Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer

¹Comprehensive Cancer Center, Departments of ²Community and Family Medicine, ³Obstetrics and Gynecology, and ⁴Surgery, Duke University Medical Center, and ⁵Department of Statistical Science, Duke University, Durham, North Carolina; ⁶Mayo Clinic College of Medicine, Rochester, Minnesota; ⁷Department of Cancer Epidemiology and Prevention, The M. Sklodowska-Curie, Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; ⁸Division of Cancer Epidemiology and Genetics, National Cancer Institute and ⁹Core Genotyping Facility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; ¹⁰Department of Occupational and Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lodz, Poland; ¹¹The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Australia for Australian Cancer Study and the Australian Ovarian Cancer Group; ¹²Peter MacCallum Center, East Melbourne, Victoria, Australia; ¹³H. Lee Moffitt Cancer Center, Tampa, Florida; ¹⁴Department of Preventive Medicine, USC/Keck School of Medicine, Norris Comprehensive Cancer Center, ¹⁵Department of Urology, University of Southern California Norris Comprehensive Cancer Center, and ¹⁶University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California; ¹⁷Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii; ¹⁸Gynaecolgical Cancer Research Centre, University College London, EGA Institute for Women's Health, London, United Kingdom; ¹⁹Department of Virus, Hormones and Cancer, Copenhagen, Danish Cancer Society and ²⁰The Gynaecologic Clinic, The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; ²¹Department of Gynecology and Obstetrics, Aarhus University Hospital, Skejby, Aarhus, Denmark; ²²Cancer Research UK Genetic Epidemiology Unit and ²³Cancer Research UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom; ²⁴Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; ²⁵Department of Epidemiology, School of Medicine, University of California, Irvine, Irvine, California; ²⁶Obstetrics and Gynecology Epidemiology Center and ²⁷Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and ²⁸The Ovarian Cancer Association Consortium, Durham, North Carolina

^* To whom correspondence should be addressed. E-mail: schil001{at}mc.duke.edu.

	Abstract

The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (BF) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r² = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07–1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01–1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349–9]

Key Words: TP53, polymorphisms, ovarian cancer, epidemiology