Genetic Determinants of Postmenopausal Breast and Endometrial Cancer

Breast cancer is overall the most common cancer in women worldwide and endometrial cancer is the most common gynaecological cancer in the industrialized world. History of a first-degree relative with breast or endometrial cancer has been related to a twofold increase in risk of the respective diseases. Whilst genetic risk factors for endometrial cancer in general or for breast cancer in women not carrying any high-penetrance mutations are largely unknown, a polygenic model has been suggested to account for residual familial risk. This model anticipates small effects of common, low-penetrance genetic risk variants in combination with environmental influence. We thus set out to study common variation in key breast and endometrial cancer genes in relation to a) breast or endometrial cancer risk overall or in subgroups of environmental risk factors, b) the risk of tumour characteristics-defined breast cancer, or c) breast cancer death. In this population-based case-control study, we included 1579 breast cancer cases, 705 endometrial cancer cases and 1565 shared controls. All participants donated tissue or whole blood and provided detailed information about various lifestyle factors through questionnaires. The CYP17, ATM, CHEK2 and ERBB2 genes have all been suggested to play a key role in cancer aetiology and progression. They are important candidate genes in breast and endometrial cancer aetiology specifically through their involvement in the estrogen metabolism pathway, DNA-damage response or cell proliferation. We genotyped common single nucleotide polymorphisms (SNPs) and rare variants in these genes in all cases and controls. Using regression models, we then assessed the effect of the variants and their haplotypes on cancer risk and survival. We found that the rare 1100delC deletion in CHEK2 was more common in breast cancer cases than controls and increased breast cancer risk with an odds ratio of 2.26 (95% CI 0.99–5.15) for carriers versus non-carriers. Our results also indicated an increased risk of developing endometroid endometrial cancer for homozygous carriers of the rare allele (AA) of a tagSNP (rs4987886) in CHEK2 (P = 0.005), when contrasted with GG carriers. In addition, we found a decreased endometrial cancer risk among non-smoking carriers of a haplotype in ATM (P = 0.0007) and among carriers of a haplotype in CHEK2 who had experienced menopause below 49 years of age (P = 0.0009), compared to non-carriers of these haplotypes. We found no effect of genetic variation in CYP17 on breast cancer risk regardless of histopathology or menopausal hormone use. The ATM, CHEK2 or ERBB2 genes did not appear to affect the risk of tumour characteristics-defined breast cancer or breast cancer death. We did not find any evidence supporting a role for the ATM and ERBB2 genes in breast cancer aetiology, and the ERBB2 gene also did not seem to have an effect on endometrial cancer risk. Our estimate of the breast cancer risk related to the CHEK2*1100delC is in line with previous studies published in Northern European populations. Further studies regarding CHEK2 or ATM in relation to endometrial cancer risk are however required for corroboration since our results became statistically non-significant after multiple testing adjustment. LIST OF PUBLICATIONS This thesis is based on the following papers: I. Einarsdóttir K, Rylander-Rudqvist T, Humphreys K, Ahlberg S, Jonasdottir G, Weiderpass E, Chia KS, Ingelman-Sundberg M, Persson I, Liu J, Hall P, Wedrén S. CYP17 gene polymorphism in relation to breast cancer risk: a case-control study. Breast Cancer Research 2005; 7(6):R890-R896. II. Einarsdóttir K, Humphreys K, Bonnard C, Palmgren J, Iles MM, Sjölander A, Li Y, Chia KS, Liu E, Hall P, Liu J, Wedrén S. Linkage Disequilibrium Mapping of CHEK2: Common Variation and Breast Cancer Risk. PLoS Medicine 2006; 3(6):e168. III. Einarsdóttir K, Rosenberg LU, Humphreys K, Bonnard C, Palmgren J, Li Y, Li Y, Chia KS, Liu ET, Hall P, Liu J, Wedrén S. Comprehensive analysis of the ATM, CHEK2 and ERBB2 genes in relation to breast tumour characteristics and survival: a population-based case-control and follow-up study. Breast Cancer Research 2006; 8(6):R67 IV. Einarsdóttir K, Humphreys K, Bonnard C, Li Y, Li Y, Chia KS, Liu ET, Hall P, Liu J, Wedrén S. Effect of ATM, CHEK2 and ERBB2 tagSNPs and Haplotypes on Endometrial Cancer Risk. Human Molecular Genetics 2006; Advance Access December 12