Genetic aberrations in soft tissue leiomyosarcoma

Yang, Jilong; Du, Xiaoling; Chen, Kexin; Ylipää, Antti; Lazar, Alexander J.; Trent, Jonathan C.; Lev, Dina; Pollock, Raphael E.; Hao, Xishan; Hunt, Kelly K.; Zhang, Wei

doi:10.1016/j.canlet.2008.06.013

Cited by 99 publications

(76 citation statements)

References 39 publications

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“…The involvement of RB1 in pathogenesis of different malignancies as well as a role for RB1 in leiomyosarcoma is a frequent reported finding. [47][48][49] In contrast, a loss in 13q was only detected in a single leiomyoma indicating a potential use of intact RB as a surrogate marker for leiomyomas. Confirmation of this finding in a larger number and variety of leiomyomas is warranted.…”

Section: Discussionmentioning

confidence: 96%

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

et al. 2016

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Smooth muscle tumors of the uterus are a diagnostically challenging group of tumors. Molecular surrogate markers reliably distinguishing between benign and malignant tumors are not available. Therefore, the diagnosis is based on morphologic criteria. The aim was to investigate a well-characterized group of challenging uterine smooth muscle tumors consisting of 20 leiomyomas, 13 leiomyomas with bizarre nuclei, and 14 leiomyosarcomas for copy number alterations, MED12 mutations and FH deletions to search for potential diagnostically useful surrogate markers. MED12 mutations were detected in 47, 15, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. MED12 mutations in leiomyomas with bizarre nuclei were detected outside the hotspot region. FH-deletions were seen in 27, 30.8, and 25% of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas, respectively. By using copy number alteration profiling a clear separation of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas could not be observed. Copy number alterations revealed clear genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas. Leiomyosarcomas showed a similar pattern of gains and losses as leiomyomas with bizarre nuclei, with additional copy number alterations and more homozygous losses and high-level amplifications compared to leiomyomas with bizarre nuclei. In conclusion, this study demonstrates that known FH-deletions, a recurrent molecular change in leiomyomas, occur in morphologically challenging variants of leiomyomas, leiomyomas with bizarre nuclei and leiomyosarcomas. Although MED12 mutations are common in leiomyomas, they infrequently occur in leiomyomas with bizarre nuclei and leiomyosarcomas. The genetic similarities between leiomyomas with bizarre nuclei and leiomyosarcomas raise the intriguing possibility that uterine leiomyomas with bizarre nuclei and leiomyosarcomas are closely related and challenge the traditional concept that leiomyoma with bizarre nuclei is a tumor with just marked 'degenerative' cellular changes. These findings support the hypothesis that tumor progression within uterine smooth muscle tumors might occur.

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Section: Discussionmentioning

confidence: 96%

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

et al. 2016

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“…None of these genes has convincing tumorigenic roles in leiomyosarcoma, and the tumor genes implicated thus far in leiomyosarcoma, including TP53, MDM2, CDKN2A, RB1, and JUN, are ubiquitous oncogenes and tumor suppressors in human cancers rather than being specific for smooth muscle neoplasia. 18 Nonetheless, occasional cases of leiomyosarcoma are reported to arise from leiomyoma, [19][20][21][22] and the possibility of biological continuum between certain leiomyoma and leiomyosarcoma is suggested by existence of histologically and clinically intermediate lesions-including cellular leiomyoma, atypical leiomyoma, leiomyoma with increased mitotic activity, STUMP, intravascular leiomyomatosis, and benign metastasizing leiomyoma. These observations suggest that certain uncommon leiomyoma subtypes have potential for progression to bona-fide leiomyosarcoma.…”

Section: Discussionmentioning

confidence: 99%

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

et al. 2013

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Leiomyoma and leiomyosarcoma share morphological features and smooth muscle differentiation, and both arise most frequently within the uterine corpus of middle-aged women. However, they are considered biologically unrelated tumors due to their disparate clinical, cytogenetic, and molecular features. MED12, the mediator complex subunit 12 gene, has been recently implicated as an oncogene in as many as 70% of sporadic uterine leiomyoma. In the present study, we show MED12 hotspot exon 2 mutations in extrauterine leiomyoma (3 of 19 cases) and in leiomyosarcoma (3 of 13 uterine cases). We also show that MED12 mutations are found in both primary and metastatic leiomyosarcoma. Immunoblotting studies demonstrated MED12 protein expression in 100% of leiomyomas (13) Keywords: fibroid; leiomyoma; leiomyosarcoma; MED12; oncogene; smooth muscle tumor; uterus Seventy percent of women in the general population develop uterine leiomyomas, 1 and B25% of women experience substantial symptoms from these tumors, leading to over 200 000 hysterectomies annually in the United States. 1 By contrast, uterine leiomyosarcomas are infrequent, with an estimated incidence of 0.64 per 100 000 women. Nonetheless, uterine leiomyosarcomas are among the most common sarcomas, accounting for 2-5% of tumors of the uterine body. [2][3][4] There is substantial morphological overlap between leiomyoma and low-grade spindle cell leiomyosarcoma, and diagnostic distinction between these entities relies on histopathological criteria, including nuclear atypia, mitotic activity, and tumor cell necrosis. 5 Morphological variants and unusual features can further complicate the diagnosis between leiomyoma versus leiomyosarcoma, as in smooth muscle tumors of uncertain malignant potential that cannot be unequivocally classified as benign or malignant. 6 Recently, somatic mutations affecting MED12 (the mediator complex subunit 12 gene) were discovered in B70% of sporadic uterine leiomyoma. 7,8 Mediator is a modular protein complex of 25 subunits that regulates RNA polymerase II-mediated transcription, thereby orchestrating cell development and survival in cooperation with CDK8. 9,10 MED12 is located on chromosome sub-band Xq13.1 and is composed of 45 exons, although all MED12 mutations thus far described in uterine leiomyoma have affected exon 2 exclusively, with mutation hotspots in codons 36-44.In the present study, we analyzed leiomyomas and leiomyosarcomas of various biological behaviors and anatomical locations to better determine the relevance of MED12 exon 2 mutations across a broad spectrum of smooth muscle neoplasia. In these studies, we also determined whether MED12 expression is dysregulated in smooth muscle neoplasia compared with a normal myometrium control. These studies demonstrate that MED12 mutations are the first known oncogenic mechanism shared by uterine and extrauterine leiomyoma and uterine leiomyosarcoma.

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“…Subsequently, a search for a common genomic aberration was undertaken. Even though genomic imbalances are common in LMS, with the estimated occurrence exceeding 90%, no consistent, recurrent aberrations have yet been observed at the chromosomal level [3][4][5][6]. The majority of tumors have complex karyotypes, presenting with numerous gains and losses, including an amplification at 17p [3][4][5][6].…”

Section: Discussionmentioning

confidence: 99%

“…Chromosome 17p gains are presumed to be relatively common in LMS, with the estimated frequency of 33-55% [4]. Proximal 17p gains frequently occur also in other sarcomas, including osteosarcoma, chondrosarcoma and malignant fibrous histiocytoma [3,5].…”

Section: Discussionmentioning

confidence: 99%

Primary leiomyosarcoma of the mesentery in two sisters: clinical and molecular characteristics

Koczkowska¹,

Lipska²,

Grzeszewska³

et al. 2013

pjp

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Mesenteric leiomyosarcoma (LMS) is a very rare malignancy whose familiar occurrence has not yet been reported. We present two sisters who developed intestinal LMS. Pathological analysis of the tumor samples, including evaluation of smooth muscle actin+, desmin+, Myf4-, DOG-1-, S100-, CD34-and CD117-confirmed LMS diagnosis. Molecular analysis of the lesions, both primary tumors and a liver metastasis, revealed several genomic imbalances, with recurrent chromosomal aberration: interstitial gain at chromosome 17p11.2-13.1 with the minimal overlapping region of 9.2 Mb. Our study provides further evidence for the significant role of the genes located in this region in the early stage of carcinogenesis.

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Genetic aberrations in soft tissue leiomyosarcoma

Cited by 99 publications

References 39 publications

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

Primary leiomyosarcoma of the mesentery in two sisters: clinical and molecular characteristics

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