A rare coincidence of different types of driver mutations among uterine leiomyomas (UL)

Molecular Cytogenetics

Jörn Bullerdiek⁴  Burkhard Maria Helmke²  Dirk Koczan¹  Sabine Bartnitzke⁴  Dominique Nadine Markowski⁴  Carsten Holzmann³ 

[1] Institute of Immunology, University of Rostock, University Rostock Medical Center, Schillingallee 70, Rostock, D-18057, Germany;Present address: Institute of Pathology, Elbe Kliniken, Klinikum Stade, Bremervörder Str. 111, Stade, D- 21682, Germany;Institute of Medical Genetics, University Rostock Medical Center, Ernst-Heydemann-Strasse 8, Rostock, D-18057, Germany;Center of Human Genetics, University of Bremen, Leobener Strasse ZHG, Bremen, D-28359, Germany

关键词: MED12L;    MED12;    HMGA2;    Genetic types;    Uterine leiomyoma;   

Others  :  1229984
DOI  :  10.1186/s13039-015-0177-9

 received in 2015-06-26, accepted in 2015-09-22,  发布年份 2015

【 摘 要 】

Mutations of mediator subcomplex 12 (MED12) and of high mobility group protein AT-hook 2 (HMGA2) are driver mutations in uterine leiomyomas (UL) that have not been observed to coexist in one tumor and even rarely coexist in different UL tumors of one patient. Here we describe a patient who underwent hysterectomy because of multiple leiomyomas which were studied by cytogenetics, MED12 hotspot sequencing, and copy number variation arrays. Two of the UL tumors had different HMGA2 rearrangements not detected by G-banding. Two UL tumors had deletions of the long arm of chromosome 3, in one case associated with a MED12 mutation. Both deletions lead to the loss of MED12L showing strong similarity with MED12. It remains to be determined if this gene can play a role in leiomyomagenesis independent of MED12. In summary, the patient presented exhibits an unusual coincidence of different driver mutations among her leiomyomas.

【 授权许可】

   
2015 Holzmann et al.

【 图 表 】

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【 参考文献 】

• [1]Schoenmakers EF, Wanschura S, Mols R, Bullerdiek J, Van den Berghe H, Van de Ven WJ. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet. 1995; 10:436-44.
• [2]Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ et al.. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011; 334:252-5.
• [3]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; 131:1528-36.
• [4]Mehine M, Kaasinen E, Mäkinen N, Katainen R, Kämpjärvi K, Pitkänen E et al.. Characterization of uterine leiomyomas by whole-genome sequencing. N Engl J Med. 2013; 369:43-53.
• [5]Bertsch E, Qiang W, Zhang Q, Espona-Fiedler M, Druschitz S, Liu Y et al.. MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol. 2014; 27:1144-53.
• [6]Markowski DN, Helmke BM, Bartnitzke S, Löning T, Bullerdiek J. Uterine fibroids: do we deal with more than one disease? Int J Gynecol Pathol. 2014; 33:568-72.
• [7]Pérot G, Croce S, Ribeiro A, Lagarde P, Velasco V, Neuville A et al.. MED12 alterations in both human benign and malignant uterine soft tissue tumors. PLoS One. 2012; 7: Article ID e40015
• [8]Kämpjärvi K, Mäkinen N, Kilpivaara O, Arola J, Heinonen H-R, Böhm J et al.. Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer. Br J Cancer. 2012; 107:1761-5.
• [9]Ravegnini G, Mariño-Enriquez A, Slater J, Eilers G, Wang Y, Zhu M et al.. MED12 mutations in leiomyosarcoma and extrauterine leiomyoma. Mod Pathol. 2013; 26:743-9.
• [10]Markowski DN, Huhle S, Nimzyk R, Stenman G, Löning T, Bullerdiek J. MED12 mutations occurring in benign and malignant mammalian smooth muscle tumors. Genes Chromosomes Cancer. 2013; 52:297-304.
• [11]Matsubara A, Sekine S, Yoshida M, Yoshida A, Taniguchi H, Kushima R et al.. Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours. Histopathology. 2013; 62:657-61.
• [12]De Graaff MA, Cleton-Jansen A-M, Szuhai K, Bovée JVMG. Mediator complex subunit 12 exon 2 mutation analysis in different subtypes of smooth muscle tumors confirms genetic heterogeneity. Hum Pathol. 2013; 44:1597-604.
• [13]Schwetye KE, Pfeifer JD, Duncavage EJ. MED12 exon 2 mutations in uterine and extrauterine smooth muscle tumors. Hum Pathol. 2014; 45:65-70.
• [14]Markowski DN, Tadayyon M, Bartnitzke S, Belge G, Maria Helmke B, Bullerdiek J. Cell cultures in uterine leiomyomas: rapid disappearance of cells carrying MED12 mutations. Genes Chromosomes Cancer. 2014; 53:317-23.
• [15]Pandis N, Heim S, Bardi G, Flodérus UM, Willén H, Mandahl N et al.. Chromosome analysis of 96 uterine leiomyomas. Cancer Genet Cytogenet. 1991; 55:11-8.
• [16]Sandberg AA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: leiomyoma. Cancer Genet Cytogenet. 2005; 158:1-26.
• [17]Hennig Y, Deichert U, Bonk U, Thode B, Bartnitzke S, Bullerdiek J. Chromosomal translocations affecting 12q14-15 but not deletions of the long arm of chromosome 7 associated with a growth advantage of uterine smooth muscle cells. Mol Hum Reprod. 1999; 5:1150-4.
• [18]Hodge JC, Morton CC. Genetic heterogeneity among uterine leiomyomata: insights into malignant progression. Hum Mol Genet. 2007; 16 Spec No:R7-13.
• [19]Cin PD, Moerman P, Deprest J, Brosens I, Van Den Berghe H. A new cytogenetic subgroup in uterine leiomyoma is characterized by a deletion of the long arm of chromosome 3. Genes Chromosomes Cancer. 1995; 13:219-20.
• [20]Klemke M, Meyer A, Nezhad MH, Bartnitzke S, Drieschner N, Frantzen C et al.. Overexpression of HMGA2 in uterine leiomyomas points to its general role for the pathogenesis of the disease. Genes Chromosomes Cancer. 2009; 48:171-8.
• [21]Holzmann C, Markowski DN, Koczan D, Küpker W, Helmke BM, Bullerdiek J. Cytogenetically normal uterine leiomyomas without MED12-mutations - a source to identify unknown mechanisms of the development of uterine smooth muscle tumors. Mol Cytogenet. 2014; 7:88. BioMed Central Full Text