No abstract

Desmoplastic melanoma (DM) and malignant peripheral nerve sheath tumor (MPNST) can appear morphologically and immunophenotypically similar. We attempted to determine whether microarray comparative genomic hybridization could detect copy number differences between them to aid in the diagnosis. S-100 immunohistochemistry was performed on 5 cases of DM and 9 cases of MPNST using formalin-fixed paraffin-embedded specimens. Genomic DNA was extracted from microdissected cells. Whole genome amplification was performed on 5 of 5 DMs and 6 of 9 MPNST cases. A multiplex polymerase chain reaction assay was used to determine the quality of the DNA samples, which were run on the Spectral Chip 2600 bacterial artificial chromosome array platform. DM showed gains involving chromosomes 1p, 2p, 9q, 13q, 14q, and 20q and losses involving chromosomes 5p, 11p, 12q, 15q, and 18q. Several cancer-associated genes were involved, including gain of BCL2L1, ARTN, AMPK, NRAS, and CCNA1 and loss of IGF2, CDKN1C, PAX6, WT1, TRAF6, MAPK8IP1, and IMP3. MPNST had gains involving chromosomes 1p, 2q, and 19p and loss of chromosome 21q. Gains of MUM1, APC2, MAP2K2, JMJD2B, SP110, PTMA, GPI, and CDKN2D were detected. DM and MPNST have chromosomal alterations detected by array comparative genomic hybridization that might be useful in distinguishing these 2 tumors, although further studies with a larger sample size will be needed to test this.

Split-hand/split-foot malformation (SHFM1) has been reported to be caused by deletions, duplications or rearrangements involving the 7q21.3 region harboring DSS1, DLX5, and DLX6. We report on a female patient with unilateral syndactyly of the third and fourth fingers of the right hand and overgrowth and lateral deviation of the right great toe. There was a split foot malformation on the right, with absent fifth toe. The left hand was apparently normal and left foot was intact. The patient has no hearing loss. We performed conventional G-banding karyotype analysis, array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). G-banding karyotype result was normal 46,XX. However, a duplication of 719 kb (96,303,736-97,022,335; NCBI build36/hg18, March 2006) was identified at the 7q21.3 region by aCGH. The array result was also confirmed by FISH analysis. The duplicated region harbors only DLX5 and DLX6, which are known for their role in SHFM1. Additionally, FISH analysis of parental samples showed de novo origin of this abnormality in the patient. This is the first report that highlights the duplication of 719 kb at 7q21.3, harboring only DLX5 and DLX6 associated with the SHFM1 phenotype.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by peripheral cytopenias due to ineffective hematopoiesis and significant cytologic atypia in one or more of the myeloid lineages. There is a variable risk of progression to acute myeloid leukemia, which is dependent on the blast count and certain recurrent cytogenetic abnormalities. Cytogenetic characterization is important in both diagnosis and prognosis, but can be of limited value in lower-risk MDS subtypes because of the low frequency of karyotypic abnormalities detected by chromosome analysis. Recently, array comparative genomic hybridization (aCGH) has been shown to be an important technique in detecting gross and cryptic copy number changes in leukemias. However, there is little data on aCGH application in MDS. We used a custom design 105,000 probe oligonucleotide aCGH platform to analyze 44 bone marrows, in which a diagnosis of MDS was made to determine the clinical utility of oligonucleotide aCGH. All bone marrows were analyzed by morphology, flow cytometry, cytogenetics, and fluorescent in situ hybridization (FISH). Gender matched normal controls were used to assess copy number alterations in MDS samples. We classified significant gains and losses as a minimum of 10% deviation from the baseline of at least 10 contiguous oligonucleotide probes spanning at least 1 Mb and as not within a previously defined region of copy number polymorphism in the Database of Genomic Variants. Array CGH was able to detect all cytogenetically identified imbalances present in more than 1 cell, but as expected did not detect any of the balanced translocations or inversions. Of the 24 cases that were cytogenetically normal, 9 (38%) had anomalies detected by aCGH. In 5 (25%) of the 20 cases with at least one cytogenetic abnormality detected previously by chromosome analysis, additional imbalances were identified by aCGH. Recurrent copy number losses detected by aCGH were observed in 13/44 (29.5%) of cases and included 5q21 in 5 cases, chromosome 7 in 2 cases, 12p13 in 3 cases, 13q21-31 in 3 cases, and 20q12-13 in 2 cases. Oligonucleotide aCGH was able to provide extremely high resolution of the boundaries of the gains and losses due to the high oligonucleotide probe density. In 14/44 cases (31.8%), oligonucleotide aCGH provided novel information not provided by conventional cytogenetics and FISH and can be used to precisely define recurrent gains and losses. Our data demonstrates the clinical applicability of oligonucleotide aCGH in the diagnosis of MDS in addition to conventional cytogenetics to detect new cryptic abnormalities which may provide novel targets for therapy.