Journal of the National Cancer Institute Advance Access published online on March 11, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn037
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© The Author 2008. Published by Oxford University Press.
BRIEF COMMUNICATION |
Association of a Common AKAP9 Variant With Breast Cancer Risk: A Collaborative Analysis
Affiliations of authors: Helmholtz-University Group Molecular Epidemiology (BF, MW, BB), Divisions of Molecular Genetic Epidemiology (BF, MW, KH, BB) and Cancer Epidemiology (SK, TS, JCC), and Research Group Molecular Genetics of Breast Cancer (KA, UH), German Cancer Research Center, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany; Center for Family Medicine, Karolinska Institute, Huddinge, Sweden (KH); The Queensland Institute of Medical Research, Herston, Queensland, Australia (ABS, XC, JB, AOCSMG, GCT); Institutes of Human Genetics (CS, CRB) and Transfusion Medicine and Immunology, Red Cross Blood Service of Baden-Württemberg-Hessen, Faculty of Mannheim (PB), University of Heidelberg, Heidelberg, Germany; Division of Molecular Gynaeco-Oncology, Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Cologne, Germany (BW, RKS); Center of Molecular Medicine Cologne, University Hospital of Cologne, Cologne, Germany (BW, RKS); Centre for Molecular, Environmental and Analytic Epidemiology (JLH), The University of Melbourne (ABCFSI), Victoria, Australia; Department of Gynaecology and Obstetrics, Klinikum rechts der Isar at the Ludwig Maximilians and Technical University, Munich, Germany (AM, MK); Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany (DFJ, EM); Bioglobe GmbH, Hamburg, Germany (RS); Sections of Cancer Genetics (EW, RH) and Epidemiology (JP), Institute of Cancer Research, Sutton, Surrey, UK; Dr Margarete Fischer Bosch Institute of Clinical Pharmacology and University Tuebingen, Stuttgart, Germany (HB, CJ); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus Bonn, Bonn, Germany (YDK); Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin, Ruhr University Bochum, Bochum, Germany (TB); Cancer Research UK Epidemiology and Genetics Group, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (IdSS, JP); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (NJ, OF); Department of Oncology (PPDP, AMD, KAP) and Cancer Research-UK Genetic Epidemiology Unit, Department of Public Health and Primary Care (DFE), University of Cambridge, Cambridge, UK; Peter MacCallum Cancer Centre, East Melbourne, Australia (kConFaBI, AOCSMG)
Correspondence to: Barbara Burwinkel, PhD, Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany (e-mail: b.burwinkel{at}dkfz.de).
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ABSTRACT |
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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).
Prior knowledge Sequence variations, or polymorphisms, in A-kinase anchoring protein (AKAP) genes are involved in carcinogenesis. Study design Analysis of AKAP single-nucleotide polymorphisms in breast cancer patients and control subjects in seven case–control studies performed in Europe and Australia and their associations with familial and nonfamilial breast cancer. The function of the polymorphisms was predicted. Contribution Polymorphisms in AKAP9 M4631 were associated with increased risks for familial and nonfamilial breast cancer. The polymorphisms were predicted to affect the function of the encoded protein. Implications The functional consequence of the AKAP9 M4631 polymorphism may involve the PKA pathway. Limitations The functional consequence of the polymorphism was not tested and is unknown. Whether or not the association also occurs in other populations is unknown.
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Germline mutations in the high-penetrance genes BRCA1 and BRCA2 account for up to 25% of the familial risk of breast cancer (1,2). The excess familial risk may be largely subject to polygenic inheritance due to the combined effects of multiple low-penetrance genetic variants (3). Most association studies have focused on nonsynonymous single-nucleotide polymorphisms (SNPs) in cancer-related genes that are expected to be directly associated with disease. Whereas genes whose products are involved in DNA repair (BRCA1, BRCA2, ATM, CHEK2, TP53, BRIP1, and PALB2) and metabolism of carcinogens (GSTM1, GSTT1, NAT1, and NAT2) and estrogen (COMT, CYP1A1, CYP17A1, CYP19A1, and NCOA3) have been studied extensively (4–11), the role of A-kinase anchoring protein (AKAP)–encoding genes has remained largely underinvestigated.
AKAP family members are structurally different yet functionally related proteins that bind and anchor the Ser/Thr protein kinase A (PKA) to specific subcellular sites, thereby confining PKA activity to potential substrates, such as cyclic adenosine monophosphate (cAMP) (12,13). PKA overexpression, which is a hallmark of the vast majority of human tumors, leads to the activation of effectors along the RAS–RAF–MAPK pathway and, as a result, is associated with a poor prognosis in several tumor types, including breast cancer (14–16). The two main PKA subtypes are defined by the identity of their regulatory subunits, RI and RII. Although several "dual specificity" AKAPs exist, most AKAPs bind specifically to the PKA RII holoenzyme through lipid modifications and protein–protein interaction domains to trigger PKA-mediated phosphorylation events (12). AKAPs also serve as scaffolding proteins and bring together PKA with signal terminators, such as phosphatases, cAMP-specific phosphodiesterases, and components of other signaling pathways to form multiprotein signaling complexes (12,13). Recent studies have identified the C-terminal AKAP10 (D-AKAP2) 646V variant as deleterious because it is associated with reduced PKA-RI
subcellular localization and with susceptibility to clinical phenotypes, such as cardiac dysfunction and breast cancer (17–19).
There is accumulating evidence that AKAP expression and gene variation are directly associated with cancer development. AKAP3 mRNA expression appears to be associated with poor prognosis in epithelial ovarian cancer (20), and genetic alterations of AKAP9, AKAP11, AKAP12, and AKAP13 are associated with the etiology of colorectal and lung cancer (21,22) and oral (23), gastric (24), prostate, and breast (25,26) cancers.
In this study, all 52 nonsynonymous AKAP SNPs that have been identified to date were tested for their functional impact by means of literature/database searches (PubMed/Ensembl) and in silico programs (27). Six putative protein-damaging polymorphisms were selected for analysis of breast cancer risk. Using a case–control study design, we genotyped AKAP3 E118G, AKAP5 P100L, AKAP6 F2171Y, AKAP9 M463I, AKAP9 N2792S, and AKAP12 E920G in 1110 familial case patients and 1131 control subjects from Germany (step I). Familial, BRCA1/2 mutation–negative case patients were used to increase the statistical power. The increased power of using familial case patients is estimated to reduce the sample size required to find a small relative risk by two- to fourfold (28). We found an association with increased familial breast cancer risk for AKAP9 M463I and N2792S carriers. To further examine the relevance of these findings, we subsequently analyzed AKAP9 M463I, which is in strong linkage disequilibrium (LD) with AKAP9 N2792S, in 9523 breast cancer case patients and 13770 control subjects from Germany, the United Kingdom, and Australia (step II).
A detailed description of the seven contributing studies is shown in Supplementary Data (available online). In brief, the participating studies were the following: Australian Breast Cancer Family Study (ABCFS) (5,29,30), British Breast Cancer Study (BBCS) (4,21,22,30,31), Gene Environment Interaction and Breast Cancer in Germany (GENICA) (9,32), German Familial Breast Cancer Study (GFBCS) (33), Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer/Australian Ovarian Cancer Study (kConFaB/AOCS) (5,34–36), Mammacarcinoma Riskfactor Investigation (MARIE), and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) (37–39).
All studies were approved by the appropriate local Institutional Review Board or Human Research Ethics Committees, and written informed consent was obtained from all participants. For all studies, we defined familial breast cancer patients as having at least one affected first-degree family member and/or bilateral breast cancer and/or were younger than 40 years (28,30). According to this definition, familial breast cancer case patients are individuals who are potentially genetically enriched for the detection of low-penetrance genes that act in a complex genetic trait (2,8). Thus, patients with bilateral breast cancer are (statistically) equivalent to patients in families with three members (themselves and two other members) who have breast cancer (28).
Of the nonsynonymous SNPs identified in AKAP1–14, we selected candidate nonsynonymous SNPs that 1) showed in silico evidence to be probably damaging to the function of the respective protein by applying the in silico tools SIFT (http://blocks.fhcrc.org/sift) and PolyPhen (http://coot.embl.de/PolyPhen) (27), 2) occurred with an allele frequency greater than 0.05, and 3) had not been previously analyzed for an association with breast cancer risk. Applying these criteria, we found seven putative functionally relevant SNPs. Due to technical reasons, we did not analyze the AKAP1 A18V (rs17761023) variant, which was predicted (Ensembl) to reside within a transmembrane domain responsible for protein cleavage.
Initial genotyping of the AKAP variants (step I: GFBCS study, Table 1) was carried out by using TaqMan allelic discrimination, as previously described (41). TaqMan primers and probes were provided by the assay-by-design service (Applied Biosystems, Foster City, CA) and designed on the basis of GenBank sequences NT_009759 [GenBank] (AKAP3 E118G, rs2072355), NT_026437 [GenBank] (AKAP5 P100L, rs2230491), NT_026437 [GenBank] (AKAP6 F2171, rs4647899), NT_007933 [GenBank] (AKAP9 M463I, rs6964587 and AKAP9 N2792S, rs6960867), and NT_025741 [GenBank] (AKAP12 E920G, rs13212161).
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The extended analyses (step II) of rs6964587 (AKAP9 M463I) were conducted using TaqMan (GENICA, GFBCS, MARIE, and SEARCH studies), iPLEX (Sequenom, San Diego, CA) (ABCFS, kConFaB/AOCS, and MARIE studies), and customized Illumina Sentrix Bead Arrays (BBCS). For quality control, more than 3% of randomly selected samples in each study were subjected to repeated analysis, yielding a concordance rate of 100%. Genotyping call rates for all studies were greater than 95%.
The primary test for association was a 2-df 
2 test comparing genotype frequencies between case patients and control subjects for each study. Relative risks were estimated as odds ratios (ORs) using unconditional logistic regression for the general model (three genotype levels) and the dominant model (two genotype levels). Age (as a continuous variable) and study (as a categorical variable) were included in the regression models as covariates. The analyses were repeated for each study separately and for the combined data (step II). Deviations of the genotype frequencies in the control subjects from those expected under Hardy–Weinberg equilibrium (HWE) were assessed using Pearson's goodness-of-fit 2 test with 1 df. All analyses were performed using the Statistical Analysis System software (version 9.1.; SAS Institute Inc., Cary, NC). The extent of heterogeneity across studies was examined by Cochran 2 test or Q test using the Comprehensive Meta-analysis Version 2 (Biostat, Englewood, NJ, 2005). Power calculation was carried out with the power and sample size software PS (http://biostat.mc.vanderbilt.edu/twiki/bin/view/Main/PowerSampleSize). LD calculation was performed by the Haploview software (42). All statistical tests were two-sided.
In the genotyping analysis of the six initial AKAP variants (step I), we found no association of the AKAP3 E118G, AKAP5 P100L, AKAP6 F2171Y, and AKAP12 E920G variants with familial breast cancer in a German population (GFBCS, Table 1). AKAP9 M463I and N2792S were marginally associated with an increased risk of familial breast cancer (for M4631, TT + GT vs GG: OR = 1.22, 95% confidence interval [CI] = 1.02 to 1.45, P = .03, and for N2792S, GG + AG vs AA: OR = 1.22, 95% CI = 1.03 to 1.45, P = .02; Table 1). The minor allele frequencies in control subjects of the SNPs analyzed were 0.19 (AKAP3 E118G), 0.13 (AKAP5 P100L), 0.27 (AKAP6 F2171Y), 0.37 (AKAP9 M463I), 0.37 (AKAP9 N2792S), and 0.09 (AKAP12 E920G). The null findings for AKAP3 rs2072355, AKAP5 rs2230491, and AKAP12 rs13212161 are supported by the data published in the Cancer Genetic Markers of Susceptibility database (adjusted P values for these three SNPs were .87, .76, and .27, respectively). This National Cancer Institute (NCI) enterprise conducts whole-genome association studies to identify breast cancer susceptibility genes using Illumina HumanHap550 assays on approximately 1200 case patients and control subjects (US female nurses; https://caintegrator.nci.nih.gov/cgems/). Their whole-genome association studies, however, did not include AKAP6 rs4647899 or AKAP9 rs6964587 or rs6960867.
According to the GFBCS data, AKAP9 M463I and N2792S polymorphisms showed strong LD in control subjects (D' = .98, r2 = .97), covering an LD block of 367 kb in size (42). We chose AKAP9 M463I for the advanced analysis and included case patients and control subjects from the ABCFS, BBCS, GENICA, kConFaB/AOCS, MARIE, and SEARCH studies (step II). The genotype distributions in control subjects were consistent with HWE in all seven studies.
We found a statistically significant association of AKAP9 M463I T allele with an increased breast cancer risk in a dose-dependent manner (Ptrend = .0002). The combined adjusted odds ratios (step II) were 1.17 (TT vs GG, 95% CI = 1.08 to 1.27, P = .0003) (Figure 1, B), 1.08 (GT vs GG, 95% CI = 1.02 to 1.15, P = .01), and 1.10 (TT + GT vs GG, 95% CI = 1.04 to 1.17, P = .001) (Figure 1, A). When we restricted the analysis to breast cancer case patients who were defined as familial, the odds ratios were slightly higher: 1.27 (TT vs GG, 95% CI = 1.12 to 1.45, P = .0003) (Figure 1, D), 1.12 (GT vs GG, 95% CI = 1.02 to 1.24, P = .02), and 1.16 (TT + GT vs GG, 95% CI = 1.06 to 1.27, P = .001) (Figure 1, C). The phenomenon of increasing risks with familial aggregation has been observed previously (3,5,28,43) and indicates that susceptibility alleles that confer low risk are slightly more common in patients with a family history of breast cancer than in patients with sporadic breast cancer, leading to differences in allele frequencies between familial case patients and control subjects (28). With the present overall sample size (step II), we had a power of 90% at a statistical significance level of .05 to detect an odds ratio greater than 1.09 for breast cancer and greater than 1.16 for familial breast cancer with respect to M463I.
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No heterogeneity across studies was observed (P = .49), and the T allele frequencies of AKAP9 M463I in control subjects ranged from 0.37 to 0.39 (mean = 0.38). Assuming dominant penetrance and the estimated effects to be true, AKAP9 M463I would account for a population attributable fraction of approximately 5.6% (5). Odds ratios were greater than 1.0 for all studies but one—the Australian familial breast cancer group kConFaB/AOCS. This result is most likely due to chance because the upper confidence intervals for the kConFaB/AOCS subgroup analysis include the risk estimates observed for all studies combined and because results for the other Australian study (the ABCFS) were similar to the overall findings.
According to the functional predictions using the programs PolyPhen and SIFT, AKAP9 M463I is deleterious (27). To some extent, in silico prognoses about the functional impact of nonsynonymous amino acid exchanges are speculative. However, these algorithms have been shown to be approximately 80% successful in benchmarking studies (44). Our findings that the AKAP9 M463I T allele is associated with breast cancer support both in silico predictions. It is also of interest that this variant has previously been found to be associated with colorectal and lung cancer risk (21,22). However, it is possible that the AKAP9 N2792S G allele—due to strong LD and also being predicted to be deleterious—accounts for the observed association or that AKAP9 M463I and N2792S provoke risk enhancement mutually, resulting in shifted PKA localization and function. Alternatively, it is possible that neither of these variants are directly associated with breast cancer but are in LD with one or more other, perhaps rare, variants that are associated with risk in this or neighboring genes.
Ciampi et al. (45) reported an in-frame fusion between the C-terminal catalytic domain (exons 9–18) of the Ser/Thr kinase BRAF and the N-terminus (exons 1–8) of AKAP9, leading to constitutive BRAF and MAPK pathway activation in thyroid papillary carcinomas (44–47). In the AKAP9–BRAF fusion protein, AKAP9, which is normally localized to the centrosome and Golgi, lacks the C-terminal centrosomal domain and thus loses its centrosomal localization in cancer cells. Furthermore, wild-type AKAP9 could not be immunohistochemically detected within the centrosomes of cancer cells in all patients with the AKAP9–BRAF mutant, suggesting competitive inhibition of wild-type AKAP9 by AKAP9–BRAF (43). Hence, the deregulation of the multitude of cellular AKAP9 functions in cells that harbor AKAP9–BRAF mutants may affect a variety of physiologic processes.
We hypothesize that the T allele of AKAP9 M463I has oncogenic potential by altering PKA compartmentalization. As part of the AKAP9–BRAF fusion protein, this variant (located in exon 8) may also affect BRAF protein activation and give rise to carcinogenesis.
A limitation of our study is that the functional effect of AKAP9 463I (and/or AKAP9 2792S) has not been shown. If the AKAP9 463I and/or the 2792S variant are functionally responsible for the risk association, and considering the high allele frequency of AKAP9 463I (and AKAP9 2792S) the observed association is likely to occur also in other populations. However, if AKAP9 463I (and AKAP9 2792S) are not functionally relevant and are in LD with a perhaps rare causative variant, the association might not be observed or might be even stronger in other ethnic groups. Further studies investigating populations of different ethnic groups will help to clarify this issue.
In summary, by combining the results of seven independent case–control studies, we found that the T allele of AKAP9 M463I was associated with an increased breast cancer risk. The risk association of the AKAP9 M463I T allele was slightly stronger when the analysis was confined to familial breast cancer.
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Funding |
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ABCFS was supported by the National Health and Medical Research Council (NHMRC) of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation and the US National Cancer Institute, National Institutes of Health (RFA # CA-95-003) as part of the Breast Cancer Family Registries (CFRs) and through cooperative agreements with the Fox Chase Cancer Center, Huntsman Cancer Institute, Columbia University, Northern California Cancer Center, Cancer Care Ontario, and The University of Melbourne.
The GENICA study was supported by the German Human Genome Project and funded by the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung) (01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114). Genotyping analyses were supported by the German Cancer Research Center (DKFZ), Heidelberg, Germany.
The German familial breast cancer samples were collected within a project funded by the Deutsche Krebshilfe. It was supported by the Center of Molecular Medicine Cologne and the European Union (LSHC-CT-2004-503465).
kConFaB is supported by the National Breast Cancer Foundation, the National Health and Medical Research Council of Australia, and the Cancer Councils of Queensland, New South Wales, Western Australia, South Australia, and Victoria. The Clinical Follow-up Study of kConFaB is funded by the National Health and Medical Research Council (NHMRC) of Australia (145684 and 288704).
The AOCS, which provided control samples only for the study, was supported by the US Army Medical Research and Materiel Command (DAMD17-01-1-0729), the National Health and Medical Research Council of Australia (199600), the Cancer Council Tasmania and Cancer Foundation of Western Australia. The genotyping and analysis were supported by grants from the National Health and Medical Research Council (NHMRC). ABS is funded by an NHMRC Career Development Award, and G. Chenevix-Trench and J. L. Hopper are NHMRC Senior Principal Research Fellows.
The MARIE study was supported by the Deutsche Krebshilfe e. V. (Project No. 70-2892-BR I).
SEARCH was funded by a program grant from Cancer Research UK.
Control subjects were drawn from the EPIC-Norfolk cohort that was supported by Cancer Research UK and the Medical Research Council with additional support from the Stroke Association, British Heart Foundation, Department of Health, Research into Ageing, and Academy of Medical Sciences.
D. F. Easton is a Principal Research Fellow and P. P. D. Pharoah a Senior Clinical Research Fellow of Cancer Research UK.
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NOTES |
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We thank kConFaB nurses, staff of the Familial Cancer Clinics, Heather Thorne, Eveline Niedermayr, Helene Holland, and Gillian Dite for their contributions to the kConFaB and ABCFS studies and the Clinical Follow-up Study of kConFaB for supplying some data. The AOCS Management Group members include David Bowtell, Adele Green, Penny Webb, Anna DeFazio, and Dorota Gertig.
We thank the study participants and the SEARCH research team for their contributions: Mitul Shah, Hannah Munday, Clare Jordan, Barbara Perkins, Judy West, Karen Redman, Craig Luccarini, Don Conroy, Kristy Driver, and Jonathan Morrison and the Eastern Cancer Registry and Intelligence Unit. We thank Robert Luben and the EPIC management team (K. -T. Khaw, S. Bingham, and N. Wareham) for access to control samples and data.
We also wish to thank all participants who joined the studies and are grateful to J. L. Bermejo, U. Eilber, B. Kaspereit, N. Knese, K. Smit, and B. Pesch for their valuable contributions. The content of this manuscript does not necessarily reflect the views or policies of the NCI or any of collaborating centers in the Breast Cancer Family Registries (CFRs), nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFRs. The sponsors had no role in the study design, the data collection and analysis, the interpretation of the results, the preparation of the manuscript, or the decision to submit the manuscript for publication.
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Manuscript received September 11, 2007; revised January 16, 2008; accepted January 24, 2008.
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J Natl Cancer Inst 2008 100: 375.
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