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Genomics of uterine leiomyomas: insights from high-throughput sequencing.
Fertil Steril. 2014 Sep; 102(3):621-9.FS

Abstract

Uterine leiomyomas are benign smooth-muscle tumors of extremely low malignant potential. Early work utilizing classical cytogenetics revealed that a subset of uterine leiomyomas harbor recurrent chromosomal rearrangements, such as translocations affecting the HMGA2 gene. Our understanding of the genetics of many tumor types has deepened remarkably with the emergence of next-generation sequencing technologies. Exome sequencing identified that the majority of leiomyomas display highly specific MED12 mutations. Further studies suggest that these MED12 hotspot mutations are also frequent in breast fibroadenomas, but not in other human tumors. Whole-genome sequencing showed that a subset of leiomyomas display complex chromosomal rearrangements resembling chromothripsis. These were formed in a single event of chromosomal breakage and random reassembly involving one or a limited number of chromosomes. Although most leiomyomas have been shown to arise independently, these studies also revealed that distinct nodules within a uterus may display identical genetic changes indicating a common clonal origin. A minority of leiomyomas were also found to display deletions within the COL4A5-COL4A6 genes, leading to upregulation of the adjacent gene IRS4. The findings derived from high-throughput sequencing combined with previous knowledge have led to an emerging molecular classification of leiomyomas, suggesting that there are several distinct pathogenic pathways involved in leiomyoma formation. The evidence points to at least 4 molecular subclasses: leiomyomas with MED12 mutation, FH inactivation, HMGA2 overexpression, and COL4A6-COL4A5 deletion. Elucidating the molecular pathogenesis of leiomyomas should be relevant for developing treatments for this very common disease.

Authors+Show Affiliations

Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.Department of Medical Genetics and Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland. Electronic address: pia.vahteristo@helsinki.fi.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

25106763

Citation

Mehine, Miika, et al. "Genomics of Uterine Leiomyomas: Insights From High-throughput Sequencing." Fertility and Sterility, vol. 102, no. 3, 2014, pp. 621-9.
Mehine M, Mäkinen N, Heinonen HR, et al. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil Steril. 2014;102(3):621-9.
Mehine, M., Mäkinen, N., Heinonen, H. R., Aaltonen, L. A., & Vahteristo, P. (2014). Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertility and Sterility, 102(3), 621-9. https://doi.org/10.1016/j.fertnstert.2014.06.050
Mehine M, et al. Genomics of Uterine Leiomyomas: Insights From High-throughput Sequencing. Fertil Steril. 2014;102(3):621-9. PubMed PMID: 25106763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genomics of uterine leiomyomas: insights from high-throughput sequencing. AU - Mehine,Miika, AU - Mäkinen,Netta, AU - Heinonen,Hanna-Riikka, AU - Aaltonen,Lauri A, AU - Vahteristo,Pia, Y1 - 2014/08/05/ PY - 2014/05/30/received PY - 2014/06/27/revised PY - 2014/06/27/accepted PY - 2014/8/10/entrez PY - 2014/8/12/pubmed PY - 2014/11/12/medline KW - COL4A5-COL4A6 KW - CUX1 KW - HMGA2 KW - MED12 KW - Uterine leiomyoma KW - chromothripsis SP - 621 EP - 9 JF - Fertility and sterility JO - Fertil. Steril. VL - 102 IS - 3 N2 - Uterine leiomyomas are benign smooth-muscle tumors of extremely low malignant potential. Early work utilizing classical cytogenetics revealed that a subset of uterine leiomyomas harbor recurrent chromosomal rearrangements, such as translocations affecting the HMGA2 gene. Our understanding of the genetics of many tumor types has deepened remarkably with the emergence of next-generation sequencing technologies. Exome sequencing identified that the majority of leiomyomas display highly specific MED12 mutations. Further studies suggest that these MED12 hotspot mutations are also frequent in breast fibroadenomas, but not in other human tumors. Whole-genome sequencing showed that a subset of leiomyomas display complex chromosomal rearrangements resembling chromothripsis. These were formed in a single event of chromosomal breakage and random reassembly involving one or a limited number of chromosomes. Although most leiomyomas have been shown to arise independently, these studies also revealed that distinct nodules within a uterus may display identical genetic changes indicating a common clonal origin. A minority of leiomyomas were also found to display deletions within the COL4A5-COL4A6 genes, leading to upregulation of the adjacent gene IRS4. The findings derived from high-throughput sequencing combined with previous knowledge have led to an emerging molecular classification of leiomyomas, suggesting that there are several distinct pathogenic pathways involved in leiomyoma formation. The evidence points to at least 4 molecular subclasses: leiomyomas with MED12 mutation, FH inactivation, HMGA2 overexpression, and COL4A6-COL4A5 deletion. Elucidating the molecular pathogenesis of leiomyomas should be relevant for developing treatments for this very common disease. SN - 1556-5653 UR - https://www.unboundmedicine.com/medline/citation/25106763/Genomics_of_uterine_leiomyomas:_insights_from_high_throughput_sequencing_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0015-0282(14)00604-9 DB - PRIME DP - Unbound Medicine ER -