Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

Abstract

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.

Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets

“…This is consistent with data from other soft tissue sarcomas, in which significantly increased numbers of somatic copy number alteration were reported in leiomyosarcoma. 39 These data confirm prior studies demonstrating that high grade myxofibrosarcoma is among the most highly complex sarcoma types. [19][20][21] Hierarchical clustering based on copy number alterations revealedexcept for two patientsa phylogenetic relationship of tumors/ tumor areas from the same patient.…”

“…The same phenomenon, even if less evident due to low tumor content in the metastatic sample, was observed for P25. Similar data were shown for leiomyosarcoma metastases, 39 as well as for breast cancer, where regional lymph node metastases had a less complex composition compared with their primary indicating that in primary tumors and metastatic cell clones diverge early on during tumor progression and evolve independently. 40 As focal events are meant to be drivers for tumorigenesis and progression we applied our recently published algorithms for the detection of focal events.…”

Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germlineCHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma

“…This result does not support a central role for FH deficiency in the genesis of our patient's LMS, which is essentially in keeping with the leiomyoma subtype with HMGA2 aberrations ( Mehine et al 2016 ). Somatic FH deletion is not an uncommon event in leiomyomas and LMSs, but the exact role of this genomic alteration in smooth muscle tumor malignant progression requires further study ( Liegl-Atzwanger et al 2016 ).…”

Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors

“…These alterations have already been reported in these benign lesions. [36][37][38][39] In fact, some bizarre nuclei leiomyomas inexplicably show rearranged profiles (in our experience lower than leiomyosarcomas) and a good outcome. Furthermore, the origin of this subtype of leiomyoma is not clear either.…”