Development of a Predictive Model for Early Differential Diagnosis of Uterine Leiomyomas and Leiomyosarcomas

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Updated on 10 August 2022
ct scan
body mass index
uterine fibroid
uterine myomectomy


The development of an accurate and non-invasive diagnostic method is a priority in areas such as gynecology and oncology, specifically to improve the health of those patients with surgical indication for diagnosis of myometrial tumors: leiomyomas and/or leiomyosarcomas.

Recently, Next Generation Sequencing (NGS) technology has been successfully applied in different areas of knowledge, being effective not only for the detection of DNA mutations, but also providing through bioinformatic tools, new insights in the understanding of chromosomal instability. In addition, the detection of circulating tumor DNA (ctDNA) through this type of techniques could revolutionize the non-invasive detection and monitoring of this type of tumors.

The proposed study aims to perform the differential molecular analysis of myometrial tumor tissue (uterine leiomyomas / leiomyosarcomas), as well as peripheral blood of a group of patients with surgical indication of hysterectomy, laparoscopic or laparotomic myomectomy by diagnosis of myometrial tumors. Thus, the obtained samples will be processed for the realization of techniques of massive parallel sequencing or NGS that, together with a specialized bioinformatic software, will facilitate the interpretation of the obtained data.

Combination of both platforms, sequencing and bioinformatics, will offer a high potential for the discovery of genetic variants and genomic markers. Depending on the results of these analyses, differential diagnosis of leiomyoma and leiomyosarcoma could be determined, in addition to increasing knowledge of myometrial biology and associated pathologies in a clinical and therapeutic context. Moreover, the application of this technology could allow the development of biomarkers and targeted therapies effective in the treatment of uterine leiomyomas and/or leiomyosarcomas.


Leiomyomas (LM) are the most common benign gynecological tumors that affect approximately 70% of women of reproductive age, being responsible for 200,000 hysterectomies per year in the United States (USA). Despite its benign nature, LM represents a major public health problem due to its significant level of morbidity, which manifests as a spectrum of clinical symptoms such as heavy menstrual bleeding, anemia, pelvic pain, infertility and recurrent pregnancy loss, among others.

Uterine leiomyosarcoma (LMS) is a rare uterine malignancy that arises from the smooth muscle of uterine wall. It accounts for only 1-2% of uterine malignancies and occurs mainly after menopause. LMS is notorious for its aggressive nature and poor prognosis.

Although uterine LM and LMS are considered biologically unrelated tumors due to their cytogenetic and molecular disparity, both share morphological features that can complicate the diagnosis through current clinical tests or factors.

Nowadays, long-term therapeutic options for LM are limited. Currently, laparoscopic morcellation is the most widely used surgical technique in the treatment of large LM. However, this type of surgery carries the risk of occult dissemination of malignant tumors such as LMS, characterized by early metastases, poor prognosis and high recurrence rates, with limited therapeutic efficacy. In fact, the United States Food and Drug Administration (FDA) has estimated that 1 in 352 of women with surgical indication of LM could have LMS, and treatment in this case could result in tumor spread. Given this need, Igenomix, through a recent pilot study with 26 samples, has identified new genetic targets that potentially differentiate leiomyosarcomas and leiomyomas, through integrated comparative genomic and transcriptomic analyses. This allowed to lay the foundations, not only to improve the understanding of the pathogenesis of these uterine tumors, but also provides a first step towards the preoperative diagnosis of leiomyomas and leiomyosarcomas by liquid biopsy.

Based on this pilot study, a new clinical study is proposed to proceed with further identification of genetic markers and develop a preoperative diagnosis of LM and LMS by liquid biopsy. A total sample size of 1,000 patients with suspected LMS is expected to be recruited in this study, considering the frequency of surgeries in which obtaining a sample is intended, as well as the frequency of patients who will accept tissue donation for research. Moreover, a cut-off point with a preliminary analysis every 100 patients will be established, in which the laboratory data is combined with those derived from the Pathological Anatomy (Gold Standard), so that when a total of 40 LMS is reached the study will end.

During the development of the study, after obtaining informed consent from eligible patients, the samples (tumor tissue and peripheral blood) will be collected at the time of surgery, which the patient had already planned by medical indication according to the usual clinical practice. Thus, the participation of the subject in this study will entail only a single visit coinciding with the day of the surgery. In addition, samples available from patients that underwent surgery before the study could be also included if, after being duly informed, the patient agrees to participate in the study and signs the study consent form. Exceptionally, samples from patients who could not consent due to major reasons (such as death of the subject or impossibility to be found) could also be included in the study upon approval of the appropriated Ethic Committee according to the local regulations for this type of situations. In any case, the investigators will ensure that there is no expressed objection from the donors in their clinical history and that samples will be codified in order to assure anonymity.

Samples will be sent to histopathological diagnosis and to Igenomix, that will develop and optimize laboratory protocols to detect changes at the DNA (Whole Exome Sequencing) and RNA (RNAseq) level in order to achieve the described outcomes. This new approaches focused on NGS, could allow not only the detection of tumor-specific mutations but, in combination with bioinformatics tools, could provide new knowledge to understand chromosomal instability in the tumors.

According to the histopathological diagnosis, patients will be treated by their respective doctors and followed up to determine their evolution. If the proposed hypothesis from NGS results is confirmed and the objectives are achieved, in a second phase of the project, a diagnostic tool will be developed to extend the non-invasive genetic diagnosis of uterine leiomyomas and leiomyosarcomas in peripheral blood through the free DNA analysis of circulating tumor cells. The possibility of being able to quantify and characterize the circulating tumor DNA (ctDNA) by means of this type of techniques, could revolutionize the non-invasive detection and the follow-up of this type of tumors.

Condition Sarcoma, Sarcoma (Pediatric), leiomyoma, Soft Tissue Sarcoma, fibroids, leiomyosarcoma, Leiomyomas, UTERINE FIBROID, Uterine Fibroids
Treatment Biopsy and peripheral blood collection
Clinical Study IdentifierNCT04214457
Last Modified on10 August 2022

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