Association of a Common AKAP9 Variant With Breast Cancer Risk: A Collaborative Analysis

Abstract

Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).

Genetic variations as cancer prognostic markers: review and update

“…Moreover, the genes that are somatically mutated (deleted or amplified in tumors) are the ''positional candidate genes'' that we often investigate in cancer susceptibility studies [Imreh et al, 2003;Oldenburg et al, 2007]. Utilization of such approaches has elucidated many cancer susceptibility alleles: XRCC3 (MIM] 600675) [Han et al, 2006;Manuguerra et al, 2006] and ERCC2 (MIM] 126340) [Manuguerra et al, 2006] (two DNA repair genes associated with risks of several cancer sites); the polymorphisms from CYP1B1 gene (MIM] 601771) (involved in estrogen metabolism) [Paracchini et al, 2007]; MTHFR (MIM] 607093) (a folate metabolism gene) [Macis et al, 2007]; and AKAP9 (MIM] 604001) (a signal transduction gene) [Frank et al, 2008], all of which are associated with breast cancer risk. These candidates are also all reasonable prognostic factors to evaluate.…”

Analysis of 17β-hydroxysteroid dehydrogenase types 5, 7, and 12 genetic sequence variants in breast cancer cases from French Canadian Families with high risk of breast and ovarian cancer

“…Furthermore, although the CGEMS study did not find a significant association between their HSD17B12 allelic variants and breast cancer risk, it should be noted that the "sporadic" breast cancer cases involved in their study are mostly post-menopausal, while our study only includes cases from high-risk families. Further analyses using larger cohorts, such as those used in recent studies [71,75] are warranted to determine the involvement of HSD17B12 allelic variants in breast cancer risk. It would also be of importance to perform these large-scale studies in pre-menopausal breast cancer cases, especially taking into consideration the pivotal role of this enzyme in estradiol synthesis.…”

Pharmacological targeting of AKAP-directed compartmentalized cAMP signalling

“…Several AKAPs are differentially expressed in cancer cells and tissues [184,185] where they play important roles by regulating proliferation, migration, invasion and survival [186][187][188][189].…”

“…AKAP450 is highly expressed in colorectal carcinoma cells and its knockdown resulted in attenuation of proliferation and metastasis in a Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1)-dependent mechanism [197]. Moreover, single nucleotide polymorphisms (SNPs) in the encoding AKAP9 gene result in variants associated with breast cancer [187,198]. AKAP450 promotes initiation of DNA synthesis, thus favouring cell cycle progression [199].…”