Uterine leiomyomas, or fibroids, are benign smooth muscle tumours that grow in the womb. In many cases, uterine fibroids are asymptomatic, although can cause heavy bleeding, lower back pain and complications during pregnancy and labour in some cases. Most women with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, caused by mutations in the FH gene, develop uterine fibroids (Lehtonen, 2011). However, fibroids are also common in the general population, with an estimated 77% of women of child bearing age affected in the US (Cramer and Patel, 1990). Risk factors include hormone levels, family history, ethnicity and weight (Flake et al., 2003).
A number of genetic mutations have been observed in uterine fibroids and are thought to be causative: activating point mutations in the MED12 gene (70%) (Mäkinen et al., 2011); translocations involving 12q15, most commonly with 14q24, which increases the expression of HMGA2 (10%) (Ligon and Morton, 2000); deletions of 7q (8%) (Ligon and Morton, 2000); rearrangements involving 6p21 affecting the HMGA1 gene (2.5%) (Ligon and Morton, 2000); and inactivating mutations in FH, which accounts for cases within the context of HLRCC (Lehtonen, 2011), and a small proportion (1.3%) of sporadic cases (Lehtonen et al., 2004). However, the mechanism of how these genetic changes arise and drive disease is unknown.
In order to address this question, Mehine et al. (2013) performed whole genome sequencing on 38 uterine fibroids and matched control tissue from 30 women. While they did not find evidence of any additional predisposition genes, they did observe complex chromosomal rearrangements in 15/38 (40%) samples, suggesting that chromosome shattering (chromothripsis) is a common cause of uterine leiomyomas.
Chromothripsis was first reported by Stephens et al. in 2011, and describes how – in contrast to the traditional model of tumorigenesis where tumours acquire multiple mutations sequentially over time – up to 2-3% of all cancers are caused by a single catastrophic event that produces tens to hundreds of genomic rearrangements. It is thought that mechanical stress causes one or a few chromosomes to shatter into small lengths of DNA, which are then reassembled by DNA repair machinery (Forment et al., 2012). However, due to the extensive damage caused by chromosome shattering, the repair machinery is unable to correctly reassemble the chromosome and attaches DNA fragments in the wrong order, and duplicates some regions while other regions are lost altogether, resulting in a “patchwork” chromosome.
Mehine et al. found that although the chromosomal rearrangements observed in their cohort of uterine fibroids were generally less complex than in previously reported cases of chromothripsis, some samples had up to 20 arrangements, indicating that the rearrangements were likely to be occurring through the same mechanism. This is perhaps surprising as chromothripsis is generally considered to be associated with aggressive cancers with poor prognosis (Forment et al., 2012), whereas uterine fibroids are benign.
Additionally, the authors report that in three of five women with multiple fibroids, the genomic rearrangements in some spatially separated fibroids were the same, suggesting that fibroid cells are able to migrate and seed the growth of new tumours. This is particularly intriguing as this behaviour is typically associated with metastatic cancer cells, whereas uterine fibroids are benign. Furthermore, the metastatic cells in this study did not seem to have increased malignant potential.
Metastasis of benign cells has been reported in lymphangioleiomyomatosis (LAM), where overproliferation of smooth muscle tissue causes lung cyst development. Recurrent disease has been reported in patients with lung transplants, suggesting that LAM cells arise elsewhere and migrate to the lungs (Karbowniczek et al., 2003). Indeed, Jo et al. describe the case of a Korean woman with uterine fibroids that were suspected to have metastasised and formed skeletal muscle, lung and breast tumours, suggesting that the ability to migrate may be a common characteristic of leiomyoma-type cells.
The full extent to which chromothripsis or metastatic behaviour in otherwise benign cells causes disease is not known at present. However, this study suggests that both mechanisms are fairly common in uterine leiomyoma, suggesting that both mechanisms are likely to underpin other diseases as well.
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Forment JV, Kaidi A, & Jackson SP (2012). Chromothripsis and cancer: causes and consequences of chromosome shattering. Nature reviews. Cancer, 12 (10), 663-70 PMID: 22972457
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Jo JH, Lee JH, Kim DC, Kim SH, Kwon HC, Kim JS, & Kim HJ (2006). A case of benign metastasizing leiomyoma with multiple metastasis to the soft tissue, skeletal muscle, lung and breast. The Korean journal of internal medicine, 21 (3), 199-201 PMID: 17017672
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Lehtonen HJ (2011). Hereditary leiomyomatosis and renal cell cancer: update on clinical and molecular characteristics. Familial cancer, 10 (2), 397-411 PMID: 21404119
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Ligon AH, & Morton CC (2000). Genetics of uterine leiomyomata. Genes, chromosomes & cancer, 28 (3), 235-45 PMID: 10862029
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Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, Gentile M, Yan J, Enge M, Taipale M, Aavikko M, Katainen R, Virolainen E, Böhling T, Koski TA, Launonen V, Sjöberg J, Taipale J, Vahteristo P, & Aaltonen LA (2011). MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science (New York, N.Y.), 334 (6053), 252-5 PMID: 21868628
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Mehine M, Kaasinen E, Mäkinen N, Katainen R, Kämpjärvi K, Pitkänen E, Heinonen HR, Bützow R, Kilpivaara O, Kuosmanen A, Ristolainen H, Gentile M, Sjöberg J, Vahteristo P, & Aaltonen LA (2013). Characterization of uterine leiomyomas by whole-genome sequencing. The New England journal of medicine, 369 (1), 43-53 PMID: 23738515
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