Microarray-based comparative genomic hybridization of cancer targets reveals novel, recurrent genetic aberrations in the myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis, cytopenias, and a risk of transformation to acute myeloid leukemia (AML). However, only approximately 50% of primary MDS patients show clonal cytogenetic aberrations. To determine whether high-resolution microarray analysis would reveal new or additional aberrations, we analyzed 35 samples derived from patients with a diagnosis or suspicion of MDS and abnormal karyotypes. We used a whole-genome oligonucleotide microarray with targeted coverage of approximately 1900 genes associated with hematologic and other cancers. Clinically relevant copy number aberrations (CNAs) were identified by microarray-based comparative genomic hybridization (aCGH) in all samples (range 1-31, median 5). In 28 of 35 samples (80%), aCGH revealed new cytogenetic aberrations not seen by karyotype or fluorescence in situ hybridization (FISH). Furthermore, 132 cryptic aberrations (≤5 Mb) were identified in 25 cases (71.4%) including deletions of NF1, RUNX1, RASSF1, CCND1, TET2, DNMT3A, HRAS, PDGFRA and FIP1L1. Additionally, aCGH clarified known complex aberrations in 17 of 35 samples (48.6%). Finally, our results using whole-genome arrays with higher density coverage targeted to cancer features demonstrate the usefulness of arrays to identify rare and cryptic recurring imbalances that may prove to be significant in disease progression or transformation to AML and may improve the suitability or efficacy of molecularly targeted therapy.

Duplication of the STS region in males is a benign copy-number variant.

Copy-number variants (CNVs) are a common finding in the human genome, with copy gains occurring at a higher frequency than losses in several databases of genomic variants in normal individuals. Copy gains of the steroid sulfatase (STS) gene have been seen in both males and females. Although deletion of STS in males is known to cause X-linked ichthyosis, the clinical significance of STS copy gains is less clear, with the duplication reported in individuals with abnormal phenotypes and normal relatives. We identified 72 males submitted to our laboratory for microarray-based comparative genomic hybridization with duplications in the STS region (chrX:6,465,812-8,093,195). In 40 (56%) patients, maternal blood was available, and the duplication was found to be inherited from the patient's apparently phenotypically normal mother in each of the 40 patients. We also identified three females who inherited a duplication of the STS region from phenotypically normal fathers, and a phenotypically normal uncle who had the same duplication as his nephews. In the remaining cases the inheritance could not be confirmed owing to lack of parental samples available for testing. Of the 72 subjects, 10 (14%) had an additional CNV elsewhere in the genome known to be clinically significant and likely causative of the patient's presenting symptoms. Based on the frequency with which duplications have been identified in clinically normal and abnormal individuals, we suggest a gain of STS in males is a population variant and unlikely to be clinically significant.