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

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Abstract

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.

LanguageEnglish
Pages807-815
Number of pages9
JournalCarcinogenesis
Volume35
Issue number4
Early online date11 Dec 2013
DOIs
Publication statusPublished - 1 Apr 2014

Fingerprint

G-structures
G-Quadruplexes
Germ-Line Mutation
Polymorphism
Haplotype
Age of Onset
Cancer
Mutation
Haplotypes
3' Flanking Region
Neoplasms
Penetrance
Alleles
Duplication
Introns
RNA Splicing
Guanine
Messenger RNA
RNA
Alternatives

Keywords

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

Cite this

Sagne, Charlotte ; Marcel, Virginie ; Bota, Maria ; Martel-Planche, Ghyslaine ; Nobrega, Amanda ; Palmero, Edenir Inêz ; 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. / Age at cancer onset in germline TP53 mutation carriers : association with polymorphisms in predicted G-quadruplex structures. In: Carcinogenesis. 2014 ; Vol. 35, No. 4. pp. 807-815.
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abstract = "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.",
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author = "Charlotte Sagne and Virginie Marcel and Maria Bota and Ghyslaine Martel-Planche and Amanda Nobrega and Palmero, {Edenir In{\^e}z} and Laury Perriaud and Mathieu Boniol and Stephan Vagner and Cox, {David G.} and Chan, {Chang S.} and Jean-Louis Mergny and Magali Olivier and Patricia Ashton-Prolla and Janet Hall and Pierre Hainaut and Achatz, {Maria Isabel}",
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Sagne, C, Marcel, V, Bota, M, Martel-Planche, G, Nobrega, A, Palmero, EI, Perriaud, L, Boniol, M, Vagner, S, Cox, DG, Chan, CS, Mergny, J-L, Olivier, M, Ashton-Prolla, P, Hall, J, Hainaut, P & Achatz, MI 2014, 'Age at cancer onset in germline TP53 mutation carriers: association with polymorphisms in predicted G-quadruplex structures' Carcinogenesis, vol. 35, no. 4, pp. 807-815. https://doi.org/10.1093/carcin/bgt381

Age at cancer onset in germline TP53 mutation carriers : association with polymorphisms in predicted G-quadruplex structures. / Sagne, Charlotte; Marcel, Virginie; Bota, Maria; Martel-Planche, Ghyslaine; Nobrega, Amanda; Palmero, Edenir Inêz; 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.

In: Carcinogenesis, Vol. 35, No. 4, 01.04.2014, p. 807-815.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Age at cancer onset in germline TP53 mutation carriers

T2 - Carcinogenesis

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

VL - 35

SP - 807

EP - 815

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 4

ER -