USP18 null mice and the derived cell lines represent clinically-relevant models of leiomyosarcoma and can provide insights into both leiomyosarcoma biology and therapy.
USP18 null mice and the derived cell lines represent clinically-relevant models of leiomyosarcoma and can provide insights into both leiomyosarcoma biology and therapy.
MED12 mutations were the most common alterations in conventional and mitotically active leiomyomas and leiomyosarcomas, while leiomyomas with bizarre nuclei were most often FH deficient and cellular tumors showed frequent HMGA2 overexpression.
Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.
Abnormal p53 staining patterns (strong/diffuse or null) were observed in six of 12 (50%) myxoid and six of 11 (55%) conventional leiomyosarcomas but none of the IMT (P < 0.0001), correlating with TP53 mutation/deletion (P = 0.0001).
MED12 mutations are restricted to benign smooth muscle tumours (leiomyomas) of the uterus or of the Müllerian system, but decreased protein expression has also been observed in uterine leiomyosarcomas independently of mutational status, suggesting a possible epigenetic mechanism.
Furthermore, the low but existing risk of MED12-mutated fibroids to undergo malignant transformation after a leiomyoma-STUMP (smooth muscle tumors of uncertain malignant potential)-leiomyosarcoma sequence excludes the latter mutation as a suitable stand-alone marker for benign growth.
We have reported that mesenchymal stromal/stem cells (MSCs) deficient for p53 alone or together with RB (p53(-/-)RB(-/-)) originate leiomyosarcoma after subcutaneous (s.c.) inoculation.
MED12 mutations were detected in 54% of classical uterine leiomyomas (15/28) and in 15% of cases in myometrium adjacent to leiomyomas (2/13); 34% of leiomyoma/leiomyomatosis in pelvic/retroperitoneal sites (10/29); 0% of extrauterine leiomyomas (0/29); 8% of smooth muscle tumor of uncertain malignant potential (1/12); 30% of uterine leiomyosarcomas (6/20); and 4% of extrauterine leiomyosarcomas (1/25).
(2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC).
Among uterine smooth muscle tumours, MED12 mutations are frequently present in conventional leiomyomas, but are significantly less common in histological variants of leiomyoma and leiomyosarcoma.
Immunoblotting studies demonstrated MED12 protein expression in 100% of leiomyomas (13) and leiomyosarcomas (20), irrespective of MED12 exon 2 mutation status or histological grade.
To further address the occurrence of fibroid-type MED12 mutations in smooth muscle tumors, we have analyzed samples from 34 leiomyosarcomas (LMS), 21 UL, two extrauterine leiomyomas (EL), and 10 canine genital leiomyomas for the presence of MED12 mutations of the UL-type.
The lack of mediator complex subunit 12 mutations in extrauterine leiomyomas and leiomyosarcomas indicates that these tumors arise through a different pathway, emphasizing the genetic heterogeneity of smooth muscle tumors.
Interestingly all classical leiomyomas exhibit MED12 protein expression while 40% of atypical leiomyomas, 50% of STUMP and 80% of leiomyosarcomas (among them the two mutated ones) do not express MED12.