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

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 (Share all genes) Dizygotic (Share ½ of genes) Treloar et al. Amer J Ob Gyn 1992: 167(82-8)

RACE: Strong predictor of risk Increased Incidence Rates Black women 30.6/1000 woman-years White women 8.9/1000 woman-years Increased Relative Risk Black women 3.25 ( ) 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: , Estimated 2 x risk to relatives in families with myoma uteri over general population. Kurbanova et al: Genetika 25: , 1989.

The Zebras: Rare Syndromes

OMIM Online Mendelian Inheritance in Man fcgi?db=OMIMhttp://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 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 Uterine Leiomyomas and Sarcomas Cutaneous Leiomyomas Papillary renal cell cancer Autosomal dominant Launonen et al: PNAS 98: , 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-CoA Succinate 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, Alam et al: Hum Molec Genet 12: , 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

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, 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 History of endometriosis5.2 Menorrhagia1.5 Parous5.0 Uterine size > 12 weeks0.1 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 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: Ext 80081