title: Expression profiling of uterine leiomyomata cytogenetic subgroups reveals distinct signatures in matched myometrium: transcriptional profilingof the t(12;14) and evidence in support of predisposing genetic heterogeneity.
abstract: Uterine leiomyomata (UL), the most common neoplasm in reproductive-age women, are classified into distinct genetic subgroups based on recurrent chromosome abnormalities. To develop a molecular signature of UL with t(12;14)(q14-q15;q23-q24), we took advantage of the multiple UL arising as independent clonal lesions within a single uterus. We compared genome-wide expression levels of t(12;14) UL to non-t(12;14) UL from each of nine women in a paired analysis, with each sample weighted for the percentage of t(12;14) cells to adjust for mosaicism with normal cells. This resulted in a transcriptional profile that confirmed HMGA2, known to be overexpressed in t(12;14) UL, as the most significantly altered gene. Pathway analysis of the differentially expressed genes showed significant association with cell proliferation, particularly G1/S checkpoint regulation. This is consistent with the known larger size of t(12;14) UL relative to karyotypically normal UL or to UL in the deletion 7q22 subgroup. Unsupervised hierarchical clustering demonstrated that patient variability is relatively dominant to the distinction of t(12;14) UL compared with non-t(12;14) UL or of t(12;14) UL compared with del(7q) UL. The paired design we employed is therefore important to produce an accurate t(12;14) UL-specific gene list by removing the confounding effects of genotype and environment. Interestingly, myometrium not only clustered away from the tumors, but generally separated based on associated t(12;14) versus del(7q) status. Nine genes were identified whose expression can distinguish the myometrium origin. This suggests an underlying constitutional genetic predisposition to these somatic changes which could potentially lead to improved personalized management and treatment.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Boston, MA 02115, USA.
authors.forename: Jennelle C
authors.initials: JC
authors.lastname: Hodge
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Dreyfuss
authors.forename: Priya
authors.initials: P
authors.lastname: Somasundaram
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Christacos
authors.forename: Marissa
authors.initials: M
authors.lastname: Rousselle
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Quade
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Park
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stewart
authors.forename: Cynthia C
authors.initials: CC
authors.lastname: Morton
mesh_terms: D002869:Chromosome Aberrations; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D007889:Leiomyoma / Q000235:genetics* / Q000473:pathology; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D014594:Uterine Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D025743:HMGA2 Protein