TY - JOUR
T1 - Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival
AU - Azzato, Elizabeth M.
AU - Tyrer, Jonathan
AU - Fasching, Peter A.
AU - Beckmann, Matthias W.
AU - Ekici, Arif B.
AU - Schulz-Wendtland, Rüdiger
AU - Bojesen, Stig E.
AU - Nordestgaard, Børge G.
AU - Flyger, Henrik
AU - Milne, Roger L.
AU - Arias, José Ignacio
AU - Menéndez, Primitiva
AU - Benítez, Javier
AU - Chang-Claude, Jenny
AU - Hein, Rebecca
AU - Wang-Gohrke, Shan
AU - Nevanlinna, Heli
AU - Heikkinen, Tuomas
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Margolin, Sara
AU - Mannermaa, Arto
AU - Kosma, Veli Matti
AU - Kataja, Vesa
AU - Beesley, Jonathan
AU - Chen, Xiaoqing
AU - Chenevix-Trench, Georgia
AU - Couch, Fergus J.
AU - Olson, Janet E.
AU - Fredericksen, Zachary S.
AU - Wang, Xianshu
AU - Giles, Graham G.
AU - Severi, Gianluca
AU - Baglietto, Laura
AU - Southey, Melissa C.
AU - Devilee, Peter
AU - Tollenaar, Rob A.E.M.
AU - Seynaeve, Caroline
AU - García-Closas, Montserrat
AU - Lissowska, Jolanta
AU - Sherman, Mark E.
AU - Bolton, Kelly L.
AU - Hall, Per
AU - Czene, Kamila
AU - Cox, Angela
AU - Brock, Ian W.
AU - Elliott, Graeme C.
AU - Reed, Malcolm W.R.
AU - Greenberg, David
AU - Anton-Culver, Hoda
AU - Ziogas, Argyrios
AU - Humphreys, Manjeet
AU - Easton, Douglas F.
AU - Caporaso, Neil E.
AU - Pharoah, Paul D.P.
N1 - Funding Information:
Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS) thanks Pilar Zamora from La Paz University Hospital, Madrid, and Anna González-Neira, Charo Alonso, Tais Moreno, and Guillermo Pita from the Spanish National Cancer Research Centre (CNIO). Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC) thanks Ursula Eilber and Tanya Koehler for competent technical assistance. Helsinki Breast Cancer Study (HEBCS) thanks Dr Kirsimari Aaltonen and R. N. Hanna Jäntti for their help with the patient data and gratefully acknowledges the Finnish Cancer Registry for the cancer data. Karolinska Breast Cancer Study (KARBAC) thanks the Cancer Society in Stockholm, the Nilsson Ehle Foundation, and the Swedish Society of Medicine. Kuopio Breast Cancer Project (KBCP) is grateful to Eija Myöhänen for her assistance. The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) thanks David Duffy for helpful comments on the manuscript; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow-Up Study for their contributions to this resource; and the many families that contribute to kConFab. Leiden University Medical Centre Breast Cancer Study (ORIGO) thanks C. J. van Asperen, P. E. A. Huijts, E. Krol-Warmerdam, and J. Blom for patient accrual, administering questionnaires, and managing clinical information. Polish Breast Cancer Study (PBCS) thanks Drs Neonila Szeszenia-Dabrowska and Beata Peplonska of the Nofer Institute of Occupational Medicine (Lodz, Poland); Witold Zatonski of the Department of Cancer Epidemiology and Prevention, the M. Sklodowska-Curie Cancer Center and Institute of Oncology (Warsaw, Poland); Louise Brinton and Stephen Chanock from the Division of Cancer Epidemiology and Genetics of the National Cancer Institute; and Pei Chao from Information Management Services (Silver Spring, MD, USA) for their valuable contributions to the study. Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) thanks the women who have taken part in the study, the SEARCH study team and the consultants and general practitioners throughout East Anglia for their help in recruiting patients, and the staff of the Eastern Cancer Registration and Information Centre and the Thames Cancer Registry for providing outcome and clinical data. Sheffield Breast Cancer Study (SBCS) thanks Helen Cramp, Sabapathy Balasubramanian, Sue Higham, and Dan Connley for assistance with subject recruitment and data collection and Simon Cross for assistance with histopathology.
Funding Information:
Cancer Research UK (C1287 and A7497 to D.F.E.). E.M.A. is supported by the National Cancer Institute and the National Institutes of Health (NIH)– Cambridge Graduate Partnership Program. Bavarian Breast Cancer Cases and Controls (BBCC) was supported by the ELAN Fonds of the University of Erlangen, and P.A.F. is funded by Dr Mildred Scheel Stiftung and Deutsche Krebshilfe e.V. CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Copenhagen University Hospital, Herlev Hospital. Spanish National Cancer Centre Breast Cancer Study (CNIO-BCS) was supported by the Genome Spain Foundation, the Red Temática de Investigación Cooperativa en Cáncer, and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI081120 to J.Ben., PI081583 to R.L.M.]. Genetic Epidemiology Study of Breast Cancer by Age 50 (GESBC) was supported by the Deutsche Krebshilfe e.V. (70492) and GESBC genotyping in part by the state of Baden-Württemberg through the Medical Faculty of the University of Ulm (P.685). Helsinki Breast Cancer Study (HEBCS) has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (110663), the Finnish Cancer Society, and the Sigrid Juselius Foundation. Kuopio Breast Cancer Project (KBCP) is supported by grants from erityisvaltionosuus (EVO) funds of Kuopio University Hospital, EVO funds of Vaasa Central Hospital, the Finnish Cancer Foundation, and the Academy of Finland. The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer is supported by grants from the National Breast Cancer Foundation and the National Health and Medical Research Council (NHMRC) (145684, 288704, and 454508) and by the Queensland Cancer Fund; the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia; and the Cancer Foundation of Western Australia. Mayo Clinic Breast Cancer Study (MCBCS) was supported by grants from the NIH (P50 CA116201 and R01 CA122340). Melbourne Collaborative Cohort Study (MCCS) was supported by NHMRC (209057, 251533, 396414, and 504711). Infrastructure support for the MCCS recruitment and follow-up is provided by the Cancer Council Victoria, whereas cohort recruitment was partly funded by VicHealth. Genotyping was in part supported by the Prostate Cancer Foundation of Australia. Leiden University Medical Centre Breast Cancer Study (ORIGO) was supported by the Dutch Cancer Society. Polish Breast Cancer Study was funded by intramural research funds of the National Cancer Institute, Department of Health and Human Services. SASBAC was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US NIH, and the Susan G. Komen Breast Cancer Foundation. Sheffield Breast Cancer Study (SBCS) was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. University of California Irvine Breast Cancer Study (UCIBCS) is supported by the NIH, National Cancer Institute (CA-58860), and the Lon V. Smith Foundation (LVS-18840).
PY - 2010/5
Y1 - 2010/5
N2 - Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.
AB - Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.
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U2 - 10.1093/jnci/djq057
DO - 10.1093/jnci/djq057
M3 - Article
C2 - 20308648
AN - SCOPUS:77952064652
SN - 0027-8874
VL - 102
SP - 650
EP - 662
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 9
ER -