ANDROGEN RECEPTOR EXON 1 CAG REPEAT LENGTH AND RISK OF OVARIAN CANCER Amanda B. SPURDLE 1 * , Penelope M. WEBB 2 , Xiaoqing CHEN 1 , Nicholas G. MARTIN 3 , Graham G. GILES 4 , John L. HOPPER 5 and Georgia CHENEVIX-TRENCH 1 1 Cancer Unit, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research and The University of Queensland, Brisbane, Queensland, Australia 2 Department of Social and Preventive Medicine, University of Queensland Medical School, Herston, Queensland, Australia 3 Epidemiology Unit, The Queensland Institute of Medical Research and The University of Queensland, Brisbane, Queensland, Australia 4 Cancer Epidemiology Centre, Anti-Cancer Council of Victoria, Australia 5 Centre for Genetic Epidemiology, The University of Melbourne, Carlton, Australia Epidemiological studies indicate that ovarian cancer is an endocrine-related tumour. We conducted a case-control comparison to assess the androgen receptor (AR) exon 1 polymorphic CAG repeat length (CAG n ) as a risk factor for epithelial ovarian cancer. AR CAG n was determined for 319 case subjects with ovarian adenocarcinoma and 853 unaf- fected control subjects (comprising 300 unrelated adult fe- male monozygotic twins, and 553 adult females sampled randomly from the population using the electoral rolls). The CAG n distributions of case subjects and control subjects were compared as a continuum, and by dichotomising alleles according to different CAG n cut-points. Logistic regression was used to calculate age-adjusted odds ratio (OR) estimates. Analyzed as a continuous variable, there was no difference between case subjects and control subjects for the smaller, larger or average allele sizes of the CAG n genotype, before or after adjusting for age. The mean (95% CI) for the average CAG n was 22.0 (21.8 –22.2) for case subjects and 22.0 (21.9 – 22.1) for control subjects (p > .9). Analysis of CAG n as a dichotomous variable showed no difference between case subjects and control subjects for the median cutpoint (> 22), or for another cut-point previously reported to act as a modifier of breast cancer risk (> 29). Our data provide no evidence for an association between ovarian cancer risk and the genotype defined by the AR exon 1 CAG n polymorphism, although we cannot exclude small effects, or threshold ef- fects in a small subgroup. Int. J. Cancer 87:637– 643, 2000. © 2000 Wiley-Liss, Inc. Ovarian cancer is the main cause of death among women with gynaecological malignancies, and the lifetime risk in Australian women is 1 in 99 (AIHW and AACR, 1998). Other than age, family history is the strongest risk factor for ovarian cancer (Parazzini et al., 1991; Purdie et al., 1995). For example, in Australia, having one first-degree relative with ovarian cancer was found to be associated with a fourfold increase in risk of ovarian cancer (Purdie et al., 1995). Hereditary ovarian cancer can be caused by mutations in the breast cancer susceptibility genes BRCA1 and BRCA2, or in the mismatch repair genes hMSH2 and hMLH1 (reviewed by Boyd and Rubin, 1997). However, muta- tions in these genes are unlikely to contribute greatly to the aetiology of ovarian cancer in general, since most ovarian cancer cases are “sporadic” in that they do not appear to have a family history of the disease, and likewise the vast majority (99%) of Australian women with ovarian cancer would not be classified as “high-risk” familial cases. Furthermore, the rarity of mutations in BRCA1, BRCA2 and the mismatch repair genes would suggest that they are unlikely to explain more than a small proportion of familial aggregation in ovarian cancer, and BRCA1 mutations have been shown to account for only about 5% of ovarian cancer cases diagnosed before the age of 70 years in a population-based UK study (Stratton et al., 1997), while a recent UK study of familial ovarian cancer detected BRCA1 and BRCA2 mutations in only 20% of families with two cases of ovarian cancer (Gayther et al., 1999). It is thus likely that common “low-risk” allelic variants in these or other genes account for at least some predisposition to ovarian cancers occurring in the general population. In an attempt to identify such low-risk ovarian cancer susceptibility genes, we are using the candidate gene approach to compare large samples of women with ovarian cancer and control subjects. Epidemiological studies indicate that ovarian cancer is an en- docrine-related tumour (Parazzini et al., 1991), and androgens have been implicated in the aetiology of the disease (Risch, 1998). Elevated levels of androstenedione and dehydroepiandrosterone have been observed in case subjects (Helzlsouer et al., 1995), androgen receptors have been identified within epithelial cells of normal ovaries (Al-Timimi et al., 1985), and animal models indi- cate that testosterone stimulates the growth of ovarian surface papillomas and cystadenomas in vivo (Silva et al., 1997). The androgen receptor (AR) gene is involved in various path- ways, including the differentiation, development and regulation of cell growth. A role in cancer predisposition is suggested by re- ported associations between prostate cancer risk and the length of the polymorphic exon 1 CAG repeat (CAG n ) within the AR transactivation domain (Irvine et al., 1995; Giovanucci et al., 1997; Hakimi et al., 1997; Ingles et al., 1997; Stanford et al., 1997). From the two largest research studies, one with 269 high- grade prostate cancer case subjects and 588 control subjects found a relative risk of 2.1 (95% confidence interval [CI] = 1.1– 4.0) for CAG n  19 (Giovanucci et al., 1997), while a second study of 281 prostate cancer case subjects and 246 control subjects found a relative risk of 2.2 (95% CI = 1.1– 4.7) for CAG n  22 in a subgroup of relatively thin individuals (body mass index  24.4) (Stanford et al., 1997). Furthermore, early onset prostate cancer case subjects have been reported to have shorter repeat lengths (Hardy et al., 1996), and CAG n  22 also appears to be associated with an increased risk of benign prostatic hyperplasia (Giovanucci et al., 1999). Biological significance of the CAG repeat length variation is suggested by in vitro studies, which have demonstrated that smaller repeat lengths exhibit greater transactivation capabilities (Chamberlain et al., 1994). In vivo, greatly expanded CAG n ( 39) has been shown to be associated with spinal and bulbar muscular atrophy (SBMA) (La Spada et al., 1991). The biological impor- tance is emphasized at the extreme lengths within the SBMA range, with an increase in repeat length correlating with younger age at onset of this disorder, and also with the likelihood of clinical Grant sponsor: National Health and Medical Research Council; Grant number: 98 1311. *Correspondence to: Amanda B. Spurdle, Ph.D., Cancer Unit, Queens- land Institute of Medical Research, P.O. Royal Brisbane Hospital, Queens- land, 4029, Australia. Fax: +617 3362 0105. E-mail: mandyS@qimr.edu.au Received 21 December 1999; Accepted 20 March 2000 Int. J. Cancer: 87, 637– 643 (2000) © 2000 Wiley-Liss, Inc. Publication of the International Union Against Cancer