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Pathogenesis of fibroids
Paul van Kesteren
Fibroids
Degenerated fibroids
Calcified fibroid
Myxoid degeneration
Cystic degeneration
Lipoleiomyoma
Intravenous leiomyomatosis
Fibroid phenotype
• Various subtypes
• Underlying mechanisms that cause this variation
Pathogenesis: risk factors
- Hypertension (OR 4.90 (2.31–10.38))
- Soy milk (OR 2.52 (1.89–3.35))
- Diet: conserved and sweetened food: OR 3.17 (2.25–4.46)
Stewart et al, BJOG. 2017 Sep;124(10):1501-1512
Pathogenesis: risk factors
- Parity: (≥3 vs 0; OR 0.17 (0.08–0.36))
- OC: (Current vs never; OR, 0.3 (0.2–0.6)
- Depot MPA: (Ever vs never; OR 0.42 (0.34–0.53))
- Smoking: in case of low BMI, current vs never; OR 0.3 (0.2–0.5)
Stewart et al, BJOG. 2017 Sep;124(10):1501-1512
Pathogenesis: genetic influence
Racial differences
Black vs white OR 2,9 (95% CI 2,5-3,2)
• Larger and more numerous fibroids
• More severe symptoms (anemia, pain)
• Age at diagnosis 37,5 vs 41,6 jr
• Age at hysterectomy 41,7 vs 44,6 jr
Kjerulff et al, J Reprod Med. 1996 Jul;41(7):483-90
It’s all in the Family (?)
Twins: fibroid concordance (Maturitas 2000;37:15–26)
• Finnish twin cohort study. Ultrasound: 15 pairs concordant, 14 pairs
discordant
• Hospitalization for fibroids:
• MZ 49 pairs concordant vs 271 pairs discordant (18%)
• DZ 49 pairs concordant vs 499 pairs discordant (8%)
Incidence 1st degree family members 31,5% vs 15,2 % control group 144 Japanese women 45-54 years with surgery for fibroids vs 288
controls
(J Epidemiol 2002;12(3):249-53)
It’s all in the Family (?)
Relative risk for positive family history (Ann Epidemiol 2013; 23: 286-290)
• 660 Afro-americans (RR, 1.2; 95% CI, 1.1-1.3)
• 412 whites (RR, 1.3; 95% CI, 1.1-1.6)
Genetic defect
• Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)
• Multiple uterine and dermal
fibroids
• Increased incidence of renal
cell carcinoma
• Heterozygotic gene defect
coding for fumarate hydratase
• 1q42.3-43
Genetics
Finding genes for Fibroids Study (Am J Hum Genet. 2012 Oct 5;91(4):621-8)
• 385 sibling-pairs (both fibroids, white) and
family members without fibroids
• Whole-genome Single Nucleotide
Polymorfism linkage scan
LOD score:
(Logarithm of the
odds score)
Statistical
estimation whether
two genes are
inherited
Fertil Steril. 2017 Feb;107(2):457-466.e9.
Results of Human Genome studies:
Genetic heterogeneity Different genes play a (modest) role
Zoom into the fibroid cell
Fibroid volume expansion:
- Formation of extracellular matrix (collagen, proteoglycans,
fibronectin)
- Growth of fibroid cells
How do fibroids start to grow?
Fibroid = monoclonal tumour: • All cells from that fibroid originate
from one single cell
Mutation of a somatic myometrial stem cell • N Eng J Med 2013; 369:1344-55
Affected biochemical pathways
Let7-HMGA2-p14Arf pathway: • Cell renewal and aging
MED12 - WNT--catenin - TGF- pathway:
• Stimulates:
• Stem cell renewal
• Cell proliferation
• Formation of extracellular matrix
Let7-HMGA2-p14Arf pathway
7,5% of fibroids have rearrangements in chromosome 12q14-15
HMGA2 gene overexpression (High-Mobility Group AT-hook 2) HMGA2 overexpression: • Supresses p14Arf
- Positive effect on cell renewal
- Supresses cell senescence
MED12 - WNT--catenin - TGF- pathway
70 % fibroid stem cells: MED12 mutation (Xq13.1) (Science 2011;334:252-4. 80 patients, 225 fibroids)
Mediator Complex Subunit 12
Subunit of a large mediator complex
MED12 - WNT--catenin - TGF- pathway
Mediator complex regulates gene transcription • Bridging transcription factors to RNA
polymerase II
MED12 mutation disturbance in DNA transcription
Mutated MED12: + -catenin pathway Stimulates tissue growth
+ TGF- receptor expression cell proliferation
extra cellular matrix
MED12 - WNT--catenin - TGF- pathway
Less common somatic mutations in fibroids
Deletions affecting collagen: type IV, alpha5: COL4A5 type IV, alpha6: COL4A6 Biallelic inactivation of fumarate hydratase (FH) HMGA1 (high-mobility group AT-hook 1) Mehine et al, Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1315-20
Mehine et al, Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1315-20
• Complex interaction between affected genetic alterations
• Somatic mutations
- increase transcription of various genes
- influence several signalling pathways
Specific fibroid phenotype
- MED 12
- Small fibroids
- More ECM
- Smooth muscle cells and fibroblasts
- HMGA2
- Large solitary fibroids
- Smooth muscle cells
- Smooth muscle cells progesterone dependent
- Fibroblasts mainly estrogen dependent
Laughlin-Tommaso and Stewart, Obstet Gynecol 2018;132:961–71
Ulipristal Acetate
• Attenuates the TGF-ß pathway - decrease of ECM protein production
Lewis et al, Fertil Steril. 2019 Apr;111(4):806-815
• UPA decreases expression of proteoglycans (ECM) - Aggrecan
- Versican and Brevican
Britten et al, Reprod Sci. 2019 Feb;26(2):184-197
Targeted therapies on fibroid phenotype and
underlying altered pathways
• UPA for ECM rich fibroids
• TGF-ß
• Aromatase inhibitors in fibroblast-rich fibroids
Conclusions
Despite racial and familial predisposition: pathogenesis of
fibroids is scarcely reflected in genomic DNA alterations
Each fibroid is a monoclonal tumour, induced by a somatic
mutation of the stem cell
Two most common DNA alterations in fibroids affect HMGA2
and MED12 pathways
Many more genes show increased transcription and more
pathways are involved
Knowledge of specific fibroid phenotype and underlying genetic
alterations can target medical therapy
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