Three main uterine leiomyoma molecular subtypes include tumors with MED12 mutation, molecular aberrations leading to HMGA2 overexpression, and biallelic loss of FH. These aberrations are mutually exclusive and can be found in approximately 80-90% of uterine leiomyoma, in which they seem to be a driver event. Approximately 10% of uterine leiomyoma, however, does not belong to any of these categories. Uterine leiomyoma with HMGA2 overexpression is the most common subtype in cellular and second most common category of usual leiomyoma. In some of these tumors, rearrangement of HMGA2 gene is present. The most common fusion partner of HMGA2 gene is RAD51B. Limited data suggests that RAD51B fusions with other genes may be present in uterine leiomyoma. In our study, we described two cases of uterine leiomyoma with RAD51B::NUDT3 fusion, which occur in one case of usual and one case of highly cellular leiomyoma. In both cases, no other driver molecular aberrations were found. The results of our study showed that RAD51::NUDT3 fusion can occur in both usual and cellular leiomyoma. RAD51B may be a fusion partner of multiple genes other than HMGA2 and HMGA1. In these cases, RAD51B fusion seems to be mutually exclusive with other driver aberrations defining molecular leiomyoma subtypes. RAD51B::NUDT3 fusion should be added to the spectrum of fusions which may occur in uterine leiomyoma, which can be of value especially in cellular leiomyoma in the context of differential diagnosis against endometrial stromal tumors.

Carlos Simon Foundation INCLIVA Health Research Institute 46010 Valencia Spain

Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Studničkova 2 128 00 Prague 2 Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University Thomayer University Hospital Prague Czech Republic

Department of Pathology Charles University 3rd Faculty of Medicine University Hospital Kralovske Vinohrady Prague Czech Republic

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Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: a systematic review. BJOG. 2017;124(10):1501–1512. doi: 10.1111/1471-0528.14640. PubMed DOI

Binzer-Panchal A, Hardell E, Viklund B, Ghaderi M, Bosse T, Nucci MR, Lee CH, Hollfelder N, Corcoran P, Gonzalez-Molina J, Moyano-Galceran L, Bell DA, Schoolmeester JK, Måsbäck A, Kristensen GB, Davidson B, Lehti K, Isaksson A, Carlson JW. Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes. Clin Cancer Res. 2019;25(7):2155–2165. doi: 10.1158/1078-0432.CCR-18-2792. PubMed DOI

Lu B, Jiang R, Xie B, Wu W, Zhao Y. Fusion genes in gynecologic tumors: the occurrence, molecular mechanism and prospect for therapy. Cell Death Dis. 2021;12(8):783. doi: 10.1038/s41419-021-04065-0.. PubMed DOI PMC

Momeni-Boroujeni A, Mohammad N, Wolber R, Yip S, Köbel M, Dickson BC, Chiang S. Targeted RNA expression profiling identifies high-grade endometrial stromal sarcoma as a clinically relevant molecular subtype of uterine sarcoma. Mod Pathol. 2021;34(5):1008–1016. doi: 10.1038/s41379-020-00705-6. PubMed DOI

Rommel B, Holzmann C, Bullerdiek J. Malignant mesenchymal tumors of the uterus - time to advocate a genetic classification. Expert Rev Anticancer Ther. 2016;16(11):1155–1166. doi: 10.1080/14737140.2016.1233817. PubMed DOI

Mehine M, Kaasinen E, Mäkinen N, Katainen R, Kämpjärvi K, Pitkänen E, Heinonen HR, Bützow R, Kilpivaara O, Kuosmanen A, Ristolainen H, Gentile M, Sjöberg J, Vahteristo P, Aaltonen LA. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med. 2013;369(1):43–53. doi: 10.1056/NEJMoa1302736. PubMed DOI

Mehine M, Mäkinen N, Heinonen H-R, Aaltonen LA, Vahteristo P. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil. Steril. 2014;102(3):621–629. doi: 10.1016/j.fertnstert.2014.06.050. PubMed DOI

Mehine M, Khamaiseh S, Ahvenainen T, Heikkinen T, Äyräväinen A, Pakarinen P, Härkki P, Pasanen A, Bützow R, Vahteristo P. 3'RNA Sequencing Accurately Classifies Formalin-Fixed Paraffin-Embedded Uterine Leiomyomas. Cancers (Basel) 2020;12(12):3839. doi: 10.3390/cancers12123839. PubMed DOI PMC

Mäkinen N, Kämpjärvi K, Frizzell N, Bützow R, Vahteristo P. Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer. 2017;16(1):101. doi: 10.1186/s12943-017-0672-1. PubMed DOI PMC

Kämpjärvi K, Mäkinen N, Mehine M, Välipakka S, Uimari O, Pitkänen E, Heinonen HR, Heikkinen T, Tolvanen J, Ahtikoski A, Frizzell N, Sarvilinna N, Sjöberg J, Bützow R, Aaltonen LA, Vahteristo P. MED12 mutations and FH inactivation are mutually exclusive in uterine leiomyomas. Br J Cancer. 2016;114(12):1405–1411. doi: 10.1038/bjc.2016.130. PubMed DOI PMC

Lehtonen R, Kiuru M, Vanharanta S, Sjöberg J, Aaltonen LM, Aittomäki K, Arola J, Butzow R, Eng C, Husgafvel-Pursiainen K, Isola J, Järvinen H, Koivisto P, Mecklin JP, Peltomäki P, Salovaara R, Wasenius VM, Karhu A, Launonen V, Nupponen NN, Aaltonen LA. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. Am J Pathol. 2004;164(1):17–22. doi: 10.1016/S0002-9440(10)63091-X. PubMed DOI PMC

Bertsch E, Qiang W, Zhang Q, Espona-Fiedler M, Druschitz S, Liu Y, Mittal K, Kong B, Kurita T, Wei JJ. MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol. 2014;27(8):1144–1153. doi: 10.1038/modpathol.2013.243. PubMed DOI PMC

Dundr P, Gregová M, Hojný J, Krkavcová E, Michálková R, Němejcová K, Bártů M, Hájková N, Laco J, Mára M, Richtárová A, Zima T, Stružinská I. Uterine cellular leiomyomas are characterized by common HMGA2 aberrations, followed by chromosome 1p deletion and MED12 mutation: morphological, molecular, and immunohistochemical study of 52 cases. Virchows Arch. 2022;480(2):281–291. doi: 10.1007/s00428-021-03217-z. PubMed DOI

Mäkinen N, Kämpjärvi K, Frizzell N, Bützow R, Vahteristo P. Characterization of MED12, HMGA2, and FH alterations reveals molecular variability in uterine smooth muscle tumors. Mol Cancer. 2017;16(1):101. doi: 10.1186/s12943-017-0672-1.. PubMed DOI PMC

Velagaleti GV, Tonk VS, Hakim NM, Wang X, Zhang H, Erickson-Johnson MR, Medeiros F, Oliveira AM. Fusion of HMGA2 to COG5 in uterine leiomyoma. Cancer Genet Cytogenet. 2010;202(1):11–16. doi: 10.1016/j.cancergencyto.2010.06.002. PubMed DOI

Ingraham SE, Lynch RA, Kathiresan S, Buckler AJ, Menon AG. hREC2, a RAD51-like gene, is disrupted by t(12;14) (q15;q24.1) in a uterine leiomyoma. Cancer Genet Cytogenet. 1999;115(1):56–61. doi: 10.1016/s0165-4608(99)00070-9. PubMed DOI

Jokinen V, Mehine M, Reinikka S, Khamaiseh S, Ahvenainen T, Äyräväinen A, Härkki P, Bützow R, Pasanen A, Vahteristo P. 3'RNA and whole-genome sequencing of archival uterine leiomyomas reveal a tumor subtype with chromosomal rearrangements affecting either HMGA2, HMGA1, or PLAG1. Genes Chr Cancer. 2023;62(1):27–38. doi: 10.1002/gcc.23088. PubMed DOI PMC

Machado-Lopez A, Alonso R, Lago V, Jimenez-Almazan J, Garcia M, Monleon J, Lopez S, Barcelo F, Torroba A, Ortiz S, Domingo S, Simon C, Mas A. Integrative Genomic and Transcriptomic Profiling Reveals a Differential Molecular Signature in Uterine Leiomyoma versus Leiomyosarcoma. Int J Mol Sci. 2022;23(4):2190. doi: 10.3390/ijms23042190. PubMed DOI PMC

Stružinská I, Hájková N, Hojný J, Krkavcová E, Michálková R, Dvořák J, Němejcová K, Matěj R, Laco J, Drozenová J, Fabian P, Hausnerová J, Méhes G, Škapa P, Švajdler M, Cibula D, Frühauf F, Bártů MK, Dundr P. A comprehensive molecular analysis of 113 primary ovarian clear cell carcinomas reveals common therapeutically significant aberrations. Diagn Pathol. 2023;18(1):72. doi: 10.1186/s13000-023-01358-0. PubMed DOI PMC

Mehine M, Kaasinen E, Heinonen HR, Mäkinen N, Kämpjärvi K, Sarvilinna N, Aavikko M, Vähärautio A, Pasanen A, Bützow R, Heikinheimo O, Sjöberg J, Pitkänen E, Vahteristo P, Aaltonen LA. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proc Natl Acad Sci U S A. 2016;113(5):1315–1320. doi: 10.1073/pnas.1518752113. PubMed DOI PMC

Mehine M, Mäkinen N, Heinonen HR, Aaltonen LA, Vahteristo P. Genomics of uterine leiomyomas: insights from high-throughput sequencing. Fertil Steril. 2014;102(3):621–629. doi: 10.1016/j.fertnstert.2014.06.050. PubMed DOI

Gregová M, Hojný J, Němejcová K, Bártů M, Mára M, Boudová B, Laco J, Krbal L, Tichá I, Dundr P. Leiomyoma with Bizarre Nuclei: a Study of 108 Cases Focusing on Clinicopathological Features, Morphology, and Fumarate Hydratase Alterations. Pathol Oncol Res. 2020;26(3):1527–1537. doi: 10.1007/s12253-019-00739-5. PubMed DOI

Ferrero H. HMGA2 involvement in uterine leiomyomas development through angiogenesis activation. Fertil Steril. 2020;114(5):974–975. doi: 10.1016/j.fertnstert.2020.07.044. PubMed DOI

Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, Gentile M, Yan J, Enge M, Taipale M, Aavikko M, Katainen R, Virolainen E, Böhling T, Koski TA, Launonen V, Sjöberg J, Taipale J, Vahteristo P, Aaltonen LA. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Sci. 2011;334(6053):252–255. doi: 10.1126/science.1208930. PubMed DOI

Äyräväinen A, Pasanen A, Ahvenainen T, Heikkinen T, Pakarinen P, Härkki P, Vahteristo P. Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy. Hum. Reprod. 2020;35(10):2237–2244. doi: 10.1093/humrep/deaa187. PubMed DOI

Carter CS, Skala SL, Chinnaiyan AM, McHugh JB, Siddiqui J, Cao X, Dhanasekaran SM, Fullen DR, Lagstein A, Chan MP, Mehra R. Immunohistochemical Characterization of Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH) in Cutaneous Leiomyomas for Detection of Familial Cancer Syndromes. Am J Surg Pathol. 2017;41(6):801–809. doi: 10.1097/PAS.0000000000000840. PubMed DOI PMC

Harrison WJ, Andrici J, Maclean F, Madadi-Ghahan R, Farzin M, Sioson L, Toon CW, Clarkson A, Watson N, Pickett J, Field M, Crook A, Tucker K, Goodwin A, Anderson L, Srinivasan B, Grossmann P, Martinek P, Ondič O, Hes O, Trpkov K, Clifton-Bligh RJ, Dwight T, Gill AJ. Fumarate Hydratase-deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings. Am J Surg Pathol. 2016;40(5):599–607. doi: 10.1097/PAS.0000000000000573. PubMed DOI PMC

Berta DG, Kuisma H, Välimäki N, Räisänen M, Jäntti M, Pasanen A, Karhu A, Kaukomaa J, Taira A, Cajuso T, Nieminen S, Penttinen RM, Ahonen S, Lehtonen R, Mehine M, Vahteristo P, Jalkanen J, Sahu B, Ravantti J, Mäkinen N, Rajamäki K, Palin K, Taipale J, Heikinheimo O, Bützow R, Kaasinen E, Aaltonen LA. Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma. Nature. 2021;596(7872):398–403. doi: 10.1038/s41586-021-03747-1. PubMed DOI

Galindo LJ, Hernández-Beeftink T, Salas A, Jung Y, Reyes R, de Oca FM, Hernández M, Almeida TA. HMGA2 and MED12 alterations frequently co-occur in uterine leiomyomas. Gynecol Oncol. 2018;150(3):562–568. doi: 10.1016/j.ygyno.2018.07.007. PubMed DOI

Markowski DN, Bartnitzke S, Löning T, Drieschner N, Helmke BM, Bullerdiek J. MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups. Int J Cancer. 2012;131(7):1528–1536. doi: 10.1002/ijc.27424. PubMed DOI

George JW, Fan H, Johnson B, Carpenter TJ, Foy KK, Chatterjee A, Patterson AL, Koeman J, Adams M, Madaj ZB, Chesla D, Marsh EE, Triche TJ, Shen H, Teixeira JM. Integrated Epigenome, Exome, and Transcriptome Analyses Reveal Molecular Subtypes and Homeotic Transformation in Uterine Fibroids. Cell Rep. 2019;29(12):4069–4085.e6. doi: 10.1016/j.celrep.2019.11.077. PubMed DOI PMC

Sandberg AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: leiomyosarcoma. Cancer Genet Cytogenet. 2005;161(1):1–19. doi: 10.1016/j.cancergencyto.2004.11.009. PubMed DOI

Peng Y, Laser J, Shi G, Mittal K, Melamed J, Lee P, Wei JJ. Antiproliferative effects by Let-7 repression of high-mobility group A2 in uterine leiomyoma. Mol Cancer Res. 2008;6(4):663–673. doi: 10.1158/1541-7786.MCR-07-0370. PubMed DOI

Wang T, Zhang X, Obijuru L, Laser J, Aris V, Lee P, Mittal K, Soteropoulos P, Wei JJ. A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas. Genes Chr Cancer. 2007;46(4):336–347. doi: 10.1002/gcc.20415. PubMed DOI

Grudzien-Nogalska E, Jiao X, Song MG, Hart RP, Kiledjian M. Nudt3 is an mRNA decapping enzyme that modulates cell migration. RNA. 2016;22(5):773–781. doi: 10.1261/rna.055699.115. PubMed DOI PMC

Voz ML, Agten NS, Van de Ven WJ, Kas K. PLAG1, the main translocation target in pleomorphic adenoma of the salivary glands, is a positive regulator of IGF-II. Cancer Res. 2000;60(1):106–113. PubMed

Zhu L, Sun Y, Wu Q, Zhang C, Ling J. CAPN6 Regulates Uterine Leiomyoma Cell Proliferation and Apoptosis through the Rac1-Dependent Signaling Pathway. Ann Clin Lab Sci. 2020;50(1):24–30. PubMed

Mannoor K, Liao J, Jiang F. Small nucleolar RNAs in cancer. Biochim Biophys Acta. 2012;1826(1):121–128. PubMed PMC

Ko YA, Jamaluddin MFB, Adebayo M, Bajwa P, Scott RJ, Dharmarajan AM, Nahar P, Tanwar PS. Extracellular matrix (ECM) activates β-catenin signaling in uterine fibroids. Reprod. 2018;155(1):61–71. doi: 10.1530/REP-17-0339. PubMed DOI

Dimitrova IK, et al. Gene expression profiling of multiple leiomyomata uteri and matched normal tissue from a single patient. Fertil Steril. 2009;91(6):2650–2663. doi: 10.1016/j.fertnstert.2008.03.071. PubMed DOI PMC

Agaimy A, Clarke BA, Kolin DL, Lee CH, Lee JC, McCluggage WG, Pöschke P, Stoehr R, Swanson D, Turashvili G, Beckmann MW, Hartmann A, Antonescu CR, Dickson BC. Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma. Am J Surg Pathol. 2022;46(9):1298–1308. doi: 10.1097/PAS.0000000000001915. PubMed DOI PMC

Ainsworth AJ, Dashti NK, Mounajjed T, Fritchie KJ, Davila J, Mopuri R, Jackson RA, Halling KC, Bakkum-Gamez JN, Schoolmeester JK. Leiomyoma with KAT6B-KANSL1 fusion: case report of a rapidly enlarging uterine mass in a postmenopausal woman. Diagn Pathol. 2019;14(1):32. doi: 10.1186/s13000-019-0809-1. PubMed DOI PMC

Choi J, Manzano A, Dong W, Bellone S, Bonazzoli E, Zammataro L, Yao X, Deshpande A, Zaidi S, Guglielmi A, Gnutti B, Nagarkatti N, Tymon-Rosario JR, Harold J, Mauricio D, Zeybek B, Menderes G, Altwerger G, Jeong K, Zhao S, Buza N, Hui P, Ravaggi A, Bignotti E, Romani C, Todeschini P, Zanotti L, Odicino F, Pecorelli S, Ardighieri L, Bilguvar K, Quick CM, Silasi DA, Huang GS, Andikyan V, Clark M, Ratner E, Azodi M, Imielinski M, Schwartz PE, Alexandrov LB, Lifton RP, Schlessinger J, Santin AD. Integrated mutational landscape analysis of uterine leiomyosarcomas. Proc Natl Acad Sci U S A. 2021;118(15):e2025182118. doi: 10.1073/pnas.2025182118. PubMed DOI PMC