Leiomyoma, Uterine

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2019-09-22

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Omim

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A number sign (#) is used with this entry because at least one form of uterine leiomyoma (UL) is known to be due to fusion between an isoform of the recombinational repair gene RAD51B (602948) and the high mobility group protein gene HMGIC (HMGA2; 600698).

Uterine leiomyomas have been observed with other fusion partners of the HMGIC gene, namely ALDH2 (100650), COX6C (124090), and HEI10 (608249). Uterine leiomyomata also occur in association with skin leiomyomata and renal cell cancer on the basis of mutations in the gene encoding fumarate hydratase (FH; 136850; see 150800). There is evidence also that leiomyoma development involves a myofibroblast phenotype characterized by dysregulation of genes encoding extracellular matrix proteins, particularly reduced expression of dermatopontin (125597), a feature shared with keloids (148100).

Cytogenetics

In histologically benign uterine leiomyomas from 34 patients, Heim et al. (1988) found an apparently identical reciprocal translocation t(12;14)(q14-15;q23-24) in the tumors of 4 patients. A fifth patient showed a t(2;14)(p11;p11). In 22 cases the tumor had a normal female complement, and in the remaining 7 tumors, no karyotype could be established.

Vanni and Lecca (1988) found a translocation t(X;12)(p22.3;q15) in a single uterine leiomyoma and suggested that the 12q14-q15 region may have 1 or more genes involved in neoplastic proliferation inasmuch as the same area has been involved in pleomorphic salivary gland adenoma (181030) and in adipose tumors (151900).

Schoenmakers et al. (1999) demonstrated that an unusual isoform of the RAD51B gene on 14q23-q24 is the preferential translocation partner of HMGIC in uterine leiomyomas with a translocation t(12;14).

Pathogenesis

To study the molecular mechanisms involved in the pathogenesis of uterine leiomyomas, Lessl et al. (1997) determined the transcript levels of the immediate early genes c-fos (164810), c-myc (190080), and c-jun (165160), and of the estrogen receptor (ESR; 133430) and progesterone receptor (PGR; 607311), in tissue samples of human myometrium and leiomyoma. They found a distinct and significant reduction of c-fos mRNA in the tumor. These data were substantiated by their finding lower c-fos protein levels in leiomyomas and less abundant transcripts of c-jun and c-myc in most leiomyoma when compared to myometrium samples. Immunohistochemical studies for ESR and PGR protein confirmed these results. The authors concluded that deregulated expression of protooncogenes, especially of c-fos, is linked to the pathogenesis of leiomyomas.

To investigate the molecular pathogenesis of uterine leiomyomas, Mao et al. (1999) performed an allelotype of 102 leiomyomas from 12 patients, using 67 fluorescently-tagged oligonucleotide primers amplifying microsatellite loci covering all autosomes. No areas of the genome showed frequent loss of heterozygosity (LOH); however, the highest rate of LOH (9%) was observed on 7q, consistent with previous cytogenetic observations. Uterine leiomyomas are sometimes multiple, and in general, multiplicity of other types of neoplasm is associated with genetic predisposition to the disease. Because multiple tumors were available from each of the 12 patients studied, Mao et al. (1999) looked for evidence of allele-specific LOH, which might indicate the presence of an underlying predisposition gene. However, no evidence for allele-specific LOH was detected, indicating that if cases of multiple uterine leiomyomas are due to an underlying predisposition gene, it is unlikely to be a recessive oncogene.

Mapping

Hodge et al. (2009) analyzed the (TC)n repeat in the 5-prime UTR of the HMGA2 gene and 17 SNPs spanning the HMGA2 gene in 248 white families with sister-pairs affected with uterine leiomyomata and identified a significant association between transmission of a single TC repeat allele, TC227, corresponding to 27 TC repeats, and development of UL (corrected p = 0.0049). The same TC227 repeat was also associated with decreased stature (611547).

Associations Pending Confirmation

Cha et al. (2011) conducted a genomewide association study in which 457,044 SNPs were analyzed in 1,607 individuals with clinically diagnosed uterine fibroids and 1,428 female controls. SNPs showing suggestive associations (p less than 5 x 10(-5)) were further genotyped in 3,466 additional cases and 3,245 female controls. Three loci on chromosomes 10q24.33, 22q13.1, and 11p15.5 revealed genomewide significant associations with uterine fibroids. The SNPs showing the most significant association in a combination analysis at each of these loci were rs7913069 (p = 8.65 x 10(-14), odds ratio = 1.47), rs12484776 (p = 2.79 x 10(-12), odds ratio = 1.23), and rs2280543 (p = 3.82 x 10(-12), odds ratio = 1.39), respectively.

A genetic component to uterine leiomyomata predisposition is supported by analyses of ethnic predisposition, twin studies, and familial aggregation. Eggert et al. (2012) genotyped and analyzed a genomewide SNP linkage panel in 261 white uterine leiomyomata-affected sister-pair families from the Finding Genes for Fibroids study. Two significant linkage regions were detected, in 10p11 (lod = 4.15) and 3p21 (lod = 3.73), and 5 additional linkage regions were identified with lod scores greater than 2.00. GWAs were performed in 2 independent cohorts of white women, and a metaanalysis was conducted. One SNP (rs4247357) was identified with a p value that reached genomewide significance (p = 3.05 x 10(-8), odds ratio = 1.299). The candidate SNP is under a linkage peak and in a block of linkage disequilibrium in chromosome 17q25.3, which spans the genes fatty acid synthase (FAS; 600212), coiled-coil domain-containing protein-57 (CCDC57), and SLC16A3 (603877). By tissue microarray immunohistochemistry, Eggert et al. (2012) found elevated (3-fold) FAS levels in uterine leiomyomata-affected tissue compared to matched myometrial tissue. FAS transcripts and/or protein levels are upregulated in various neoplasms and implicated in tumor cell survival.

Molecular Genetics

Because mutations in the gene encoding fumarate hydratase (FH) underlie syndromic forms of uterine leiomyomas, namely multiple cutaneous and uterine leiomyomata (150800), Gross et al. (2004) investigated whether mutations in the FH gene may predispose women to developing nonsyndromic UL. They performed a genetic linkage study with DNA from 123 families containing at least 1 affected sister pair. In addition, to assess the frequency of FH loss specifically in UL with 1q rearrangements, they performed a FISH analysis of UL with 1q rearrangements. Analysis of the genotyping data revealed evidence suggestive of linkage to the FH region among study participants who were less than 40 years of age at diagnosis (p = 0.04). FISH results showed that 1 copy of FH was absent in 9 of 11 ULs. Gross et al. (2004) concluded that loss of FH may be a significant event in the pathogenesis of a subset of nonsyndromic ULs.

Makinen et al. (2011) performed whole-exome sequencing on 18 uterine leiomyomas derived from 17 different patients and identified tumor-specific mutations in the MED12 gene in 10. Analysis of 207 additional tumors identified mutations in MED12 (300188), a subunit of the Mediator complex, in 70% (159/225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex (see 180660). All mutations identified by Makinen et al. (2011) resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis.