Genomics of uterine leiomyomas: insights from high-throughput sequencing

Mehine, Miika; Mäkinen, Netta; Heinonen, Hanna-Riikka; Aaltonen, Lauri A.; Vahteristo, Pia

doi:10.1016/j.fertnstert.2014.06.050

Cited by 177 publications

(150 citation statements)

References 96 publications

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“…In addition, the frequency of FH deletion in our group of leiomyomas was higher than initially reported. 36 In concordance with the literature, MED12 mutations and FH deletions were mutually exclusive in leiomyoma 36 as well as leiomyoma with bizarre nuclei and leiomyosarcoma.…”

Section: Discussionsupporting

confidence: 84%

“…This is in concordance with the literature reporting MED12 mutations in frequencies between 48 and 92%. 36 Our study included an expanded spectrum of leiomyoma subtypes and the results clearly demonstrate that MED12 mutations can occur in all leiomyoma subtypes investigated irrespective of the tumor size. All diagnostically challenging leiomyomas with a prior history of lupron treatment demonstrated a MED12 mutation and minimal genomic alterations demonstrating no significant differences to usual leiomyomas.…”

Section: Discussionsupporting

confidence: 55%

“…Nevertheless, highthroughput sequencing in combination with genetic and cytogenetic data has laid the basis for molecular classification of uterine leiomyomas. 35,36,42 The only known common oncogenic mechanism shared by benign and malignant smooth muscle tumors are mutations in MED12 (refs 24-26,31,35) that are frequently detected in uterine leiomyomas and to a much lesser extent in atypical uterine smooth muscle tumors and uterine leiomyosarcomas, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, one could suggest a potential time-based relationship, a 'pre-malignant' condition, would need to progress to cancer. 31,36,37 However, the vast majority of leiomyoma with bizarre nuclei is treated by hysterectomy and is excised before a putative transformation into clear-cut leiomyosarcoma could occur. Large multicenter studies following patients with leiomyoma with bizarre nuclei over a period of time without surgical treatment to investigate their biology are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Fumarate Hydratase (FH)-deletions and rearrangements of high motility group protein 2 (HMGA2) have been proposed as independent somatic driver mutations in leiomyoma. [35][36][37] The focus of this study was to explore copy number alterations, MED12 mutational status, and FH-deletions in diagnostically challenging smooth muscle tumors with special emphasis on leiomyoma with bizarre nuclei, hormonally treated leiomyoma and uterine leiomyosarcoma.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 84%

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

et al. 2016

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Chromothripsis and Human Genetic Disease

Nazaryan‐Petersen

Tommerup

2016

Encyclopedia of Life Sciences

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Chromothripsis (CTH) is a newly discovered mutational mechanism, which in a single catastrophic event results in localised complex structural rearrangements confined to one or a few chromosomes. After an initial shattering or clustered fragmentation of a chromosomal region, the fragments join together in random order and orientation. During this process some of the generated fragments may be lost. It is not entirely clear which factors trigger the localised fragmentation; however, several mechanisms have been proposed, such as ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei, LINE1‐endonucleases, etc. CTH may disrupt multiple genes and/or regulatory regions. When it is incompatible with cell survival, the result should be apoptosis. However, if a cell escapes apoptosis, the extensive genomic rearrangements may have different phenotypic outcomes: cancer (somatic), congenital and developmental disorders (germline), neutral or even beneficial effects. Key Concepts Chromothripsis is a phenomenon where multiple localised double‐stranded DNA breaks result in complex genomic rearrangements. Chromothripsis occurs within a single cell cycle. Ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei and LINE1‐endonucleases are proposed to have a role in chromothripsis. Chromothripsis in somatic cells may trigger cancer development. Chromothripsis in the germline may result in congenital and developmental disorders.

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Fumarate hydratase mutation associated uterine leiomyomas: A case report and literature review

Zhu,

Li,

Zhuang

et al. 2024

Clinical Case Reports

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Key Clinical MessageThe patient was found to have multiple uterine myomas at the age of 19, underwent laparoscopic myomectomy at the age of 20, and underwent laparotomic myomectomy again at the age of 23 due to the recurrence of uterine myoma. At the age of 25, the patient reappeared with symptoms and recurrence, and was diagnosed with uterine leiomyomas (ULMs) of FH mutation and high‐grade squamous intraepithelial lesion (HSIL/CIN III) with gland involvement, after complete examination. Fumarate hydratase (FH) mutation screening is important when gynecologists encounter patients with early onset and multiple ULMs, it can give early diagnosis and treatment and fertility guidance. The patient had their uterus removed at the age of 26. FH mutation screening is important when gynecologists encounter patients with early onset and multiple ULMs, it can give early diagnosis and treatment and fertility guidance. It is also helpful for early diagnosis of renal cell carcinoma.

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Genomics of uterine leiomyomas: insights from high-throughput sequencing

Cited by 177 publications

References 96 publications

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors

Chromothripsis and Human Genetic Disease

Fumarate hydratase mutation associated uterine leiomyomas: A case report and literature review

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