TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies.
BACKGROUND
Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer.


METHODS
Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype.


RESULTS
The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes).


CONCLUSIONS
Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies.


BACKGROUND
German Research Foundation (DFG).
Klug
Stefanie J
SJ
Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Centre, Johannes Gutenberg-University of Mainz, Mainz, Germany. klug@imbei.uni-mainz.de
Ressing
Meike
M
Koenig
Jochem
J
Abba
Martin C
MC
Agorastos
Theodoros
T
Brenna
Sylvia M F
SM
Ciotti
Marco
M
Das
B R
BR
Del Mistro
Annarosa
A
Dybikowska
Aleksandra
A
Giuliano
Anna R
AR
Gudleviciene
Zivile
Z
Gyllensten
Ulf
U
Haws
Andrea L F
AL
Helland
Aslaug
A
Herrington
C Simon
CS
Hildesheim
Alan
A
Humbey
Olivier
O
Jee
Sun H
SH
Kim
Jae Weon
JW
Madeleine
Margaret M
MM
Menczer
Joseph
J
Ngan
Hextan Y S
HY
Nishikawa
Akira
A
Niwa
Yoshimitsu
Y
Pegoraro
Rosemary
R
Pillai
M R
MR
Ranzani
Gulielmina
G
Rezza
Giovanni
G
Rosenthal
Adam N
AN
Roychoudhury
Susanta
S
Saranath
Dhananjaya
D
Schmitt
Virginia M
VM
Sengupta
Sharmila
S
Settheetham-Ishida
Wannapa
W
Shirasawa
Hiroshi
H
Snijders
Peter J F
PJ
Stoler
Mark H
MH
Suárez-Rincón
Angel E
AE
Szarka
Krisztina
K
Tachezy
Ruth
R
Ueda
Masatsugu
M
van der Zee
Ate G J
AG
von Knebel Doeberitz
Magnus
M
Wu
Ming-Tsang
MT
Yamashita
Tsuyoshi
T
Zehbe
Ingeborg
I
Blettner
Maria
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics; D011110:Polymorphism, Genetic; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000821:virology; D055815:Young Adult