Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MYCLASS (Towards prevention, early diagnosis, and noninvasive treatment of uterine leiomyomas through molecular classification)

Teaser

Uterine leiomyomas (ULs), or fibroids, are among the most common human neoplasms, occurring in an estimated 77% of women of childbearing age and causing symptoms in every fourth Caucasian woman. Although bening, ULs frequently cause a variety of health complications, and...

Summary

Uterine leiomyomas (ULs), or fibroids, are among the most common human neoplasms, occurring in an estimated 77% of women of childbearing age and causing symptoms in every fourth Caucasian woman. Although bening, ULs frequently cause a variety of health complications, and infertility, and form a major burden to women’s health. As consequence of high morbidity, ULs are the leading cause of hysterectomy worldwide and have a considerable socio-economic impact. The approximate annual societal costs reach $34 billion in the United States, which is more than the equivalent costs of colon and breast cancer combined, forming a major burden to women\'s health. Despite the high prevalence and socio-economic impact of ULs – possibly due to the non-malignant nature of these lesions – relatively little research using modern high-throughput technologies has been conducted on this important condition. To date, the molecular mechanisms underlying the growth and development of ULs remain largely unknown.

ULs are frequently found incidentally during a routine pelvic examination and the diagnosis is typically confirmed by ultrasound to differentiate these lesions from other pelvic conditions. None of the current treatment options take into account the possible existence of various UL subclasses, but the lesions are seen as a single entity. Several other factors including the size, number, and location of the tumors, as well as the symptoms and reproductive desires of the patient, are essential when selecting optimal treatment. Still today, surgery is the standard method for treating ULs. For now, hysterectomy is the only definitive solution that eliminates both the symptoms and chances of recurrence, but as an invasive procedure it is far from optimal and not suitable for women who have not completed childbearing. Myomectomy is an example of a uterus-sparing treatment option. This approach, however, is also invasive. Effective drug treatments against ULs are still lacking, and ULs remain both at present and in the near future a highly significant challenge for women’s health.

Although the precise molecular mechanisms underlying the genesis of ULs are still largely unknown, various factors, in addition to ovarian hormones, seem to participate in regulating the growth and development of these lesions, including genetic factors. During the last decade, high-throughput sequencing technologies have revolutionized the field of tumor genomics, enabling comprehensive genome-wide characterization of somatic alterations in a large number of tumor specimens. Our recent breakthrough findings, derived from the use of these technologies, led us to hypothesize that ULs can and should be classified based on their molecular background. However, the current number of examined UL is relatively small and molecular classification of ULs has not gained ground even in research papers, thus our overall objective is to further define and characterize these subclasses, both molecularly and clinically. Such classification will lead to increased knowledge on UL genesis as well as improved management of the disease. This project will take the knowledge on ULs to a completely new level, being an important step towards non-invasive management of ULs. If successful, the results have the potential to benefit hundreds of millions of women worldwide. This project is expected to result in several novel discoveries of explicit scientific and clinical importance. Thus, the potential economic and societal impact of this research project are huge.

Work performed

We are systematically collecting and characterizing ULs samples, using high-throughput sequencing technologies. One main result achieved so far is the identification of germline variants associated with UL susceptibility, which resulted in a paper published in the eLife journal: here follows a short summary of the article.

We implemented the largest genome-wide association study (GWAS) on uterine leiomyomas to date by combining the UK biobank cohort and a wide spectrum of replication cohorts from varying ethnicities. The initial GWAS was performed by comparing 15,453 UL cases against a population-matched control set of 392,628 individuals. We reported 22 regions of genome-wide significant UL risk, most of which harbor genes with a conceivable role in myoma biology. The identified target genes separate into two distinct roles: first, a subset of genes that control the stability of the genome, and second, a subset of genes that control the development of female reproductive organs. For example, ESR1 encodes production of the estrogen receptor, which conveys the female hormone known to be involved in UL growth. The combined UL risk of the reported loci was replicated in six different ethnicities. Moreover, the risk score emerging from our data can stratify the female population into low-risk and high-risk quartiles that differ two-fold by their UL risk. We then examined the identified susceptibility loci further in the context of our in-house tumor and patient derived material, including molecular tumor characterization, subclassification and clinical background information. The work included a systematic assessment of risk alleles’ effect on gene expression, CpG methylation, chromosomal instability and telomere length. These efforts will continue as more data becomes available.

Final results

By the end of the project, we expect to form a comprehensive picture of molecular biology of normal myometrium and the different UL subclasses, through integration of genetic, epigenetic and expression data.