Genomic DNA instability is a common feature of the molecular pathogenesis of leiomyosarcoma and leiomyoma with bizarre nuclei

Smooth muscle tumors are the most frequent mesenchymal tumors of the uterus. The majority of the uterine smooth muscle tumors can be classified as benign or malignant based on their clinical and histologic appearances. Smooth muscle tumors with nuclear atypia can be placed in three categories: leiomyosarcoma, leiomyoma with bizarre nuclei and fumarate hydratase deficient leiomyoma.

Leiomyosarcoma, a rare tumor subtype, accounts for 1% of all uterine malignancies, but contributes to a significant proportion of uterine cancer deaths. Surgery is considered the mainstay of treatment for all soft tissue sarcomas, including uterine variants. However, uterine leiomyosarcoma is challenging to diagnose preoperatively and can mimic the appearance of benign uterine leiomyomas. Although rare, leiomyoma with bizarre nuclei manifests its atypical cells with expansive and bizarre nuclei. Several studies have reported it to have a benign course, infrequent occurrence, and no fatalities. Most but not all fumarate hydratase deficient leiomyoma (FH-LM) demonstrate atypical cells with large or round multinucleated nuclei. Although either somatic or germline fumarate hydratase inactivation can cause FH-LM, exact molecular mechanisms of somatic fumarate hydratase alternations are mostly unclear.

Contrary to FH-LM, researchers are still yet to fully understand leiomyosarcoma and leiomyoma with bizarre nuclei exact causes and their histogenesis. Previous studies have shown that leiomyoma with bizarre nuclei harbors molecular alterations often reported in leiomyosarcoma. Consequently, this observation has stirred a conversation of whether the two have shared pathogenesis or represent different tumor development and progression stages. Also, managing patients with leiomyoma with bizarre nuclei is challenging due to its recurrence risk and potential relation to leiomyosarcoma.

Investigating the genomic changes in these two tumors, leiomyosarcoma, and leiomyoma with bizarre nuclei, will provide a deeper and meaningful understanding of their molecular relationship.

In realizing this, Northwestern University researchers Dr. Tingting Gao, Dr. Brian Finkelman, Dr. Yanli Ban, Dr. Se. Yinuo Li, Dr. Ping Yin, Dr. Serdar Bulun, Dr. Xinyan Lu, and led by Professor Jian-Jun Wei together with Professor Chunfang Ha from the Ningxia Medical University conducted a study to investigate detailed genome changes, including gene expression signatures, copy number alteration, and mutational profiling of leiomyosarcoma, FH-LM, and leiomyoma with bizarre nuclei using integrated molecular profiling. The study’s objectives were to gain insights into the genomic changes in both leiomyoma with bizarre nuclei and leiomyosarcoma, clarify their molecular correspondence and bring to light biomarkers that would help address diagnostically-difficult cases clinically. The original research article is now published in the journal Cancer Science.

The research team performed integrated genomic profiling to characterize the molecular profiles of the three tumors. The profiling included RNA and whole-genome sequencing and genomic micro-array tests to investigate copy number alternations and candidate gene alterations in the three tumor types.

The authors found extensive genomic copy number alterations involving almost all chromosomes, suggesting leiomyoma with bizarre nuclei chromosomal instability. Leiomyosarcoma also had frequent copy number alterations indicating genomic instability. Leiomyosarcoma had larger copy number alteration regions suggesting that extensive genomic alterations play a critical role in leiomyosarcoma.

Principal component analysis of the copy number alteration foci revealed a significant overlap between leiomyoma with bizarre nuclei and leiomyosarcoma. This suggests that the two tumors could be closely related and could potentially have overlapping pathogenesis. Further analysis of this data indicated the two tumor types branching together in dendrograms. Also, the authors observed that a part of copy number alterations were recorded in leiomyoma with bizarre nuclei but not in leiomyosarcoma. The copy number alteration differences provide a basis for differentiating leiomyoma with bizarre nuclei from leiomyosarcoma. For example, a genomic region with ATAD3 is completely loss in most leiomyoma with bizarre nuclei but not in leiomyosarcoma. Authors further validated the candidate genes that are differentially expressed in three tumor types by immunohistochemistry. In general, the molecular basis of Leiomyosarcoma is poorly understood, as no single contributing gene has been identified in the past. They proposed ATAD3 can be used as a biomarker to differentiate leiomyoma with bizarre nuclei and leiomyosarcoma.

The authors reported 100% loss of chromosome 1q43-44 in FH-LM, but not in leiomyoma with bizarre nuclei and leiomyosarcoma. Fumarate hydratase resides in this region, and it’s responsible for FH-LM development. The findings of this study revealed that sporadic FH-LM was majorly linked to fumarate hydratase region deletion. Also, point mutations make up only a fraction of FH-LM.

The findings of the study are important not only for potential molecular targets, but also for patient stratification in clinical trials. This also emphasize the importance of integrated, comprehensive molecular profiling in analyzing and characterizing these uterine smooth muscle tumors. However, more studies are still needed into the mechanism behind the recorded genomic instability in leiomyoma with bizarre nuclei and leiomyosarcoma.