Genetic risk of uterine fibroid and its disparity

GENETIC RISK OF UTERINE FIBROID AND ITS DISPARITY AMONG RACES

GENETIC RISK OF UTERINE FIBROID AND ITS DISPARITY AMONG RACES

BY AJIDE PROMISE TEMITAYOCELL BIOLOGY AND GENETICS UNIT189040

SUPERVISOR: DR G.C ALIMBA

Introduction

Synonyms : Myoma, Uterine Leiomyoma (UL), Fibromyoma

Most common benign neoplasm of the uterus in the female.

They are hormonally dependent tumours and are not observed prior to puberty(Fields and Neinstein, 1996)

Incidence : occurs in 70% of women, severe symptoms in 20-30% of women (Marshall et al., 1997)

Symptoms: Abnormal uterine bleeding, pelvic pressure and pain, reproductive dysfunction.

Epidemiology

Most affected women have multiple tumours with an average of 6.5 tumours per uterus (Cramel and Patel, 1990)

Increased risk age 35 to 45 years , nulliparous or low parity , Black women, family history, obesity, early Menarche, Diabetes, hypertension.

Decreased risk parity, exercise, intake of green vegetables (Terry et al.,2010) .

UL cause severe morbidity but not mortality, likely resulting in limited research funding and treatment options

Figure 1: Shows Prevalence in Relation to Age of women(Lurie et al., 2005)

Table1: Epidemiology in some cities in Nigeria

Cities

Epidemiology

References

Ibadan

9.3%

(Okogbo et al., 2011)

Zaria

7.8%

(Abdullahi et al., 2003)

Ilesa

8.4%

(Fasubaa, 1990)

Lokoja

9.8%

(Ogunniyi et al., 2008)

lower prevalence reported in this study and other studies from Nigeria may be as a result of the fact that only women that presented with clinical features of uterine fibroid were screened

Management

Method/Clinical effect

Observation

Regular pelvic examination

Myomectomy

Preserves fertility

Uterine Artery Embolization

Preserves the uterus

Hysterectomy

Only curative treatment/ removal of the uterus

Medical Management

For symptomatic relief (Danazol, Gestrinone)

(Kim and Sefton, 2012)

C:\Users\Sarah\Documents\Downloads\photo (9).JPGTable 2: Management of Uterine FibroidHysterectomies involve surgical removal of the entire uterus and leave the patient unable to bear children.A surgical treatment option that leaves the uterus intact, Uterine artery embolization (UAE) is another minimally invasive option It involves guiding a catheter from a small incision in the groin, through a leg artery, to the arteries in the uterusEmbolic agents are delivered through the catheter to block blood supply to the tumors, which results in UL volume reduction (Hurst, Stackhouse et al. 2000)This will not eliminate tumors but instead relieve symptoms by reducing tumor sizeA myomectomy is a surgical procedure in which individual UL are excised and removed from the uterus

Genetic Basis of Fibroid

Acquired mutations occurs naturally (Causal factors of tumorigenesis) it could be during Menstrual cycle-related injury and repair, post- partum repair (Arno et al.,2015)

4050% of fibroids contain chromosomal abnormalities (Ligon and Morton, 2001; Sandberg, 2005), recurrent somatic mutation include:

Translocation between Chromosome 12 & 14,

Trisomy 12,

Rearrangement of short arm of Chromosome 6

Rearrangement of long arm of Chromosome 10,

Deletion of short arm of Ch.3 or Ch.7

Figure 2: Common cytogenetic subgroups found in UL: a) t(12;14)(q14-15;q23-24), b) del(7)(q22q32), c) trisomy 12, d) t(6;10)(q21;q22). Taken from (Gross and Morton 2001)

Figure 3: Schematic of a Factor thought to be involved in leiomyoma development
(Arno et al., 2015)

Translocation t(12;14)(q1415;q2324)

The high-mobility group AT-hook 2 (HMGA2) on chromosome 12

RAD51B is the preferential translocation partner on chromosome 14 (Quade et al., 2003)

Menstrual cycle-related injury
and repair, and coinciding hormonal cycling, affects myometrial stem cells that at a certain stage of fibroid development can obtain cytogenetic aberrations
mostlyinvolvingHMGA2and RAD51B.

Cytochrome C oxidase subunit VIc (COX6C) is the terminal enzyme of
the mitochondrial respiratory chain and catalyzes the electron transfer
from reduced cytochrome C to oxygen (Hofmann et al., 1998). A possible dysfunction in this activity in leiomyoma might lead to metabolic
stress. Results from one study in an Eker rat-derived cell line suggest a
role for cytochrome C in induction of apoptosis (Raymond et al., 2006).
Calbindin 1 (CALB1) (aka RTLV-H) functions as a calcium sensor and
buffer (Kojetin et al., 2006) and its expression is strongly related to the
quantity of vitamin D in the duodenum (Wasserman and Fullmer,
1989). In light of the associations of African-American ethnicity with
both increased incidence of uterine fibroids and low vitamin D status,
a number of studies have investigated a possible role for vitamin D in
fibroid biology. For example, fibroid tumor size in xenotransplants of
rat leiomyoma cells and ECM protein of human leiomyoma cells in vitro
are both significantly diminished by vitamin D treatment (Halder et al.,
2013, 2014). While it is not clear if CALB1-HMGA2 fusion transcripts
are affected by vitamin D status, it would appear that both low vitamin
D and disrupted CALB1 expression could play a role in leiomyoma development and warrant further investigation. A more complete discussion
of vitamin D deficiency and leiomyoma development is provided below in
the ethnic disparities section
Del (7) (q22q32), Cut-like homeobox 1
Translocations of the long arm of chromosome 7 occur in 17% of the
karyotypically abnormal leiomyomas (Sandberg, 2005), and loss of heterozygosity of 7q22, quite possibly involving Cut-like homeobox 1
(CUX1), occurs in 1035% of unselected cases of human fibroids
(Zeng et al., 1997; van der Heijden et al., 1998; Patrikis et al., 2003). It
is likely that this gene is also involved in leiomyoma cases with chromosome 7 deletions (Schoenmakers et al., 2013). Normally, CUX1 plays
an important role during development, cell cycle progression, cell proliferation, cell migration and invasion (Sansregret and Nepveu, 2008; Hulea
and Nepveu, 2012). Recently, CUX1 was identified as the target gene in
two individual fibroids containing a closely related pericentric and paracentric chromosomal inversion of band 7q22 (Schoenmakers et al.,
2013), which effectively leads to a monoallelic knockout of this gene.
One study did not find any somatic mutations in all coding exons of
CUX1 in 42 fibroids (Patrikis et al., 2003). A possible explanation is
that CUX1 is a tumor suppressor gene in which loss of one allele is sufficient to facilitate tumor growth (Zeng et al., 1999; Cook and McCaw,
2000)
The main function of aldehyde dehydrogenase 2 (ALDH2) is the oxidation of aldehydes into carboxylic acids. It has been shown that the human
ALDH2 promoter contains a retinoid response element (Pinaire et al.,
2003). Moreover, a fusion transcript between HMGA2 and ALDH2
has been detected in human fibroid tissue (Kazmierczak et al., 1995).
Thus, it could function in conjunction with ADH1 and CRABP2 to
deregulate the retinoic acid pathway and subsequent myometrial stem
cell differentiation. In several types of cancers, ALDHs have been
shown to be up-regulated and are also associated with differentiation
and/or expansion of the cancer stem cell population.

Genetics of Uterine Fibroid

Multiple chromosomal rearrangements are the result of a single event of multiple double-strand breaks and subsequent random repair (Forment et al., 2012) .

This Implies that there are at least two or more pathogenic mechanisms responsible for fibroid formation since 50% of fibroids have a normal karyotype

MED12 mutations are mainly found in fibroids with a normal karyotype (Markowski et al., 2012)

In women, one allele of MED12 is randomly inactivated in each cell because the gene is located on the X chromosome (Malik and Roeder, 2010)

These gene expression levels occurs frequently suggesting the acquired genetic alterations are operative in UL tumour biology.

Figure 4: The stem/progenitor cell dysregulation aetiology and growth of uterine leiomyomas (Bulun, 2013)

tubal_surg4_LGa(A) Normal myometrial stem/progenitor
cells respond to ovarian steroid hormones by self-renewal and differentiation of new myometrial smooth muscle cells during normal cycling, pregnancy and
post-partum repair. (B) The myometrial stem/progenitor cells become dysregulated, perhaps after a genetic event, and become a fibroid smooth muscle
cellandECM-producingstem/progenitorcell.(C)Thefibroidsmoothmusclestem/progenitorcellnolongerrespondstolocalfactorscorrectlytomaintain
tissue homeostasis and begins to form tumors

Heritability Studies

Studies have suggested that germline variants also contribute to Uterine fibroid

Familial aggregation; .Women with two or more affected relatives are 2.2 times more likely to have UL . p < 0.001 (Vikhlyaeva et al., 1995).

Maternal history of UL was also shown to be a signicant risk factor (DAloisio et al., 2012)

Twins study; Concordance rates for hysterectomy are reported to be nearly two fold higher in monozygotic (MZ) twin pairs compared with dizygotic (DZ) (Van Voorhis et al., 2002)

Increased susceptibility to UL is also inherited in an autosomal dominant pattern in a rare disorder - Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (Reed et al., 1973)

suggesting constitutional mutations can also operate in disease development. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a tumor-predisposition disorder caused by mutations in fumarate hydratase (FH) on chromosome 1 in band q42. HLRCC is associated with an elevated risk for developing cutaneous piloleiomyomata, renal cell cancer, and leiomyomata of the uterus. The existence of HLRCC provides further evidence that susceptibility to UL can be heritable.

Racial Differences

Racial disparity of uterine fibroid development and severity of disease is the most consistent epidemiologic characteristic of uterine fibroids.

African-American (Black women) develop the disease at a higher frequency and with more severe uterine fibroid-related symptoms (Baird et al., 2003).

Hispanic women have an intermediate disease profile and Caucasian women are the least severely affected Racial group (Wise et al., 2012).

This differences in the incidence and morbidity of UL suggest that population-specic germline variants might affect predisposition to UL.

Variables

African Race (%)(n= 268)

White Race(%) (n= 573)

Abdominal bloating and pressure/protruding abdomen 37

15

Passing blood clots during menstrual period 40

20

Heavy or prolonged menstrual bleeding 37

23

Abdominal pain/cramping/tightness 34

19

Anemia 22

6

Backache or leg pains 28

19

Constipation 15

6

Bladder symptoms 11

9

Fatigue 32

22

Menstrual pain/cramps 42

23

Painful intercourse 10

7

Lack of interest in sex 21

17

Table 3: Symptoms Reported in a study by Baird et al., 2005

Figure 5:Symptoms Plot (Baird et al., 2012)

Implications on Black Races

Symptoms associated with UL are severe in black women.

Supporting a role for a heritable component in the development of UL.

ULs were observed in 89% of black women and 59% of white women.

Black women had a younger age of diagnosis (37.5 vs. 41.6 years)

Younger age of hysterectomy (41.7 vs. 44.6 years)

Greater average uterine weight (420.8 vs. 319.1 g)

An increased likelihood of having seven or more tumours (57 vs. 36%).

Environmental risk factors, including cigarette smoking and parity, do not account for the racial differences (Eltoukhi et al., 2014)

Genome-wide association studies (GWASs)

Genome-wide scans have advanced the biological understanding of UL by testing the hypothesis from

Genetic epidemiologic analyses - familial aggregation, twin studies, and racial discrepancies

Disease prevalence and morbidity

It suggested genetic liability in risk.

To date, three genome-wide scans for UL have been performed

A GWAS in Japanese women,

A genome-wide linkage and association study in women of European decent

Admixture-based analysis in African American women

Prevalence of UL is appreciably higher in black women than white women, suggesting genetic variants unique to specific ancestries differentially influence risk for developing UL

Abbreviation: BWHS, Black Womens Health Study; FGFF, Finding Genes for Fibroids; GWAS, genome-wide association study; UL, uterine leiomyoma

Overview of Genetic Association Studies on Uterine Fibroid (Gallager and Morton 2015)

Summary & Conclusion

The most commonly mutated gene found in uterine leiomyoma is MED12.

Despite its prevalence, there is no direct evidence to support the role of mutated MED 12 in causality in the development of leiomyoma.

A GWAS study comparing Black women leiomyomas to women from other ethnic backgrounds failed to identify any specific loci correlated to a higher incidence of leiomyoma (Wise et al., 2012)

It appears that the increased incidence and severity of the disease in Black women might be due to a combination of specific genetic and environmental factors that are not independent risk factors for the disease

Determining the genetic roots of UL will lead to novel screening methods and treatment approaches to reduce the healthcare and societal burden of
this reproductive disease.

Thank You

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Black Race White Race

abdominal bloatingblood clotsheavy menstrual bleedingabdominal painanemiabackacheconstipationbladder symptomsfatiguemenstrual painpainful intercourselack of interest

Prevalence (%)Prevalence (%)

20 to 30 years 30 to 40 years 40 to 60 years

Healthcare

Genetic risk of uterine fibroid and its disparity