MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups.
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MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups. / Markowski, Dominique Nadine; Bartnitzke, Sabine; Löning, Thomas; Drieschner, Norbert; Helmke, Burkhard Maria; Bullerdiek, Jörn.
in: INT J CANCER, Jahrgang 131, Nr. 7, 7, 2012, S. 1528-1536.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - MED12 mutations in uterine fibroids--their relationship to cytogenetic subgroups.
AU - Markowski, Dominique Nadine
AU - Bartnitzke, Sabine
AU - Löning, Thomas
AU - Drieschner, Norbert
AU - Helmke, Burkhard Maria
AU - Bullerdiek, Jörn
PY - 2012
Y1 - 2012
N2 - Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates ?-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a "fibroid-type mutation" in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.
AB - Recurrent chromosomal alterations are found in roughly 20% of all uterine fibroids but in the majority cytogenetic changes are lacking. Recently, mutations of the gene mediator subcomplex 12 (MED12) have been detected in a majority of fibroids but no information is available whether or not they co-occur with cytogenetic subtypes as, e.g., rearrangements of the genes encoding high mobility group AT-hook (HMGA) proteins. In a total of 80 cytogenetically characterized fibroids from 50 patients, we were not only able to confirm the frequent occurrence of MED12 mutations but also to stratify two mutually exclusive pathways of leiomyomagenesis with either rearrangements of HMGA2 reflected by clonal chromosome abnormalities affecting 12q14~15 or by mutations affecting exon 2 of MED12. On average the latter mutations were associated with a significantly smaller tumor size. However, G>A transitions of nucleotides c.130 or c.131 correlate with a significantly larger size of the fibroids compared to other MED12 mutations thus explaining the high prevalence of the former mutations among clinically detectable fibroids. Interestingly, fibroids with MED12 mutations expressed significantly higher levels of the gene encoding wingless-type MMTV integration site family, member 4 (WNT4). Based on these findings and data from the literature, we hypothesize that estrogen and the mutated MED12 cooperate in activating the Wnt pathway which in turn activates ?-catenin known to cause leiomyoma-like lesions in a mouse model. The occurrence of a "fibroid-type mutation" in a rare histologic subtype of endometrial polyps suggests that this mechanism is not confined to uterine leiomyomas.
KW - Humans
KW - Aged
KW - Female
KW - Genotype
KW - Cells, Cultured
KW - Base Sequence
KW - Mutation
KW - Chromosome Banding
KW - Recombination, Genetic
KW - Karyotype
KW - Adenomyoma/genetics
KW - Endometrial Neoplasms/genetics/pathology
KW - HMGA2 Protein/genetics
KW - Leiomyoma/genetics
KW - Lipoma/genetics
KW - Mediator Complex/genetics
KW - Polyps/genetics
KW - Uterine Neoplasms/genetics
KW - Wnt4 Protein/genetics
KW - Humans
KW - Aged
KW - Female
KW - Genotype
KW - Cells, Cultured
KW - Base Sequence
KW - Mutation
KW - Chromosome Banding
KW - Recombination, Genetic
KW - Karyotype
KW - Adenomyoma/genetics
KW - Endometrial Neoplasms/genetics/pathology
KW - HMGA2 Protein/genetics
KW - Leiomyoma/genetics
KW - Lipoma/genetics
KW - Mediator Complex/genetics
KW - Polyps/genetics
KW - Uterine Neoplasms/genetics
KW - Wnt4 Protein/genetics
M3 - SCORING: Journal article
VL - 131
SP - 1528
EP - 1536
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 7
M1 - 7
ER -
