Genetic risk of uterine fibroid and its disparity

1. GENETIC RISK OF UTERINE
FIBROID AND ITS DISPARITY
AMONG RACES
BY
AJIDE PROMISE TEMITAYO
CELL BIOLOGY AND GENETICS UNIT
189040
SUPERVISOR: DR G.C ALIMBA

2. 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.

3. 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

4. 20 to 30 years 30 to 40 years 40 to 60 years
0
5
10
15
20
25
30
35
Prevalence (%)
Prevalence (%)
Figure 1: Shows Prevalence in Relation to Age of women
(Lurie et al., 2005)

5. 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)

6. ●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)
Table 2: Management of Uterine Fibroid

7. 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)
• 40–50% 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

8. 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)

9. Figure 3: Schematic of a Factor thought to be involved in
leiomyoma development
(Arno et al., 2015)
Translocation t(12;14)(q14–15;q23–24)
The high-mobility group AT-hook 2
(HMGA2) on chromosome 12
RAD51B is the preferential translocation
partner on chromosome 14 (Quade et al.,
2003)

10. 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.

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

13. 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 significant risk factor
(D’Aloisio 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)

14. 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-
specific germline variants might affect predisposition to UL.
•
•

15. ●
●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

16. abdominal bloating constipation
abdominal pain menstrual pain
0
5
10
15
20
25
30
35
40
45
Black Race
White Race
Figure 5:Symptoms Plot (Baird et al., 2012)

17. 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)
•

18. 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

19. Abbreviation: BWHS, Black Women’s 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)

20. 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.
•

21. Thank You