Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features

Abstract

Cytogenetic analysis of uterine leiomyomata (UL) shows that about 40% of these benign tumors have simple, clonal chromosomal rearrangements. In contrast, their presumed malignant counterpart, leiomyosarcomas (LMSs), typically has complex numerical and structural abnormalities. Several variants of benign uterine smooth-muscle tumors are defined by histologic phenotypes intermediate between typical UL and LMS, and currently, little is known about their cytogenetic and molecular genetic features. From a subset of more than 800 karyotyped ULs, we identified a group of nine cases exhibiting near-diploid karyotypes with loss of almost the entire short (p) arm of chromosome 1 [i.e., del(1)(p11p36)]. Loss of 1p was often associated with other aberrations, particularly loss of chromosomes 19 and/or 22. Of eight UL for which the histologic diagnosis was known, four were diagnosed as cellular UL; one displayed both hypercellularity and nuclear atypia. Loss of heterozygosity (LOH) analysis for chromosomal regions 1p36.23 and 1p21.1 demonstrated allelic loss for either a portion or the majority of 1p in 5 of 10 additional archival UL diagnosed with either cellular or atypical histology. RNA from two UL with loss of 1p was profiled using Affymetrix GeneChips, and those profiles were compared to our previously reported smooth-muscle tumor expression profile. The transcriptional profiles of tumors with 1p deletion were more similar to those of leiomyosarcoma than to profiles of myometrium and UL, as determined by hierarchical cluster analysis. Comparison of the transcriptional profiles for UL with and without 1p-- revealed 53 genes with differential regulation. Loss of 1p appears to define a subgroup of UL distinct from those previously recognized. Furthermore, 1p-- appears to be associated with a specific histologic phenotype. The similarity between the transcriptional profiles of LMS and UL with 1p-- suggests the possibility of a common pathogenetic mechanism.

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

“…Furthermore, when we performed the hierarchical cluster analysis, these tumors branched together even in smaller sub-clusters indicating that these histologically different entities cannot be distinguished based on copy number profiling. In concordance with the literature, leiomyosarcomas typically demonstrated the highest frequency of copy number alterations, 19,29,46 whereas leiomyomas showed a low number of copy number alterations with a few cases (20%) lacking any gains or losses. Interestingly, all cases of leiomyomas with bizarre nuclei and leiomyosarcomas showed a high number of copy number alterations involving nearly all chromosomes.…”

“…This cytogenetic profile was previously found in~3% of uterine leiomyoma. 19 In a study from Nucci et al 45 pulmonary-based smooth muscle tumors were found to harbor consistent chromosomal aberrations (19q and 22q terminal deletion) in all cases suggesting a key pathogenetic role for sequential tumor suppressor inactivation events. This is in line with our findings as these specific copy number changes were also found in leiomyomas with bizarre nuclei and leiomyosarcomas indicating that these lesions may share a common pathogenetic mechanism.…”

“…Although in general, specific genetic patterns do not correlate with morphology, deletions of 1p have been reported to be associated with cellular and atypical morphology. 19 Leiomyosarcomas account for o 2% of all uterine malignancies. 20,21 They occur in the fifth and sixth decades of life presenting with symptoms like dysfunctional uterine bleeding and pelvic pain.…”

Uterine Smooth Muscle Tumors of Uncertain Malignant Potential (STUMP): Review of Pathophysiology, Classification, Diagnosis, Treatment, and Surveillance

“…Normal myometrial tissue contains stem cells responsible for its own proliferation and self-renewal under regulated processes. Smooth muscle cells will undergo multiple cycles of growth and involution from physiologic ovarian hormone stimulation under estrogen and progesterone in the reproductive age female [8,10,11]. These cells also receive indirect paracrine signaling from stem cells to create a regulated physiologic process on the uterine myometrium.…”

“…Mehine et al and Hodge et al confirmed a malignant behavior in myometrial cells containing the chromosome 1p deletion. Further identification and classification of chromosomal mutations and signaling pathways will aide in correct diagnosis and management [11,16,17].…”