Age at cancer onset in germline TP53 mutation carriers: association with polymorphisms in predicted G-quadruplex structures

Charlotte Sagne, Virginie Marcel, Maria Bota, Ghyslaine Martel-Planche, Amanda Nobrega, Edenir Inêz Palmero, Laury Perriaud, Mathieu Boniol, Stephan Vagner, David G. Cox, Chang S. Chan, Jean-Louis Mergny, Magali Olivier, Patricia Ashton-Prolla, Janet Hall, Pierre Hainaut, Maria Isabel Achatz

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3' flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3' flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers.

Original languageEnglish
Pages (from-to)807-815
Number of pages9
Issue number4
Early online date11 Dec 2013
Publication statusPublished - 1 Apr 2014


  • age of onset
  • base sequence
  • DNA
  • G-quadruplexes
  • genes, p53
  • heterozygote detection
  • humans
  • molecular sequence data
  • neoplasms
  • polymorphism, genetic


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