Genetic variation of TP53, polycyclic aromatic hydrocarbon-related exposures, and breast cancer risk among women on Long Island, New York.
BACKGROUND
p53 participates in cell cycle control, programmed cell death/apoptosis, and DNA repair, all pathways involved in carcinogenesis. TP53 variants may influence p53 function.


OBJECTIVE
We evaluated whether three well-characterized TP53 variants -- Ex4 + 119 C > G (rs#1042522, Arg72Pro), IVS6 + 62 A > G (rs#1625895), and an IVS3 16 bp insertion/ deletion (INDEL; rs#17878362) -- were associated with breast cancer risk in a population-based case-control study.


METHODS
Genotypes and haplotypes were determined using long-range PCR in a sample of 578 cases and 390 controls.


RESULTS
For the Ex4 + 19 C > G SNP (rs1042522), women with the heterozygous genotype (G/C) had a 32% increase in breast cancer risk. Other variants were not associated with risk. We further examined whether these associations were modified by cigarette smoking status and detection of PAH-DNA adducts in circulating lymphocytes. Among current smokers, each copy of the minor alleles for the IVS6 + 62 A > G SNP (rs1625895) and the IVS3 INDEL polymorphism (rs17878362) was associated with lower breast cancer risk (OR = 0.49, 95% CI 0.27-0.90; OR = 0.42, 95% CI 0.22-0.78, respectively). However, among former smokers, the homozygous variant genotype for these 2 SNPs was observed among cases (4.1 and 3.2%, respectively) and not controls. Genotype associations were not modified by the presence or absence of DNA adducts in circulating lymphocytes. Three-loci haplotypes were not significantly associated with breast cancer risk.


CONCLUSIONS
These results should be confirmed in larger studies, but suggest that cigarette smoking may influence breast cancer risk through interaction with p53.
Gaudet
Mia M
MM
Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC, USA, gaudetm@mail.nih.gov
Gammon
Marilie D
MD
Bensen
Jeannette T
JT
Sagiv
Sharon K
SK
Shantakumar
Sumitra
S
Teitelbaum
Susan L
SL
Eng
Sybil M
SM
Neugut
Alfred I
AI
Santella
Regina M
RM
D001943:Breast Neoplasms / Q000235:genetics*; D018736:DNA Adducts / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D009518:New York; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects* / Q000097:blood; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D016159:Tumor Suppressor Protein p53; C095911:polycyclic aromatic hydrocarbons-DNA adduct