Mol. Hum. Reprod. Advance Access published online on June 30, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap050
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Detection of novel copy number variants in uterine leiomyomas using high-resolution SNP arrays
,*
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA
* Corresponding author: Aleksandar Rajkovic, MD/PhD, Departments of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, Tel: 713-798-1049 Fax: 713-798-2744, Email: rajkovic{at}bcm.tmc.edu
Uterine leiomyomas (ULs) are benign monoclonal tumors originating from myometrial tissue in the uterus. Genetic pathways that lead to myometrial transformation into leiomyomas are largely unknown. Approximately 40% of ULs are karyotypically abnormal by G-banding, however the remaining 60% of leiomyomas do not contain cytogenetically visible genomic rearrangements. Recent technological advances such as array based comparative genomic hybridization (array CGH) and dense single nucleotide polymorphism (SNP) arrays have enabled genome-wide scanning for genomic rearrangements missed by karyotype banding analysis. In the current study, we employed a high resolution SNP microarray on 16 randomly selected ULs and normal myometrium samples to detect submicroscopic (<5Mb) chromosomal aberrations. The SNP array identified gene dosage changes in 56% of the fibroids (9/16), 25% of which (4/16) had aberrations greater than 5 Mb, while 31% of which (5/16) contained only submicroscopic copy number changes (< 5 Mb). We corroborated 3/5 submicroscopic changes using quantitative PCR, meaning that ultimately, 19% of our samples (3/16) were found to contain only submicroscopic changes. Novel submicroscopic aberrations on chromosomal segments 1q42.13, 11q13.1 and 13q12.13 and large, previously unreported deletions on 15q11.2-q23, 17p-q21.31, and 22q12.2-q12.3 were identified. Previously reported deletions on 1p, 3q, 7q, 13, and chromosome 14q were also noted. RHOU, MAP3K11 and WASF3 gene copy numbers were changed in the subset of leiomyomas with submicroscopic aberrations, and these genes have previously been implicated in tumorigenesis. Our findings support the hypothesis that a significant fraction of ULs without visible cytogenetic changes harbor submicroscopic genomic rearrangements which may in turn contribute to transformation of normal myometrial tissue into leiomyomas.
Key Words: copy number variation/leiomyoma & fibroid/microdeletion & microduplication/SNP microarray/uterus
Submitted on May 11, 2009; resubmitted on June 15, 2009; accepted on June 18, 2009.