caa a22 4500 445861479 CHVBK 20180317145444.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00439-011-0957-1 doi (NATIONALLICENCE)springer-10.1007/s00439-011-0957-1 Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome [Elektronische Daten] [Chih-Chieh Wu, Ralf Krahe, Guillermina Lozano, Baili Zhang, Charmaine Wilson, Eun-Ji Jo, Christopher Amos, Sanjay Shete, Louise Strong] Li-Fraumeni syndrome (LFS) is a rare familial cancer syndrome characterized by early cancer onset, diverse tumor types, and multiple primary tumors. Germ-line TP53 mutations have been identified in most LFS families. A high-frequency single-nucleotide polymorphism, SNP309 (rs2279744), in MDM2 was recently confirmed to be a modifier of cancer risk in several case-series studies: substantially earlier cancer onset was observed in SNP309 G-allele carriers than in wild-type individuals by 7-16years. However, cancer risk analyses that jointly account for measured hereditary TP53 mutations and MDM2 SNP309 have not been systematically investigated in familial cases. Here, we determined the combined effects of measured TP53 mutations, MDM2 SNP309, and gender and their interactions simultaneously in LFS families. We used the method that is designed for extended pedigrees and structured for age-specific risk models based on Cox proportional hazards regression. We analyzed the cancer incidence in 19 extended pedigrees with germ-line TP53 mutations ascertained through the clinical LFS phenotype. The dataset consisted of 463 individuals with 129 TP53 mutation carriers. Our analyses showed that the TP53 germ-line mutation and its interaction with gender were strongly associated with familial cancer incidence and that the association between MDM2 SNP309 and increased cancer risk was modest. In contrast with several case-series studies, the interaction between MDM2 SNP309 and TP53 mutation was not statistically significant in our LFS family cohort. Our results showed that SNP309 G-alleles were associated with accelerated tumor formation in both carriers and non-carriers of germ-line TP53 mutations. Springer-Verlag, 2011 Wu Chih-Chieh Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut Krahe Ralf Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut Lozano Guillermina Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut Zhang Baili Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut Wilson Charmaine Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut Jo Eun-Ji Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut Amos Christopher Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut Shete Sanjay Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut Strong Louise Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut Human Genetics Springer-Verlag 129/6(2011-06-01), 663-673 0340-6717 129:6<663 2011 129 439 https://doi.org/10.1007/s00439-011-0957-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-011-0957-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wu Chih-Chieh Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut NATIONALLICENCE 700 1- Krahe Ralf Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut NATIONALLICENCE 700 1- Lozano Guillermina Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut NATIONALLICENCE 700 1- Zhang Baili Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut NATIONALLICENCE 700 1- Wilson Charmaine Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut NATIONALLICENCE 700 1- Jo Eun-Ji Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut NATIONALLICENCE 700 1- Amos Christopher Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut NATIONALLICENCE 700 1- Shete Sanjay Department of Epidemiology, Unit 1340, The University of Texas M. D. Anderson Cancer Center, 1155 Pressler Street, 77030, Houston, TX, USA aut NATIONALLICENCE 700 1- Strong Louise Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/6(2011-06-01), 663-673 0340-6717 129:6<663 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer