Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome

Chih-Chieh Wu, Ralf Krahe, Guillermina Lozano, Baili Zhang, Charmaine D. Wilson, Eun Ji Jo, Christopher I. Amos, Sanjay Shete, Louise C. Strong

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Abstract

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 7-16 years. 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.

Original languageEnglish
Pages (from-to)663-673
Number of pages11
JournalHuman genetics
Volume129
Issue number6
DOIs
Publication statusPublished - 2011 Jun 1

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Li-Fraumeni Syndrome
Germ-Line Mutation
Neoplasms
Mutation
Pedigree
Alleles
Incidence
Single Nucleotide Polymorphism

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Wu, Chih-Chieh ; Krahe, Ralf ; Lozano, Guillermina ; Zhang, Baili ; Wilson, Charmaine D. ; Jo, Eun Ji ; Amos, Christopher I. ; Shete, Sanjay ; Strong, Louise C. / Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. In: Human genetics. 2011 ; Vol. 129, No. 6. pp. 663-673.
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abstract = "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 7-16 years. 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.",
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Wu, C-C, Krahe, R, Lozano, G, Zhang, B, Wilson, CD, Jo, EJ, Amos, CI, Shete, S & Strong, LC 2011, 'Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome', Human genetics, vol. 129, no. 6, pp. 663-673. https://doi.org/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. / Wu, Chih-Chieh; Krahe, Ralf; Lozano, Guillermina; Zhang, Baili; Wilson, Charmaine D.; Jo, Eun Ji; Amos, Christopher I.; Shete, Sanjay; Strong, Louise C.

In: Human genetics, Vol. 129, No. 6, 01.06.2011, p. 663-673.

Research output: Contribution to journalArticle

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T1 - Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome

AU - Wu, Chih-Chieh

AU - Krahe, Ralf

AU - Lozano, Guillermina

AU - Zhang, Baili

AU - Wilson, Charmaine D.

AU - Jo, Eun Ji

AU - Amos, Christopher I.

AU - Shete, Sanjay

AU - Strong, Louise C.

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