title: Multi-variant pathway association analysis reveals the importance of genetic determinants of estrogen metabolism in breast and endometrial cancer susceptibility.
abstract: Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (p(global) = 0.034) and endometrial (p(global) = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (p(global) = 0.008) and endometrial cancer (p(global) = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (p(global) = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (p(global) = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen-estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Yen Ling
authors.initials: YL
authors.lastname: Low
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Li
authors.forename: Keith
authors.initials: K
authors.lastname: Humphreys
authors.forename: Anbupalam
authors.initials: A
authors.lastname: Thalamuthu
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Hatef
authors.initials: H
authors.lastname: Darabi
authors.forename: Sara
authors.initials: S
authors.lastname: Wedrén
authors.forename: Carine
authors.initials: C
authors.lastname: Bonnard
authors.forename: Kamila
authors.initials: K
authors.lastname: Czene
authors.forename: Mark M
authors.initials: MM
authors.lastname: Iles
authors.forename: Tuomas
authors.initials: T
authors.lastname: Heikkinen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aittomäki
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D000728:Androgens / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015331:Cohort Studies; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004967:Estrogens / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D000728:Androgens; D004967:Estrogens; D011960:Receptors, Estrogen