ABSTRACT
Recently, germline mutations of the fumarate hydratase (FH) gene, in 1q42.1, have been found to be involved in syndromes associated with uterine leiomyomas (ULs). Compelling evidence also supports a genetic liability to develop nonsyndromic UL, although susceptibility genes have not been reported to date. Loss of heterozygosity (LOH) studies have found no or rare evidence of LOH of FH in nonsyndromic UL. However, the karyotypes of these tumors were not reported, and cytogenetic aberrations of 1q42-44 have been observed infrequently in UL. To determine whether FH mutations also may predispose women to developing nonsyndromic UL, we performed a genetic linkage study with DNA from 123 families containing at least one affected sister pair. In addition, to assess the frequency of FH loss specifically in UL with 1q rearrangements, we performed a fluorescence in situ hybridization (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 (Zlr 1.7 at D1S547, P = 0.04). FISH results showed that one copy of FH was absent in 9 of 11 ULs. These data indicate that loss of FH might be a significant event in the pathogenesis of a subset of nonsyndromic ULs.
Subject(s)
Fumarate Hydratase/genetics , Fumarate Hydratase/physiology , Genetic Linkage , Leiomyoma/enzymology , Uterine Neoplasms/enzymology , Adult , Age Factors , Chromosome Banding , Chromosomes, Human, Pair 1 , DNA/metabolism , DNA Primers/metabolism , Family Health , Female , Genetic Predisposition to Disease , Genotype , Germ-Line Mutation , Humans , In Situ Hybridization, Fluorescence , Loss of Heterozygosity , Middle Aged , MutationABSTRACT
The high mobility group gene, HMGA2, is frequently expressed in uterine leiomyomata (UL) with chromosomal rearrangements of 12q15. In contrast, HMGA2 expression has not been detected in karyotypically normal UL or in myometrium, but has been detected in these tissues after culture. To characterize further the expression pattern of HMGA2, we assessed HMGA2 expression by RT-PCR followed by Southern blot hybridization, and by real-time PCR in three tissue panels: (1) primary myometrial cultures, (2) uncultured tissue from 15 karyotypically normal samples consisting of eleven 46,XX UL and four matched myometrial specimens, and (3) uncultured tissue from ten UL with 12q15 rearrangements and three matched myometrial specimens. HMGA2 expression was detected in all samples from the three panels. The level of HMGA2 expression in karyotypically normal UL was similar to the level of expression in myometrium; however, it was significantly less than the level measured in UL with 12q15 rearrangements. This expression analysis by use of detection methods of different sensitivities underscores the importance of studies of HMGA2 expression in uncultured tissues and of careful interpretation of results from experiments on cultured cells. Moreover, detection of HMGA2 expression in myometrium and in UL without 12q15 rearrangements, tissues previously thought not to express HMGA2, suggests that HMGA2 expression is required in normal adult myometrial physiology.
