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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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