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 FibroidsDepartment of Obstetrics and Gynecology

Brigham and Women’s Hospital

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).

Hypothesis:

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 0.6 + 0.05(Share all genes)

Dizygotic 0.32 + 0.09(Share ½ of genes)

Treloar et al. Amer J Ob Gyn 1992: 167(82-8)

RACE: Strong predictor of risk

• Increased Incidence RatesBlack women 30.6/1000 woman-yearsWhite women 8.9/1000 woman-years

• Increased Relative RiskBlack women 3.25 (2.71- 3.88)White women 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

Citrate

Isocitrate

Ketoglutarate

Succinyl-CoASuccinate

Fumarate

Malate

Oxaloacetate

FH

KREBS CYCLE

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

-1.5

-1

-0.5

0

0.5

1

1.5

2

D1S517 D1S2785 D1S547 D1S404 D1S2811

KL Gross et al. Genes Chrom Cancer 2004;41:183-90.

Zlr s

core

All Families Families with Dx < 40 African Am Families Caucasian Families

p=0.04

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

TowardGenotype/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 FollowingMyomectomy

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 FibroidsSpecific 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 FibroidsStudy Design

Collect epidemiologic surveys

Collect blood samples

Perform genotype analysis

Recruit 500 affected sister-pairs + family

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