Less common genotype variants of TP53 polymorphisms are associated with poor outcome in adult patients with adrenocortical carcinoma Britta Heinze 1 , Leonie J M Herrmann 1 , Martin Fassnacht 1,2 , Cristina L Ronchi 1 , Holger S Willenberg 3 , Marcus Quinkler 4 , Nicole Reisch 2 , Martina Zink 1 , Bruno Allolio 1 and Stefanie Hahner 1 1 Endocrinology and Diabetes Unit, Department of Internal Medicine I, University Hospital of Wuerzburg, University of Wuerzburg, Oberduerrbacher Strasse 6, D-97080 Wuerzburg, Germany, 2 Department of Endocrinology, Medizinische Klinik und Poliklinik IV, Hospital of the University of Munich, D-80336 Munich, Germany, 3 Department of Endocrinology and Diabetology, Medical Faculty Duesseldorf, Moorenstrasse 5, D-40225 Duesseldorf, Germany and 4 Clinical Endocrinology, Charite ´ Campus Mitte, Charite ´ University Medicine Berlin, D-10117 Berlin, Germany Correspondence should be addressed to S Hahner Email hahner_s@ medizin.uni-wuerzburg.de Abstract Context: The Li–Fraumeni tumor syndrome is strongly associated with adrenocortical carcinoma (ACC) and is caused by germline mutations in TP53 in 70% of cases. Also, TP53 polymorphisms have been shown to influence both cancer risk and clinical outcome in several tumor entities. We, therefore, investigated TP53 polymorphisms in a cohort of adult patients with ACC. Objective: Evaluation of the role of TP53 polymorphisms in adult patients with ACC. Subjects and methods: Peripheral blood for DNA extraction was collected from 72 ACC patients. Polymorphism analysis was carried out by amplification and sequencing of exons and adjacent intron sections of TP53. Results were correlated with clinical data and the distribution of the polymorphisms was compared with published Caucasian control groups. Results: Compared with control groups, genotype frequencies of analyzed TP53 polymorphisms among ACC patients were significantly different in three out of four polymorphisms: IVS2C38GOC (G/G, PZ0.0248), IVS3ins16 (NoIns/NoIns, P!0.0001; NoIns/Ins, P!0.0001), and IVS6C62AOG (G/G, P!0.0001; G/A, P!0.0001). Overall, the survival of ACC patients, which harbored at least one of the less frequent genotype variants of four analyzed polymorphisms (nZ23), was significantly inferior (median survival: 81.0 months in patients with the common homozygous genotypes vs 20.0 months in patients with the less frequent genotypes, HR 2.56, 95% CI 1.66–7.07; PZ0.001). These results were confirmed by multivariable regression analysis (HR 2.84, 95% CI 1.52–7.17; PZ0.037). Conclusion: Some TP53 polymorphisms seem to influence overall survival in ACC patients. This effect was observed for a combination of polymorphic changes rather than for single polymorphisms. European Journal of Endocrinology (2014) 170, 707–717 Introduction TP53 is a well-known tumor suppressor gene located on chromosome 17p13 with mutations frequently observed in many types of human cancers (1, 2). The corresponding protein p53 is a transcription factor that regulates the expression of stress-response genes and mediates a variety of antiproliferative processes (3). Polymorphisms of TP53 alleles occurring in the same population are often defined as single-nucleotide polymorphism (SNP) in coding and European Journal of Endocrinology Clinical Study B Heinze and others TP53 polymorphisms in adult adrenal cancer 170 :5 707–717 www.eje-online.org Ñ 2014 European Society of Endocrinology DOI: 10.1530/EJE-13-0788 Printed in Great Britain Published by Bioscientifica Ltd.