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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

Bernd Frank, Miriam Wiestler, Silke Kropp, Kari Hemminki, Amanda B. Spurdle, Christian Sutter, Barbara Wappenschmidt, Xiaoqing Chen, Jonathan Beesley, John L. Hopper, Australian Breast Cancer Family Study Investigators,, Alfons Meindl, Marion Kiechle, Tracy Slanger, Peter Bugert, Rita K. Schmutzler, Claus R. Bartram, Dieter Flesch-Janys, Elke Mutschelknauss, Katie Ashton, Ramona Salazar, Emily Webb, Ute Hamann, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Thomas Brüning, Isabel dos Santos Silva, Nichola Johnson, Paul P. D. Pharoah, Alison M. Dunning, Karen A. Pooley, Jenny Chang-Claude, Douglas F. Easton, Julian Peto, Richard Houlston, Gene Environment Interaction and Breast Cancer in Germany Group, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Investigators, Australian Ovarian Cancer Study Management Group, Georgia Chenevix-Trench, Olivia Fletcher, Barbara Burwinkel

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).

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).


CONTEXT AND CAVEATS

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.

 
Manuscript received September 11, 2007; revised January 16, 2008; accepted January 24, 2008.


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