TY - JOUR
T1 - Age at cancer onset in germline TP53 mutation carriers
T2 - association with polymorphisms in predicted G-quadruplex structures
AU - Sagne, Charlotte
AU - Marcel, Virginie
AU - Bota, Maria
AU - Martel-Planche, Ghyslaine
AU - Nobrega, Amanda
AU - Palmero, Edenir Inêz
AU - Perriaud, Laury
AU - Boniol, Mathieu
AU - Vagner, Stephan
AU - Cox, David G.
AU - Chan, Chang S.
AU - Mergny, Jean-Louis
AU - Olivier, Magali
AU - Ashton-Prolla, Patricia
AU - Hall, Janet
AU - Hainaut, Pierre
AU - Achatz, Maria Isabel
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
KW - age of onset
KW - base sequence
KW - DNA
KW - G-quadruplexes
KW - genes, p53
KW - heterozygote detection
KW - humans
KW - molecular sequence data
KW - neoplasms
KW - polymorphism, genetic
UR - http://carcin.oxfordjournals.org/content/35/4/807
U2 - 10.1093/carcin/bgt381
DO - 10.1093/carcin/bgt381
M3 - Article
C2 - 24336192
SN - 0143-3334
VL - 35
SP - 807
EP - 815
JO - Carcinogenesis
JF - Carcinogenesis
IS - 4
ER -