this case. The possible role of ds RNA-PK in leukemogenesis is briefly mentioned.     

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.     

Characteristic sequence motifs at the breakpoints of the hybrid genes FUS/CHOP, EWS/CHOP and FUS/ERG in myxoid liposarcoma and acute myeloid leukemia

We have sequenced the breakpoint regions in one acute myeloid leukemia (AML) with t(16;21)(p11;q22) resulting in the formation of a FUS/ERG hybrid gene and in four myxoid liposarcomas (MLS), three of which had the translocation t(12;16) (q13;p11) and a FUS/CHOP fusion gene and one with t(12;22;20)(q13;q12;q11) and an EWS/CHOP hybrid gene. The breakpoints were localized to intron 7 of FUS, intron 1 of CHOP, an intronic sequence of ERG and intron 7 of EWS. In two MLS cases with t(12;16) and in the AML, the breaks in intron 7 of FUS had occurred close to each other, a few nucleotides downstream from a TG dinucleotide repeat region. The break in the two MLS had occurred in the same ATGGTG hexamer and in the AML 40 nucleotides upstream from the hexamer. The third case of t(12;16) MLS had a break upstream and near a TC-dinucleotide repeat region and a sequence similar to the chi bacterial recombination element was found to flank the breakpoint. In the MLS with the EWS/ CHOP hybrid gene, the break in intron 7 of EWS had occurred close to an Alu sequence. Similarly, in all 4 MLS, the breaks in intron 1 of CHOP were near an Alu sequence. No Alu or other repetitive sequences were found 250 bp upstream or downstream from the break in the ERG intron involved in the AML case. In the AML, the MLS with ESW/CHOP and in one MLS with FUS/CHOP there were one, two and six, respectively, nucleotide identity between the contributing germline sequences in the breakpoint. In the other two MLS cases, two and three extra nucleotides of unknown origin were inserted between the FUS and CHOP sequences. At the junction and/or in its close vicinity, identical oligomers, frequently containing a trinucleotide TGG, were found in both partner genes. Our data thus show that all four genes-FUS, EWS, CHOP and ERG-contain characteristic motifs in the breakpoint regions which may serve as specific recognition sites for DNA-binding proteins and have functional importance in the recombination events taking place between the chromosomes. Different sequence motifs may, however, play a role in each individual case.     

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.     

Surface antigen phenotype can predict TEL-AML1 rearrangement in childhood B-precursor ALL: a Pediatric Oncology Group study

The t(12;21)(p13;q22) is the most common translocation in childhood B-precursor ALL. It results in a TEL-AML1 rearrangement and is associated with a good prognosis. Because many chromosomal alterations in leukemia are associated with distinct cell surface phenotypes, we investigated whether there was an association seen between surface marker expression and the TEL-AML1 rearrangement. Of 166 unselected cases of B-precursor ALL studied by Southern hybridization, 45 cases (27%) showed TEL rearrangement. Blasts of patients with TEL rearrangement were much more likely to be CD9-negative, CD45-positive, CD13 positive, and CD20 negative, but the predictive value of any of these markers for the rearrangement was very low. However, 93% of patients with the TEL rearrangement had blasts that were either negative or only partly positive for CD9; this phenotype was only seen in 27% of patients without the rearrangement. Only information about CD20 expression added to the predictive value of CD9 alone. The predictive value of the phenotype CD9 (negative or partly positive) and CD20 (negative or partly positive), for the TEL rearrangement was prospectively tested on an additional 223 cases, and found to be 88% sensitive and 71% specific for the rearrangement, with a positive predictive value of 47%. Hyperdiploidy, previously shown to correlate negatively with the rearrangement, was a slightly more sensitive indicator (94%) but had a much lower predictive value (28%). Three of eight cases found to be rearranged by Southern hybridization but lacking the characteristic phenotype failed to show evidence of the TEL-AML1 rearrangement by polymerase chain reaction, suggesting that at least some of the discordant cases may involve partner genes other than AML1 in the TEL rearrangement. We conclude that immunophenotyping is highly predictive of the TEL rearrangement. For every 100 patients with B-precursor ALL, we estimate that prescreening by phenotyping would eliminate the need for molecular testing on 57 patients and only two or three of an expected 24 patients with the TEL rearrangement would not be detected.