Large-scale analysis of chromosomal aberrations in uterine leiomyoma

Chromosomal aberrations in tumors are key indicators of genomic instability and important drivers of neoplasia. While chromosomal changes in uterine leiomyomas have been studied for decades, comprehensive evaluation of chromosomal aberrations in uterine leiomyomas on the scale of modern tumor research has been lacking.

To comprehensively characterize somatic chromosomal aberrations in uterine leiomyoma, providing a missing layer of stratified data for research toward detailed understanding of the genesis of this important tumor type.

In this retrospective study, we analyzed 1963 uterine leiomyomas from 629 patients using single-nucleotide polymorphism array data. Our goal was to identify subtype-specific chromosomal rearrangement patterns across 9 known uterine leiomyoma subtypes named after the respective driver gene: MED12, HMGA2, HMGA1, FH, YEATS4, oSRCAP, COL4A5/6, PLAG1, and NEDDYLATION, as well as tumors lacking known driver mutations. We identified recurrently deleted and gained chromosomal regions from single-nucleotide polymorphism array data and integrated these findings with gene expression and long-read sequencing data. Complex chromosomal rearrangements resembling chromothripsis were assessed through breakpoint analysis. Our findings were also scrutinized with respect to clinical background information and inherited uterine leiomyoma risk.

Approximately 39% (or 50% among tumors selected as one per patient) of uterine leiomyomas harbored chromosomal aberrations. Uterine leiomyoma subtypes displayed unique chromosomal features: fumaratedehydratase-driven and mediator complex subunit12-driven tumors were largely chromosomally stable, FH tumors harboring almost exclusively only focal 1q deletions and MED12 tumors being enriched for 7q22 deletions. Meanwhile, HMGA2, HMGA1, PLAG1, and COL4A5/6 subtypes frequently displayed extensive chromosomal aberrations. Complex chromosomal rearrangements were particularly frequent in HMGA1 and PLAG1 tumors and were typically encountered on chromosomes with known uterine leiomyoma driver genes. YEATS4 tumors harbored deletions of chromosome 16. UNKNOWN tumors were heterogeneous as expected, some exhibiting multiple large deletions in 1p, 14q, and 15q or 1p, 14q, and 22q. Chromosomal gains were rare and enriched to chromosome 1. Differential expression analysis revealed known recurrent alterations in uterine leiomyomas as well as new loci for future scrutiny, such as CDKN2C in HMGA2 tumors. Clinical characteristics were examined, notably linking chromosomal aberrations and complex chromosomal rearrangements to larger tumors and younger age at hysterectomy in select subtypes. Examined overall, somatic aberrations at germline predisposition loci preferred a loss of the protective allele.

This study revealed uterine leiomyoma subtypes to have distinct chromosomal aberration landscapes. Our large sample collection, detailed subclassification, and extensive expression data integration enabled the identification of rare aberrations and subtype-specificity not previously feasible. Further research is implicated in studying the recurrently aberrant regions to identify the specific targets. This study shows, once again, the benefits for accurate subtype information in leiomyoma research and provides a new framework for further studies, toward comprehensive knowledge on the tumorigenesis and potential subtype-specific diagnostic and therapeutic strategies.