Abstract P6-06-02: UGT1A1*28 and Breast Cancer: Increased Risk for Gilbert's Syndrome Patients

Abstract

Abstract Introduction: Estrogens are essential for the initiation and development of breast cancer (BC). Among the enzymes involved in conjugation and inactivation of estrogens and its metabolites, there is the UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in the promoter region of the UGT1A1 gene are common in patients with Gilbert's syndrome (GS), reducing the enzyme activity by about 80%. Although considered benign, patients with Gilbert's Syndrome (GS) have lower activity of UGT1A1, which may lead to a higher risk for estrogen-dependent cancers, such as breast cancer (BC). Methods: Case control-study and meta-analysis. Setting: academic tertiary hospital in Brazil. Cases: Women with recently operated BC, no previous neoplasm or immunossuppression. Controls: Healthy women, older than 40 years old, mammography BIRADS 1 or 2 in the last 12 months, no previous neoplasm or immunossupression. Interventions: data collection; sequencing of the UGT1A1 gene. Literature search: PubMed, EMBASE, SciElo, hand search. Languages: English, German, Spanish, Portuguese. Studies: case-control studies, BC patients and healthy subjects, genetic diagnosis of GS. Results: From August 2008 to November 2009, 89 cases and 56 controls were enrolled. Patients were significantly older than controls (median 52 (46-64) vs 47 (43-50) y/o p=0.013), with comparable body mass index (median 27.55 vs 25.95 p=0.46), age at menarche (median 13 vs 13 p=0.68), age at menopause (median 48 vs 45, p=0.24), age at first full-term pregnancy (median 22 vs 23 p=o.46) and proportion of individuals with first degree-relatives with BC (22% vs 19%, p=0.68). The prevalence of GS was 19.1% in cases and 12.5% in controls (adjusted OR 1.65 CI95% 0.63-4.28 p=0.29), but the study was underpowered to detect differences smaller than 21%. The meta-analysis included 10 studies with 5815 BC patients and 8255 controls. There was a weak association between GS and BC (OR 1.13 CI95% 1.01-1.26 I2=2%), which was stronger for Caucasians (OR 1.14 CI95% 1.01-1,29 I2 = 20%), estrogen-receptor positive BC (OR 1.18 CI 95% 1.02-1.35 I2=0%) and individuals with a family history of BC (OR 1.4 CI95% 1.01-1.95 I2=0%). Conclusions: In our study, the polymorphism UGT1A1 *28/*28, present in most individuals with Gilbert's syndrome, was an important risk factor for developing breast cancer. Gilbert's syndrome, usually considered benign, may be a risk factor for breast cancer. There have been no studies evaluating the incidence of BC in patients with GS. Prospective studies with patients diagnosed with SG are needed to confirm this hypothesis and assess other patients subgroups. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-06-02.