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

作者：Sagne Charlotte; Marcel Virginie; Bota Maria; Martel Planche Ghyslaine; Nobrega Amanda; Palmero Edenir Inez; Perriaud Laury; Boniol Mathieu; Vagner Stephan; Cox David G; Chan Chang S; Mergny Jean Louis; Olivier Magali; Ashton Prolla Patricia; Hall Janet; Hainaut Pierre^*; Achatz Maria Isabel

来源：Carcinogenesis, 2014, 35(4): 807-815.

DOI：10.1093/carcin/bgt381

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 similar to 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 similar to 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.G-quadruplexes (G4) are regulatory secondary structures in guanine tracts in DNA or RNA. Polymorphisms in two G4-forming regions of TP53 modulate age at cancer onset in susceptible germline TP53 mutation carriers, suggesting that these G4 regulate p53 suppressor functions.