Periodic Reporting for period 4 - MYCLASS (Towards prevention, early diagnosis, and noninvasive treatment of uterine leiomyomas through molecular classification)
Période du rapport: 2020-12-01 au 2021-05-31
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 benign, 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 number of examined UL was previously relatively small and molecular classification of ULs had not gained ground even in research papers, thus our overall objective was to further define and characterize these subclasses, both molecularly and clinically, to increase the knowledge on UL genesis and to improve the management of the disease.
Through the main results we have achieved, we have advanced the research field significantly forward and we took the knowledge on ULs to a completely new level, being an important step towards non-invasive management of ULs. Our project resulted in novel discoveries of explicit scientific and clinical importance. In conclusion, these results have the potential to benefit hundreds of millions of women worldwide. Thus, the potential economic and societal impact of this research project are huge.
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 number of examined UL was previously relatively small and molecular classification of ULs had not gained ground even in research papers, thus our overall objective was to further define and characterize these subclasses, both molecularly and clinically, to increase the knowledge on UL genesis and to improve the management of the disease.
Through the main results we have achieved, we have advanced the research field significantly forward and we took the knowledge on ULs to a completely new level, being an important step towards non-invasive management of ULs. Our project resulted in novel discoveries of explicit scientific and clinical importance. In conclusion, these results have the potential to benefit hundreds of millions of women worldwide. Thus, the potential economic and societal impact of this research project are huge.
We have systematically collected and characterized ULs samples, using high-throughput sequencing technologies. The scientific work has overall progressed along the main planned objectives. Our major achievements have been published in high quality journals and available in Green open access:
The identification of germline variants associated with UL susceptibility resulted in a paper published in the eLife journal: Välimäki et al, 2018, Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability.
By utilizing the data produced from our extensive collection of fresh frozen ULs and detailed clinical background information from the patients, we have shown that parity is associated with increased DNA damage. The manuscript, entitled “Pregnancy Provokes Chromosomal Damage in Uterine Leiomyomas”, has been submitted to Nature communication and it is currently under revision.
We have also described a novel mechanism of neoplasia – epigenetic instability caused by deficient deposition of variant histone H2A.Z - through an extensive multi-omics characterization of primary ULs. The results have been recently accepted for publication in Nature (Berta et al, “Deficient H2A.Z Deposition is Associated with Genesis of Uterine Leiomyoma”, in press).
We have developed BasePlayer, our own software for variant analyses (Katainen et al, Discovery of potential causative mutations in human coding and noncoding genome with the interactive software BasePlayer, Nature Protocols 2018). We share BasePlayer free of charge at https://baseplayer.fi.
Potential associations between clinical variables and mutation status were analysed and published in 2017 (Heinonen et al. Multiple clinical characteristics separate MED12-mutation-positive and -negative uterine leiomyomas. Scientific Reports 2017). This study discovered novel differentiating features for MED12-mutation-positive and -negative leiomyomas and emphasises the relevance of specific driver mutations in genesis and presentation of uterine leiomyomas.
Through global metabolomic profiling of ULs and myometrium specimens, we identified metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas (Heinonen et al. Global metabolomic profiling of uterine leiomyomas. British Journal of Cancer 2017). The study reveals the metabolomic heterogeneity of ULs and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumors.
By analyzing specific subclasses of UL, we discovered that somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC)-associated and sporadic ULs. (Kämpjärvi et al, MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. British Journal of Cancer, 2016).
The identification of germline variants associated with UL susceptibility resulted in a paper published in the eLife journal: Välimäki et al, 2018, Genetic predisposition to uterine leiomyoma is determined by loci for genitourinary development and genome stability.
By utilizing the data produced from our extensive collection of fresh frozen ULs and detailed clinical background information from the patients, we have shown that parity is associated with increased DNA damage. The manuscript, entitled “Pregnancy Provokes Chromosomal Damage in Uterine Leiomyomas”, has been submitted to Nature communication and it is currently under revision.
We have also described a novel mechanism of neoplasia – epigenetic instability caused by deficient deposition of variant histone H2A.Z - through an extensive multi-omics characterization of primary ULs. The results have been recently accepted for publication in Nature (Berta et al, “Deficient H2A.Z Deposition is Associated with Genesis of Uterine Leiomyoma”, in press).
We have developed BasePlayer, our own software for variant analyses (Katainen et al, Discovery of potential causative mutations in human coding and noncoding genome with the interactive software BasePlayer, Nature Protocols 2018). We share BasePlayer free of charge at https://baseplayer.fi.
Potential associations between clinical variables and mutation status were analysed and published in 2017 (Heinonen et al. Multiple clinical characteristics separate MED12-mutation-positive and -negative uterine leiomyomas. Scientific Reports 2017). This study discovered novel differentiating features for MED12-mutation-positive and -negative leiomyomas and emphasises the relevance of specific driver mutations in genesis and presentation of uterine leiomyomas.
Through global metabolomic profiling of ULs and myometrium specimens, we identified metabolites and metabolic pathways that are dysregulated in different subtypes of leiomyomas (Heinonen et al. Global metabolomic profiling of uterine leiomyomas. British Journal of Cancer 2017). The study reveals the metabolomic heterogeneity of ULs and provides the requisite framework for strategies designed to target metabolic alterations promoting the growth of these prevalent tumors.
By analyzing specific subclasses of UL, we discovered that somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC)-associated and sporadic ULs. (Kämpjärvi et al, MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. British Journal of Cancer, 2016).
As planned, we have formed a comprehensive picture of molecular biology of normal myometrium and the different UL subclasses, through integration of genetic, epigenetic and expression data.