Download Myolysis

Genetics and Fibroids:
The Future is Now
Elizabeth A. Stewart, M.D.
Associate Professor of Obstetrics, Gynecology and
Reproductive Biology
Harvard Medical School
Clinical Director, Center for Uterine Fibroids
Department of Obstetrics and Gynecology
Brigham and Women’s Hospital
Hypothesis:
Uterine leiomyomas represent a
common phenotype arising from
different underlying genetic
predispositions and somatic
mutations. (Instead of: a fibroid is a
fibroid is a fibroid).
Leukemias:
•
•
•
•
CLL
CML
ALL
AML
Genetic differences produce
differences in pathogenesis, prognosis
and treatment
CML: Understanding the specific
gene defect can lead to innovative
treatments
• Marker of Prognosis: Philadelphia chromosome
• Novel target identified: fusion protein, enzyme
Bcr-Abl tyrosine kinase
• Design of Specific Therapy: imatinib mesylate
Clinical Evidence for Genetic
Differences
Hysterectomy in Twins: Separate
genetics and environment
Monozygotic
(Share all genes)
0.6 + 0.05
Dizygotic
(Share ½ of genes)
0.32 + 0.09
Treloar et al. Amer J Ob Gyn 1992: 167(82-8)
RACE: Strong predictor of risk
• Increased Incidence Rates
Black women
White women
30.6/1000 woman-years
8.9/1000 woman-years
• Increased Relative Risk
Black women
White women
3.25 (2.71- 3.88)
1.00
Marshall et al. Obstet Gynecol 1997: 90(967-73)
Familial Aggregation: Family History
Predicts Risk
97 families (215 female patients): fibroids 2.2 x more
frequent (p <0.001) among first degree female relatives
in families with two or more verified leiomyoma cases.
Vikhylaeva et al: Intl J Gynecol Obstet 51:127-131, 1995.
Estimated 2 x risk to relatives in families with myoma
uteri over general population.
Kurbanova et al: Genetika 25:1896-1898, 1989.
The Zebras:
Rare Syndromes
OMIM
• Online Mendelian Inheritance in Man
• http://www3.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
• Brings together clinical references and
genetic information
Reed’s Syndrome: MUCL1
• Multiple cutaneous and uterine leiomyomas
OMIM 150800
• Autosomal dominant inheritance
• Cutaneous leiomyomas from erector
pilorum muscles.
Reed et al. Acta Derm Venerol 1973: 53(409-16)
HLRCC: Hereditary Leiomyomatosis and
Renal Cell Cancer
•OMIM 605839
•Uterine Leiomyomas and Sarcomas
•Cutaneous Leiomyomas
•Papillary renal cell cancer
•Autosomal dominant
Launonen et al: PNAS 98:3387-3392, 2001.
Are Reed’s syndrome and HLRCC
the same disease?
If so, we need to be more suspicious
for malignancy in all women with
cutaneous leiomyomas.
Cytogenetic and
Molecular Genetics of
Uterine Leiomyomas
Pyruvate
Acetyl-CoA
Oxaloacetate
Citrate
Malate
KREBS CYCLE
Isocitrate
FH
Fumarate
Ketoglutarate
Succinate
Succinyl-CoA
Fumarate Hydratase: The Abnormal
Gene in HLRCC and MUCL1
• Mutations result in absent or truncated
proteins or changes in highly conserved
amino acid (An absent or disabled FH
protein leads to myomas and other
findings)
Tomlison et al: Nat Genetics 30:406-10, 2002.
Alam et al: Hum Molec Genet 12: 1241-52, 2003
Fumarate Hydratase: Sometimes
involved in non-syndromic fibroids
“garden-variety fibroids”
Appears to be a more important gene for
Caucasian women
Lehtonen et al: Am J Path 164:17-22, 2004
Gross et al: Genes Chrom Cancer 41:183-90, 2004
Markers on Chromosome 1 near the FH Locus
All Families
Families with Dx < 40
African Am Families
Caucasian Families
2
p=0.04
1.5
Zlr score
1
0.5
0
D1S517
D1S2785
D1S547
D1S404
D1S2811
-0.5
-1
-1.5
KL Gross et al. Genes Chrom Cancer 2004;41:183-90.
Clinical Pearls
• Ask about skin lesions
• If cutaneous leiomyomas are present:
Be more suspicious for sarcoma
Refer family for renal cell CA screening
• African-American women have different genes
and thus may respond to treatments differently
Toward
Genotype/Phenotype
Correlation
Submucous fibroids are more likely to
have normal karyotypes.
Bronsens et al: Fertil Steril 69:-5, 1998.
Larger tumors are more likely to carry
t(12;14) and smaller tumors to have del
(7).
Rein et al: Molec Hum Repro 4:83-6,1998.
Predictors of Recurrence Following
Myomectomy
Multivariate HR
Weight gain > 30 lbs since age 18
4.8
History of endometriosis
5.2
Menorrhagia
1.5
Parous
5.0
Uterine size > 12 weeks
0.1
Stewart et al: Obstet Gynecol 99:426-32,2002.
Weight gain after age 18 increases risk of
second surgery following myomectomy
• Heavier women have more estrogen, leading
to fibroid growth.
• Abnormalities of HMGA2 lead to weight
dysregulation and fibroid regrowth.
Stewart et al: Obstet Gynecol 99:426-32,2002.
Finding Genes for Fibroids
Specific Aims
Cytogenetic and epidemiologic evidence suggests
that there is an underlying genetic predisposition to
developing fibroids:
• To identify gene(s) critical to the formation of
uterine fibroids
• To correlate genetic findings with epidemiologic
information and clinical phenotype of fibroids
Finding Genes for Fibroids
Study Design
Recruit 500 affected sister-pairs + family
Collect epidemiologic surveys
Collect blood samples
Perform genotype analysis
Finding Genes for Fibroid Study
• Enrollment goal: 50% African-American
• Families: Any location FedEx can reach
• Contact us:
www.fibroids.net
1-800-722-5520 Ext 80081