Uterine Leiomyoma: Updates in Cytogenetics
and Molecular Analysis
NeoGene Laboratory, Department of Urology, Faculty of Medicine, UNESP
INTRODUCTION
Uterine leiomyomas are benign tumors of the uterus that
arise from the smooth muscle cells of the myometrium,
considered the most common neoplasms of the female
genital tract. They also are often referred as myomas, uterine
fibroids, fibromas or fibromyomas because of their firm,
fibrous character and frequently high content of collagen
fibers.
These tumors can be solitary or multiple, varying in size
and are classified according to their location within the
uterus. The most common type, the intramural fibroid, is
located within the myometrium and results in an irregular
increase in uterine size. As a fibroid enlarges, it may expand
towards the uterine surface, at which point it would be
considered subserous, and may even infarct if it becomes
pedunculated. In contrast, submucosal tumors can grow
Key words: uterine leiomyomas, chromosomal
abnormalities, molecular alterations, genetic susceptibility,
clonality.
Correspondence to: Silvia Regina Rogatto, PhD, NeoGene Laboratory, Departamento of Urology, Faculty of Medicine - UNESP
18618-000 Botucatu, So Paulo, Brazil.
Austral
Telephone: - Asian Journal
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Cancer ISSN-0972-2556,
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6271, E-mail:
rogatto@fmb.unesp.br
Renata de Azevedo Canevari, Silvia Regina Rogatto
So Paulo University State, Botucatu, Brazil
into the uterine cavity, causing attenuation of the
endometrium, and are most often associated with bleeding
abnormalities even at an early stage of tumor development.1
In some women leiomyomas remain small, isolated and slow
growing and in others these tumors are large, multiple and
rapidly growing; the reason for the difference in size and
number remains one of the many mysteries of leiomyoma
etiology.
Regardless of their generally benign neoplastic character,
with patients usually asymptomatic, these tumors are
responsible for significant morbidity and represent a major
public health issue. They are the major cause of
hysterectomy2 or other surgical or medical interventions in
patients that show clinic alterations.3
The biological sequelae of leiomyomas can manifest with
a spectrum of clinical symptoms that include excessive
menstrual bleeding, pressure and increased abdominal
swelling, severe pelvic pain, anemia, urinary incontinence
and may lead to infertility, spontaneous abortions and
premature labor.3-5 The incidence and severity of these
symptoms associated with these tumors vary with their growth
patterns, locations, size, and number.6, 7
The idea that a leiomyoma may cause abnormal uterine
bleeding at any size and in any location within the uterus is
in agreement with recent studies into the pathogenesis of
January 2007
15
Silvia Regina Rogatto
these tumors in relation to bleeding, which suggest that it is
not the increased surface area of the endometrium or local
compression of vessels that causes the bleeding.8-10 Instead,
the likely cause of the problem appears to be growth factor
dysregulation causing uterine vascular dysfunction.8, 11
The comparison of leiomyoma to cancer is tenuous, since
this tumor rarely progresses to malignancy. In a study with a
series of 1,332 women who underwent hysterectomy or
myomectomy for symptomatic leiomyomas,12 the frequency
of uterine sarcomas (leiomyosarcoma, endometrial stromal
sarcoma, and mixed mesodermal tumor) was found to be
0.23%. Taking into account that only a small percentage of
women with uterine leiomyomas are symptomatic and may
require surgery, a more realistic figure for malignancy with
presumed uterine leiomyomas is probably much smaller than
the rates cited above.
In fact, controversy exists whether uterine sarcomas arise
from malignant degeneration of preexisting benign
leiomyomas or de novo as primary malignancies unrelated
to benign leiomyoma.5, 9, 10, 13 Although benign leiomyomas
and sarcomas may coexist in the same patient, cytogenetic
studies have demonstrated that chromosome
rearrangements in leiomyomas are distinct from the complex
rearrangements and aneuploid karyotypes characteristic of
leiomyosarcomas, suggesting that leiomyosarcomas arise de
novo via distinct pathogenetic pathways.5, 9, 14-16
Quade et al.17 using microarrays of oligonucleotides
representing 7000 unique probe sets, suggested that the
molecular pathways in leiomyoma and leiomyosarcoma were
distinct. In contrast, Christacos et al.18 identified a rare subset
of leiomyomas with deletions of chromosome 1 that have
transcriptional profiles that cluster with those of
leiomyosarcomas, suggesting that some uterine
leiomyosarcomas may in fact arise from a specific subset of
leiomyomas.
In recent years, a large number of studies have reported
the basic biological aspects of these benign tumors. In this
review, we summarize the current understanding of
cytogenetic and molecular alterations with respect to their
contributions to the development of these tumors.
EPIDEMIOLOGY OF UTERINE
LEIOMYOMA
Despite its major impact on gynecological morbidity and
high frequency, the etiology of uterine leiomyoma remains
poorly understood. Epidemiological studies suggest that risk
is inversely associated with parity, age at menarche and age
at menopause, whereas obesity, African-American ethnicity,
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 6, No.1, January 2007
late reproductive age, familial history and null parity are
associated with increased risk.19
Parity is a significant risk factor, with age at the birth of the
last child being inversely associated with risk, suggesting
that pregnancy may remove nascent tumors or promote
regression.9, 20-24 Given this finding, it is not surprising that
infertility is associated with an increased risk of leiomyomas.
It is unclear, however, whether infertility is the cause or the
result of leiomyomas.22, 25 Another example is menopause;
the lack of circulating estrogen decreases leiomyoma size
and may protect against their further development.26
Expressed in terms of clinical prevalence, most authors
agree that leiomyomas occur in about 20% to 40% of
reproductive-age women.5, 9, 27 These studies reporting the
frequencies of leiomyomas are most often based on rates of
diagnosis in symptomatic individuals by traditional
diagnostic techniques, like ultrasound or by pathological
review of hysterectomy specimens. It is unclear if the use of
these methods accurately approximates the true incidence
of leiomyomas. One study performed by Cramer and Patel28
estimated that up to 77% of women of reproductive age
have leiomyomas.
Although the initiating factors that lead to the
development of myomas are not known, there is a great
deal of evidence showing that the ovarian steroids, estrogen
and progesterone are important factors for tumor
growth.5, 22, 29-31 These tumors exhibit maximum growth
during a womans reproductive life when estrogen secretion
is maximal, demonstrating a decline in menopause and
under other hypoestrogenic conditions. Other evidence
supporting estrogen dependence of uterine leiomyoma is
the elevated levels of estrogen and progesterone receptors
found in adjacent myometrium.32-34 Postmenopausal women
have a 70% to 90% decreased risk of leiomyomas compared
with women in their forties and fifties.22 Some studies
hypothesize that leiomyoma risk in obese women is related
to an increase in circulating estrogen levels, as compared to
those in non obese women, because fat cells sequester
estrogen. This same mechanism holds true for women who
attained menarche at a 6 younger age; women experience
increased risk the earlier they are exposed to estrogen.26
The role of progesterone in the pathogenesis of uterine
myomas is somewhat confused. Some reports suggest that
progesterone may inhibit the formation and growth of
uterine leiomyomas, whereas other studies conclude that
progesterone stimulates fibroid growth.35
Although there is general agreement that estrogen and
progesterone are involved in leiomyoma growth, several
16

observations suggest that other local factors must be involved
in its pathogenesis.35 Many growth factors are elevated in
uterine leiomyomas, such as the transforming growth factor-
b, heparin-binding growth factor group, that include the
basic fibroblast growth factors, heparin-binding epidermal
growth factor, vascular endothelial growth factor and
platelet-derived growth factor, and a third group that show
alterations in expression of the insulin-like growth factors.
These growth factors regulate the proliferation,
differentiation, apoptosis, and extracellular matrix
production of the smooth muscle cells and regulate
proliferation and migration of vascular endothelial cells.36, 37
SUSCEPTIBILITY GENE IN UTERINE
LEIOMYOMA
Epidemiological data has demonstrated an inherited
predisposition to the development of uterine leiomyomas.
Inherited genetic abnormalities that predispose some
women towards leiomyoma development could be suggested
by the presence of multiple leiomyomas in the same uterus.38
Since tumor multiplicity is commonly a feature of cancer
predisposition syndromes, patients with multiple leiomyomas
may carry a mutated allele for a gene that confers a
predisposition to uterine leiomyomas.
Several evidential factors, such as racial predisposition,
familial aggregation, twin studies and associations of the
trait with known inherited syndromes, suggest that the
development of uterine leiomyoma has a strong genetic
basis, providing additional support for the existence of gene
susceptibility for their developing.39-42 However, no specific
susceptibility genes have been identified to date. The high
frequency of sporadic uterine leiomyomas in the general
population and the fact that many women with the disease
are asymptomatic, make it difficult to identify the gene
involved in the predisposition towards uterine leiomyoma.43
The possibility of such genetic liability has been supported
by cytogenetic and epidemiological data. Firstly, when
compared to other ethnic groups, women of African-
American descent are at higher risk of uterine fibroids, with
a 2- to 9-fold greater risk of developing these tumors than
women of Caucasian descent.1,9, 22, 25, 44 Usually in these
woman, the myomas tend to be larger, more numerous and
more severe. These women also tend to develop symptomatic
leiomyomas earlier than Caucasian women,9, 44 and therefore
tend to undergo definitive surgeries such as hysterectomies
at an earlier age. In one study, 73% of African-American
women recruited at random to receive a transvaginal
ultrasound were found to have leiomyomas compared to
48% of Caucasian women. 9 In a randomly selected
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 6, No.1, January 2007
Uterine Leiomyoma: Updates in Cytogenetics and Molecular Analysis
population of 1364 women aged 35 to 49 from the United
States, one study showed an estimated cumulative
leiomyoma incidence of greater than 80% in black women
and nearly 70% in Caucasian women.44 Although data are
not as readily available for other ethnic groups, rates of
leiomyomas appear to be similar in white, Hispanic and Asian
women.10
Secondly, women with a positive family history of myomas
also have a 1.5- to 3.5-fold greater risk of developing these
lesions than women without a family history.1, 22, 45 Women
from families in which two first-degree relatives have
leiomyomas showed a two-fold increased risk of developing
these tumors.46, 47 In one study of Japanese middle-aged
women, a positive first-degree history of leiomyoma was more
common in women who had this tumor than in those without
it (31.5% versus 15.2%).48 Okolo et al.49 designed a study to
compare the clinical and molecular features of uterine fibroids
with a familial prevalence and those without it. Familial
prevalence of uterine fibroids was associated with a different
pattern of clinical features when compared with leiomyomas
that occurred sporadically in families, demonstrated by
different rates of abdominal swelling, dysmenorrhea,
menorrhagia and family history of cancers. The authors
concluded that whatever triggers the transformation of an
abnormal myocyte is more common or stronger in families
with a prevalence of leiomyomas, leading to twice the number
of such tumors when compared with families in which
leiomyomas occur sporadically. In addition, familial
prevalence was associated with a multiplicity of leiomyomas,
which may explain the common clinical presentation of
abdominal swelling in such women. However, these authors
found that the heritability of leiomyomas is not race-
dependent, since the racial distribution of women in both
familial and sporadic groups was similar.
Thirdly, twin-pair studies that compared rates of
hysterectomy in monozygotic twins with those in dizygotic
twins, found a 2-fold higher correlation for hysterectomy in
monozygotic twins, strongly suggesting a genetic
predisposition for conditions treated by hysterectomy.39, 50
Following studies of many large families with multiple
affected individuals, it may be argued that inheritance of a
predisposition towards leiomyoma is autosomal dominant,
autosomal recessive or X-linked dominant. However,
definitive proof of any of these modes of inheritance does
not exist at this time. Clearly, an important avenue of future
research into the heritability of leiomyoma will involve
studying affected women and their first-degree relatives
who also have uterine leiomyomas.1
The existence of an inherited factor in the etiology of
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Silvia Regina Rogatto
leiomyoma is also suggested by the association of
characteristic with specific hereditary syndromes, that
involve multiple types of smooth muscle tumors, including
uterine leiomyomas.1, 45 Multiple cutaneous and uterine
leiomyomata is an autosomal dominant disorder
characterized by the development of leiomyomas in the
skin and uterus of affected women, and in the skin of
affected men. In rare cases, uterine leiomyomata has been
associated with a predisposition to the rare type II papillary
renal cell cancer, also known as hereditary leiomyomatosis
and renal cell cancer. The genetic locus for uterine
leiomyomata has been mapped to chromosome 1q42.3-43
and subsequently, germline mutations in the fumarate
hydratase (FH) gene have been identified. Recently, it was
shown that germline mutations of the fumarate hydratase
(FH) gene51 are responsible for the inherited syndromes of
multiple cutaneous and uterine leiomyomas (Reeds
Syndrome) (MCULs; OMIM 150800,
www.ncbi.nlm.nih.gov/Omim)52, 53 and of hereditary
leiomyomatosis and renal cell cancer (HLRCC; OMIM
605839).54 Since the FH gene has been found to be involved
in both MCUL and HLRCC, it has been proposed that
MCUL and HLRCC are the same disorder.55
The incidence of FH mutations in patients presenting with
uterine leiomyomas is unknown, although MCUL in patients
suggests that because uterine leiomyomas, unlike skin
leiomyomas, are very common and are usually not part of a
syndrome, even patients with a previous history of skin
leiomyomas presenting with leiomyomas are often not
recognized by managing clinicians as suffering from MCUL.
Thus a proportion of patients presenting with leiomyomas
may, if examined, be found to have skin leiomyomas and
have classic MCUL, although the low incidence of FH
mutations found in uterine leiomyoma suggests that this is
uncommon.56-59
Taken together, these data strongly suggest a genetic
component in the etiology of leiomyomas. Clearly, the
research of women with uterine leiomyoma and their
firstdegree relatives who also have these tumors not only
will hasten cytogenetic and molecular studies, but will also
be crucial to dissecting and defining the genetic loci that
undoubtedly contribute to the development of uterine
leiomyoma.
CYTOGENETIC ALTERATIONS IN
UTERINE LEIOMYOMA
A variety of clonal chromosome rearrangements are
associated with uterine leiomyoma. To date, more than 400
uterine leiomyomas with clonal chromosome alterations
have been cytogenetically studied by G-banding.60 These
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analyses have shown that 40% show karyotypically
detectable chromosomal abnormalities that are both
nonrandom and tumor-specific.1, 14, 19, 61-65 The majority of
uterine leiomyomas (approximately 60%) are karyotypically
normal, however, suggesting that cytogenetic aberrations
in uterine leiomyoma may be secondary changes in
genetically susceptible cells.50
Unless leiomyomas are caused by a cryptic genetic change,
which has remained unknown, the cytogenetic and
molecular genetic abnormalities described to date indicate
heterogeneity among these tumors. The pathological and
clinical heterogeneity of leiomyomas is reflected in the
cytogenetic findings in these tumors; however, within this
heterogeneity, chromosomally well-defined subgroups exist
that include deletions in 7q21-q32, rearrangements of 12q14-
q15, mainly the t(12;14)(q14-15;q23-24), trisomy 12,
rearrangements involving 6p21-p23, 10q23, 13q13-q22, and
deletions of 3q.14, 15, 61, 63, 66-72 Although these studies
demonstrated nonrandom gene-directed chromosomal and
cytogenetic alterations in leiomyomas, the results are
inconsistent with regard to the incidence of such changes,
their correlation to tumor size and whether such gross
rearrangements are primary or secondary events in the
development of fibroids.1
The most common chromosomal aberration in leiomyoma,
seen in approximately 20% of karyotypically abnormal
leiomyomas, is the characteristic translocation, t(12;14)(q14-
15;q23-24), specifically associated with leiomyoma.63, 73, 74
Other rearrangements involving 12q14-q15, such as
paracentric inversions, have also been observed.75-77 Besides
the involvement of chromosome 12 in the t(12;14),78-81
trisomy 12 is not an uncommon cytogenetic change in
leiomyomas, present in 12% of the alterations reported in
uterine leiomyomas.
An interstitial deletion of chromosome 7, del(7)(q21-q32),
is observed with a frequency of about 17% in karyotypically
abnormal leiomyomas. 72, 82-86 This deletion and the
rearrangements involving band 7q22, have been found more
consistently in leiomyomas than in any other tumor.83 The
finding of this anomaly as the sole alteration in some
leiomyomas indicates its possible role as an early genetic
event.43 In addition, del(7) may be associated with t(12;14)
or t(1;6),82, 87 suggesting the involvement of del(7) in the
karyotypic evolution of leiomyoma, although t(12;14) can
be observed as a sole change. 88 Chromosome 7
rearrangements other than deletions have also been
documented in leiomyomas and include various
translocations, implicating 7q22 as the pathogenesis region.83
Alterations involving the short arm of chromosome 6 (6p21)
18

have also been reported in uterine leiomyomas.
Rearrangements of this region occur with a frequency of
less than 5% and include t(1;6)(q23;p21), t(6;14)(p21;q24),
and t(6;10)(p21;q22), 89 as well as inversions and
translocations with other chromosomal partners.14,87,89,90
A variety of other cytogenetic abnormalities have been
reported in leiomyomas but with lower frequency. These
include changes of the chromosomes X, 1, 3, 10 and
13.60, 66, 69, 71, 91-93 Cases involving the X-chromosome,
preferentially the region Xp11-p22, include del(X)(p11.2),
t(X;12)(p22.3q15), -X, del(X)(q12) and inv(X)(p22q13).1, 93
There have also been reports of structural rearrangements
involving chromosome 1. Ring chromosomes have been
found in a few uterine leiomyomas, but they usually occur
concomitantly with other chromosomal changes and are
therefore thought to represent secondary abnormalities.75, 94, 95
Several different rearrangements of chromosome 3,
including insertions, long and short arm deletions, and
translocations with chromosome 7, have been found in
uterine leiomyoma. Chromosome 3 rearrangements are
noted to occur both singularly and concomitantly with
rearrangements on other chromosomes. Monosomy 10 and
deletions especially affecting the band 10q22, have also
been observed in these tumors. Deletions of the long arm of
chromosome 13 can occur alone or with other
rearrangements. To date, no obvious relevant candidate
genes have been identified in these chromosomes as
performing a role in uterine leiomyoma.
Although the exact significance of these chromosome
changes has not been rigorously established in all subgroups,
they can be used as a guide to studies attempting to decipher
the causative molecular events within subgroups of
leiomyoma.
An interesting question arising from cytogenetic
classification of leiomyomas with abnormal karyotypes is
whether there are correlations between tumor genotype
and clinical phenotype. Although neither a relationship
between patient age or parity and the type of chromosomal
abnormality has yet been identified, one study showed that
the presence of cytogenetic rearrangement correlates with
larger tumor size and anatomic location of the uterine
leiomyoma.96 This study showed that intramural and
subserosal tumors have more rearrangements than
submucosal leiomyoma, 35%, 29% and 12%, respectively.
Although these results imply that submucosal leiomyomas
are smaller because of their lower frequency of chromosomal
rearrangement, these tumors can be highly symptomatic;
for example, they are more often associated with
menorrhagia as a result of their anatomic proximity to the
endometrium.
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Uterine Leiomyoma: Updates in Cytogenetics and Molecular Analysis
Another study performed by Rein et al.97 and Henning et
al.98 convincingly showed a relationship between karyotype
and leiomyoma size, where tumors with a deletion on
chromosome 7 are smaller, on average, than tumors with
chromosome 12 rearrangements, but are equivalent in size
in karyotypically normal tumors.
The different types of chromosomal abnormalities and the
distinct cytogenetic subgroups present in leiomyomas may
predict heterogeneous genetic pathways leading to tumor
growth and development. Studies identifying the genes
involved in these cytogenetic rearrangements, as well as
studies of tumor clonality, have successfully begun to unravel
the genetic mechanisms involved in leiomyoma biology.
METAPHASE-BASED CGH STUDIES IN
UTERINE LEIOMIOMA
Metaphase-based comparative genomic hybridization
(CGH) readily permits the overall assessment of copy number
imbalances of tumor DNA using normal chromosomal
target slides.99 This methodology permits the observation of
DNA gains and losses in relation to the physical map of
chromosomes. The identification by CGH of regions of the
genome that are commonly altered in uterine leiomyomas
may highlight important genes that are involved in the
initiation and progression of these tumors. Gains in DNA
copy numbers may represent amplified oncogenes, whereas
the areas showing losses may contain tumor suppressor
genes.99-101
This methodology has proven to be a rapid and relatively
inexpensive way of assessing overall levels of genomic
imbalance in primary tumors.99, 102 However, one general
limitation of this method is that it cannot detect balanced
chromosomal rearrangements. For example, the reciprocal
translocations involving chromosomes 12 and 14, or other
rearrangements such as inversions of 12q14-15 and the
HMGI-C gene are consistently reported in uterine
leiomyomas,78 but these aberrations will not usually be
detected by CGH. Moreover, the sensitivity of metaphase
CGH depends not only on the quality of DNA and
hybridization efficiency, but also on the presence of a
homogeneous copy number imbalance affecting greater
than 10MB.103
There have been only three previous reports of genomic
imbalance in uterine leiomyomas using metaphase
CGH.15, 104, 105 Abnormal CGH profiles were described in
only ten of the 31 tumors analyzed in these three studies.
Ten of these cases showed genomic imbalances, including
gains on chromosomes 9, 14 and 19 and losses on
chromosomes 1, 4, 7q and 12q.15, 104 In contrast, in a previous
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Silvia Regina Rogatto
study our research group found a higher proportion of tumors
with chromosomal imbalance (82%), and a significant
frequency of previously undescribed chromosomal losses,
involving mainly 3q26-29, 7p22-15, 11p15; 11q23-25 and
15q25-26. This finding, supported by validations using
conventional cytogenetic analysis and LOH studies, suggests
that an imbalance in uterine leiomyomas may be more
common than previously reported.
Additional studies such as array-based CGH will be
required to refine the locations of these and other imbalances
in leiomyomas to further evaluate the significance of such
events in tumorigenesis.
MOLECULAR ALTERATIONS IN
LEIOMYOMA
The variety of chromosome aberrations found in uterine
leiomyomas through cytogenetic studies suggests that
multiple genes and genetic mechanisms are involved in the
pathogenesis of these tumors. Understanding the molecular
events involved in the transformation of a normal myometrial
cell into a neoplastic cell and the subsequent growth of
these leiomyoma cells could be important in determining
the pathogenesis of these tumors and providing new targets
for treatment.
Several potential candidate genes have been proposed for
possible involvement in the development of uterine
leiomyoma, including the high mobility group (HMG) genes
on chromosomes 12q15 and 6p21, estrogen receptor beta
(ESR2) on chromosome 14q22, RAD51L1 gene on
chromosome 14q23, among others.1, 61
Rearrangements involving the same region of 12q in
leiomyomas,107-109 support the notion that critical genes for
the process of tumorigenesis reside within 12q14-q15.
Following extensive efforts to map the critical region on
chromosome 12, a single yeast artificial chromosome (YAC)
clone was found to span cytogenetic breakpoints in uterine
leiomyoma, pulmonary chondroid hamartoma and lipoma
specimens with t(12;14) translocations, and was therefore
likely to include the critical gene. The HMGA2 (HMGIC)
gene was considered a positional candidate gene at 12q15
in leiomyomas and others tumors, because it mapped within
a YAC spanning the breakpoints.78, 108, 110 A significant
number of leiomyomas with t(12;14) show breaks outside
the coding region of the gene, as near as 10kb and up to
more than 100 kb upstream of HMGA2. Such extragenic
breaks suggest the disruption of regulatory sequences that
lead to the abnormal expression of HMGA2. HMGA2 is a
highly evolutionarily conserved gene that encodes the
architectural factor belonging to the heterogeneous high-
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 6, No.1, January 2007
mobility group (HMG) family of nonhistone DNA binding
proteins.111-113 Included within this family are the HMGA2
and HMGA1 proteins involved in leiomyoma.114
HMGA2 and HMGA1 are both frequently aberrantly
expressed in leiomyomas and other benign mesenchymal
lesions. Studies have shown a relationship between elevated
HMGA2 expression and cellular transformation, as well as
a role in the maintenance of the transformed state.115 Such
data are consistent with a role for HMGA2 in the regulation
of cellular proliferation. A causal relationship between
leiomyoma development and mutations of HMGA2 has
been suggested.116
HMGA1 (HMGI-Y), another architectural factor gene
that maps to 6p21, a site of recurrent chromosomal
rearrangements in benign mesenchymal tumors, has become
a candidate gene for leiomyoma development.109, 117-120
Increased HMGA1 expression has been found in leiomyomas
with 6p21 rearrangements compared to that in normal
matched myometrium. Despite the great extent of sequence
and structural similarity between the HMGA2 and HMGA1
121
their expression patterns are different, suggesting the
existence of distinct regulatory elements, as well as different
functional roles. HMGA1 expression has also been observed
in a variety of malignant tumors and nonneoplastic cells,
like normal myometrium.121-126
The estrogen receptor beta gene (ESR2) mapped on the
chromosome band 14q22 became an interesting candidate
involved in the t(12;14).127, 128 However, the ESR2 locus
was mapped approximately 2 megabases (Mb) away from
the t(12;14) breakpoint and expression analysis did not
reveal differences in ESR2 transcription levels between
leiomyomas with and without the t(12;14) abnormality.129
In addition, fluorescence in situ hybridization analysis
showed that ESR2 was not interrupted in tumors with
t(12;14).
A strong candidate as a translocation partner for HMGA2
in leiomyoma is RAD51L1 gene (RAD51B, HREC2, or
R51H2) mapping to 14q23-q24.130-132 RAD51L1 is a member
of the RAD51 recombination repair gene family and plays a
role in DNA repair recombination, although the RAD51L1
protein has not been shown to catalyze such
recombination.132 This protein may play a role in cell cycle
regulation and apoptosis133 and phosphorylates a number of
proteins, including TP53, cyclin E, and CDK2, suggesting
that RAD51L1 affects cell cycle progression.
A large number of genes or growth factors, particularly
those located in the commonly deleted area of 7q22134-136
have been identified. Despite the identification of several
20

candidate genes, to date none have been proven to have a
causative role in the genesis of leiomyoma.50, 135, 137-143
Another high mobility group gene, HMG17 (1p35), was
found to be deleted in a leiomyoma with a ring chromosome;
this result suggests that, unlike the HMG genes, a deletion
and presumed reduced expression of HMG17 may play a
role in uterine leiomyoma growth and development.144
Although no gene on chromosome 10 has been shown to
contribute to leiomyoma growth or development, two tumor
suppressor genes, PTEN/MMAC1 (10q23.3) and DMBT1
(10q25.3-26.1), are mapped in this area and are possible
candidates, as demonstrated by two studies.145, 146
In recent years, differences in gene expression have been
used to define characteristic molecular signatures for a
variety of tumors. Gene expression profiling utilizing a
number of microarray techniques is capable of identifying a
very large number of genes that are differentially expressed
between tissues. Indeed, the altered expression of some of
these genes is now thought to be the basis of most neoplasms
because they are expressed at either abnormally high or low
levels. Comparison of these profiles has allowed for their
association with different diagnostic or prognostic groups to
be determined and has provided new insights into their
pathogenetic mechanisms.
In order to identify other critical genes and potential
pathways involved in uterine leiomyoma, at least ten studies
examined the differential gene expression between uterine
leiomyoma and normal myometrium using microarray
screening procedures.17, 147-154 Arslan et al.154 compared their
results with previously published data 17, 147-149, 151, 153, 155 on
gene expression in uterine leiomyoma and identified the
overlapping gene alterations. These authors detected 80
genes with average differences greater than or equal to 2-
fold and false discovery rates of less than 5% (14
overexpressed and 66 underexpressed). Despite substantial
variations in patient characteristics (race/ethnicity, phase
of menstrual cycle, age), gene array methodology (at least
six different gene array platforms), and differences in
statistical methods and data presentation, 71 genes (28
overexpressed and 43 underexpressed in leiomyoma
compared to normal myometrium) were identified by at
least two separate studies. These included eight genes
(ADH1, ATF3, CRABP2, CYR61, DPT, GRIA2, IGF2,
MEST) identified by al least five different studies, 11 genes
(ALDH1, CD24, CTGF, DCX, DUSP1, FOS, GAGEC1,
IGFBP6, PTGDS, PTGER3, TYMS) reported by four
studies, 12 genes (ABCA, ANXA1, APM2, CCL21,
CDKN1A, CRMP1, EMP1, ESR1, FY, MAP3K5, TGFBR2,
TIMP3) identified by three studies, and 40 genes reported
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 6, No.1, January 2007
Uterine Leiomyoma: Updates in Cytogenetics and Molecular Analysis
by two different studies. This review of gene expression
data revealed concordant changes in genes regulating
retinoid synthesis, IGF metabolism, TGF- signaling and
extracellular matrix formation and that expression studies
provide clues to the relevant pathways of leiomyoma
development.
It is difficult to compare the smooth muscle tumor-associated
gene lists reported in various published studies.147, 149-153 Methods
for gene selection, as well as reagents for microarray
hybridization, differed substantially. Not surprisingly, there
was little overlap among gene lists generated by these different
studies. Nevertheless, it is possible that genes selected by more
than one study might reflect a more reliable indicator of
differential gene expression by which myometrium,
leiomyoma, and leiomyosarcoma might be distinguished.
Although experimental and clinical evidence strongly
suggest that leiomyoma growth is steroid hormone-
dependent,156 one of the surprising findings of the microarray
studies was the lack of significant changes in estrogen
receptors (except for a moderate increase in ESR1 reported
by three studies), progesterone receptors, or their nuclear
receptor cofactors.154 A possible explanation is that steroid
hormones may act through their target genes, which mediate
hormonal effects.155
The microarray method is a powerful tool for focusing the
search on genes that play important roles in the leiomyoma
phenotype. However, these studies demonstrated that
microarray analysis alone is insufficient for identifying the
pathways involved in the development of these tumors150, 153
and should be considered a screening test, while more
specific tests should be used to confirm differential mRNA
expression (quantitative real time RT-PCR, Northern blot,
etc.). In addition, several other methods, including
metaphase based comparative genomic hybridization
(CGH), array-CGH studies, and an assessment of the loss
of heterozygosity (LOH), may be used to detect regions of
the genome that harbor putative oncogenes or tumor
suppressor genes.
Loss of heterozygosity is a common form of allelic imbalance
and the detection of LOH has been used to identify genomic
regions that harbor tumor suppressor genes and to
characterize different tumor types, pathological stages and
disease progression.157 Furthermore, it has been shown that
mutations of a single tumor suppressor gene can significantly
alter the global expression pattern of a tumor.158 However,
few studies have described LOH in uterine leiomyomas
elsewhere in the genome. In addition, the frequency of
LOH in uterine leiomyomas is very low in several
microsatellite markers distributed throughout the genome,
21
Silvia Regina Rogatto
except in 7q21- q32.38, 84, 85, 136, 159, 160 In one previous study,
our research group selected a set of 15 microsatellite
polymorphism markers to examine the frequency of allele
loss in a panel of 64 human uterine leiomyomas matched to
normal DNA. The markers were chosen from regions
involved in losses identified by comparative genomic
hybridization in a subset of uterine leiomyomas described in
a previous report.106 The frequency of LOH observed was
low, except for the markers D15S87 (15q26.3), D7S493
(7p15.3) and D7S517 (7p22.2). These results suggested the
existence of at least three distinct regions mapped on 7p
(7p15.3 and 7p22.2) and 15q26.3 that might harbor tumor
suppressor genes involved in uterine leiomyomas.161
Much can be learned from these benign tumors regarding
cellular proliferation and molecular pathways leading to
tumor formation. Understanding the common pathways
may prove useful not only in understanding the biology,
initiation and progression of these tumors, but could also be
critical in their possible prevention and for the development
of novel treatment strategies.1, 36, 64
Previous studies suggested that two possible pathways
are involved in the proliferation of these tumors. One is
the mitogen-activating protein kinase (MAP-kinase)-
dependent pathway. This pathway is induced by growth
factor mediators of estradiol and inhibited by adenylate
cyclase signal transduction pathway, which was
attenuated in human uterine leiomyomas, as compared
with adjacent myometrium.162-164 The other pathway is
the transforming growth factor beta receptor signaling
pathway. Some genes in this pathway have been shown
to be overexpressed in uterine leiomyoma and altered by
treatment of the gonadotropin-releasing hormone analog
(GnRHa).152, 165
CLONALITY STUDIES OF UTERINE
LEIOMYOMA
The clonality of uterine leiomyomas has been studied in
order to understand the genetic mechanisms involved in
the genesis and growth of these tumors. Most human tumors
are believed to be cytogenetically abnormal clones of cells
derived from a single progenitor cell that has undergone
mutation. Although an initial mutation may trigger
formation of the tumor, additional mutations may occur
during tumor progression, thereby creating subclones with
a selective growth advantage and the potential for clonal
expansion. If leiomyomas arise from somatic mutations in a
myometrial cell that result in the dysregulation of the
mechanisms that control cell growth and confers a growth
advantage, the observation of clonal expansion would be
expected.
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 6, No.1, January 2007
Several clonality studies in multiple leiomyomas in the
same uterus have indicated that the various tumors develop
as monoclonal lesions and are not related, but rather initiate
independently of each other and progress by discrete and
separate somatic mutations.166-170 Since leiomyomas are
thought to be monoclonal tumors, an alteration in the genetic
material from a single myometrial cell may contribute in a
progressive loss of growth regulation and result in the
initiation and progression of leiomyoma growth.
Initially, glucose-6-phosphate dehydrogenase (G6PD)
isoenzyme analysis was used to demonstrate the
independent clonal origin of multiple leiomyomas in a single
uterus.166,171 The latter study showed that either the A or B
type allele, but not both, was present in each tumor from a
series of seven women heterozygous for this enzyme.
Furthermore, both A and B type tumors occurred in the
same individual. This observation indicated a random
pattern of inactivation among multiple tumors, with
individual tumors exclusively expressing one or the other
G6PD type, and also revealed that multiple tumors in the
same uterus most likely arise in situ from different
myometrial cells and not from a single mutated myometrial
cell. However, a low degree of G6PD isoenzyme
polymorphism among most female patients across various
ethnic groups limited the use of this approach.
In recent years, the development of sophisticated, more
informative molecular assays has enhanced our
understanding of the development of benign and neoplastic
lesions. Studies involving the inactivation of X-chromosome
linked phosphoglycerokinase (PGK)169 and androgen
receptor (AR) gene167 in uterine leiomyomas have become
a powerful technique, allowing investigators to examine
the clonality of these tumors. These studies involved DNA
digestion with methylation sensitive restriction enzymes to
assess the differences in methylation between active and
inactive X chromosomes. The results demonstrated a
random pattern of inactivation among multiple tumors, with
individual tumors expressing exclusively one allele or the
other, confirming their monoclonal nature and the
hypothesis that multiple tumors within a single uterus arise
independently. Based on an analysis of the AR gene, which
showed a monoclonal pattern of X inactivation in the
karyotypically normal cells in leiomyomas, Mashal et al.167
showed that these cells are part of the tumor clone and that
clonal expansion of tumor cells may precede the
development of cytogenetic changes in some leiomyomas,
suggesting that additional mechanisms might be involved
in the evolution of uterine leiomyomas and the induction
of somatic mutations.30 In a case of diffuse leiomyomatosis
in a 39-year-old woman, all samples showed a nonrandom
X-chromosome inactivation pattern consistent with
22

monoclonal origin of the tumors.172 However, in different
loci of the tumor, different X-chromosomes were inactivated,
supporting the independent origin of neoplastic clones and
arguing contrary to the hypothesis of a single clonal origin
of the tumors.
The use of X chromosome inactivation to analyze
clonality is based on the occurrence of random X
chromosome inactivation in early embryogenesis. Since,
for a specific progenitor, all daughter cells will inherit the
same inactivated X chromosome, this can be used as a
marker of clonality.173 Although the initial determination
of which of the X chromosomes is inactivated is made at
random, the pattern of inactivation is permanent and is
constant throughout subsequent cell divisions.174 Thus,
normal tissues of adult women consist of a mosaic of cell
types, which differ in whether the maternally or paternally
derived X chromosome has been inactivated. In contrast,
clonal cellular proliferation maintains the same pattern of
X chromosome inactivation that was determined in the
single cell of origin.175
The cytogenetic studies of multiple uterine leiomyomas
from the same uterus have also demonstrated that each
tumor is clonal and develops independently, hence these
tumors often exhibit different chromosomal
alterations. 14, 43, 87, 176, 177 In addition, the fact that
leiomyomas are monoclonal tumors derived from a single
myometrial cell, suggest that DNA repair failure may be an
early event in myoma development.166
A study of a patient with two independent leiomyomas,
each showing a different pattern of X-chromosome
inactivation but identical del(7)(q21.2q31.2) derivative
chromosomes, supports the view that identical cytogenetic
changes in multiple leiomyomas from the same patient may
represent recurrent chromosomal aberrations in smooth
muscles or be coincidental.176 Our group recently reported
the frequent involvement of allelic loss at 7p22-15 in uterine
leiomyoma.161 In addition to the previous reports, the same
allelic losses found at 7p in all three uterine leiomyomas
from same patient suggest their relevance in a subgroup of
uterine leiomyomas.178
Currently, besides X-chromosome inactivation and
cytogenetic studies, clonality evaluation in different tumor
types has been performed for loss of heterozygosity (LOH)
analysis, that utilize different microsatellite markers
distributed throughout the genome.179,180 This analysis type
is directly related to genetic alterations occurring in different
tumor tissues and, in contrast to the clonality study of X-
chromosome inactivation, this analysis is an irreversible
genetic event acquired during tumorigenesis.
Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 6, No.1, January 2007
Uterine Leiomyoma: Updates in Cytogenetics and Molecular Analysis
In a recent study of our group,178 using a total of 43 multiple
leiomyomas from 14 patients, clonality was examined based
on the LOH using 15 microssatellite markers and X-
chromosome linked AR gene inactivation analysis by
automated methodology. The results for X-chromosome
inactivation analysis showed that all informative leiomyomas
had a monoclonal origin. The same inactivated allele was
found in all tumors in nine out of the 12 informative patients,
while different inactivation patterns were observed in three
cases. LOH analysis showed a different pattern in seven of
the eight cases with allelic loss for at least one of the 15
microsatellite markers analyzed. These data support the
concept that uterine leiomyomas are derived from a single
cell, but are generated independently in the uterus.
Probably because each individual uterine leiomyoma is
monoclonal, individual lesions will demonstrate
characteristic patterns of growth.5 Although myoma size
may remain constant for many years, the general pattern in
a large population is one of slow long-term growth during
the pre-menopausal years followed by fairly rapid growth
during the fifth decade of a womans life, just prior to
menopause.5, 41, 181
CONCLUSIONS
The studies of the genetics of benign tumors, such as
leiomyoma, have demonstrated that tumor formation at
any level is complex genetically and that some key events
remain essentially unknown.
Overall, cytogenetic analyses, together with molecular
clonality and epidemiological studies, suggest that
karyotypic abnormalities in leiomyomas may be important
in the pathobiology of these tumors and may represent
secondary somatic changes in genetically susceptible cells.
Evidence to support this notion comes from the observations
of clonality in uterine leiomyoma that show mosaicism for
normal and aberrant karyotypes, thus suggesting that the
clonal expansion of cells precedes the acquisition of
cytogenetic abnormalities. It is, however, possible that
submicroscopic and molecular events, such as microdeletions
and point mutations, may affect regulatory elements not
only leading to tumorigenesis, but also promoting
chromosome instability. In addition, the investigation of such
mosaic uterine leiomyoma specimens and the elucidation
of the various and heterogeneous factors in uterine
leiomyoma tumorigenesis may well be established by further
intensive molecular investigation of the specific altered
chromosome regions defined by cytogenetic and molecular
cytogenetic analysis. Such efforts have already led to the
identification of various genes that may play some type of
role in the tumorigenesis of uterine leiomyoma. Many of
23
Silvia Regina Rogatto
these newly implicated genes may in fact be responsible for
secondary changes that affect the progression and
proliferation of the tumor.
In summary, a thorough understanding of the cytogenetics
and molecular basis, mechanisms of tumor development,
pathogenesis and clinical presentation of uterine
leiomyomas are the keys for the development of novel
strategies for less invasive treatments and prevention for
this significant womens health problem.
ACKNOWLEDGMENTS
This work was supported by the Fundao de Amparo
Pesquisa do Estado de So Paulo (FAPESP) and Conselho
Nacional de Desenvolvimento Cientfico e Tecnolgico
(CNPq), Brazil.
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