We report on a rare additional numerical chromosomal aberration in a child with Down syndrome due to free trisomy 21. The karyotype showed 48,XY,+21,+mar after GTG banding, with the marker present in 80% of cells. The supernumerary marker chromosome (SMC) was as small as approximately one-third of 18p, and with the recently developed centromere-specific multi-color fluorescence in situ hybridization (cenM-FISH) technique, it was shown that the SMC was a derivative chromosome 4. The SMC was not specifically stained by arm-specific probes for chromosome 4; thus, it has been described as der(4)(:p11 --> q11:). Microsatellite analysis resulted in a partial maternal uniparental isodisomy (UPD) for chromosome 4p15-16 and a maternal origin for two chromosomes 21. Until now only two similar cases have been described in the literature, but without clarifying the origin of the SMC and without looking for an additional UPD. This is the only reported case of a UPD 4p in a liveborn child.

All molecular alterations that lead to breast cancer are not precisely known. We are evaluating the frequency and consequences of reciprocal translocations in breast cancer. We surveyed 15 mammary cell lines by multicolor fluorescence in situ hybridization (M-FISH). We identified nine apparently reciprocal translocations. Using mBanding FISH and FISH with selected YAC clones, we identified the breakpoints for four of them, and cloned the t(3;20)(p14;p11) found in the BrCa-MZ-02 cell line. We found that the breakpoint targets the potential tumor-suppressor gene FHIT (fragile histidine triad) in the FRA3B region; it is accompanied by homozygous deletion of exon 5 of the gene and absence of functional FHIT and fusion transcripts, which leads to the loss of FHIT protein expression. Additional experiments using comparative genomic hybridization provided further information on the genomic context in which the t(3;20)(p14;p11) reciprocal translocation was found.

A 54-year-old male presented with a spontaneous peroneal nerve palsy and a diagnosis of monophasic synovial sarcoma (SS) was rendered by histologic examination. Cytogenetic analysis revealed a complex abnormal karyotype without evidence of the typical t(X;18)(p11;q11) associated with SS. Subsequent reverse transcriptase polymerase chain reaction analysis showed the presence of an SYT/SSX2 fusion transcript, confirming the presence of a cyptic t(X;18). In light of -X, -18 and marker chromosomes evident in the G-band karyotype, it was suspected that a cryptic chromosomal rearrangement involving the marker chromosomes would harbor an X;18 fusion. Multi-colored karytotyping (M-FISH) revealed a previously unrecognized t(X;18) and t(5;19) in the marker chromosomes as well as unrecognized ins(6;18) and t(16;20). The addition of M-FISH analysis in this case led to the identification of complex inter-chromosomal rearrangements, thus providing an accurate karyotype.

Rearrangements of 12p, resulting from deletions or translocations, are common findings in hematologic malignancies. In many cases, these rearrangements target the ETV6 gene (previously called TEL) located at 12p13. Various partner genes have been implicated in the formation of fusion genes with ETV6. These include PDGFRB, JAK2, NTRK3, ABL2, and ABL1, each of which encodes for proteins with tyrosine kinase activity. To date, ETV6/ABL1 transcripts have been detected in only four patients with a leukemic disorder. Here, we describe one adult with chronic myeloid leukemia and a child with T-cell acute lymphocytic leukemia with ETV6/ABL1. Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement. Molecular analysis showed the presence of two fusion transcripts in both patients as the result of alternative splicing, questioning the suggested role of these transcripts in the lineage specificity. Clinical findings of these patients were compared to those of previously reported cases, and the possible clinical and biological similarities between ETV6/ABL1 and other fusion genes leading to increased tyrosine kinase activity are discussed.