Association of breast cancer outcome with status of p53 and MDM2 SNP309.
BACKGROUND
A common single-nucleotide polymorphism (SNP) in the promoter region of the MDM2 gene, known as T-309G and referred to as SNP309 for this study, leads to increased expression of Mdm2 protein and attenuated function of the p53 tumor suppressor protein. We investigated whether genetic variants in MDM2 were associated with breast cancer incidence and survival and whether the variant status could interact with the tumor p53 status to modify breast cancer survival.


METHODS
We used multivariable logistic and Cox regression analyses to study the relationship of SNP309 status and the status of a second MDM2 SNP in exon 12 at codon 354 (SNP354) with breast cancer incidence and with disease-specific survival among 293 case patients and 317 cancer-free control subjects. Survival analysis included 248 of the 293 case patients who had known tumor p53 status. All statistical tests were two-sided.


RESULTS
We did not observe an association between SNP309 status and breast cancer incidence in the unstratified analysis, but we did find a statistically significant association between SNP354 status and breast cancer incidence (odds ratio = 3.34, 95% confidence interval [CI] = 1.88 to 5.93). We also discovered a statistically significant interaction between SNP309 status and tumor p53 expression for breast cancer survival (P(interaction) = .002). Among homozygous carriers of the common MDM2 SNP309 allele (T/T), a mutant p53 status (risk ratio [RR] of death = 2.33, 95% CI = 1.08 to 5.03) and aberrant p53 protein expression (RR = 2.61, 95% CI = 1.22 to 5.57) in breast tumors were associated with poor survival. Tumor p53 status was not associated with breast cancer survival among carriers of the variant MDM2 SNP309 allele (G/T or G/G), which is consistent with a dominant effect of the variant allele.


CONCLUSIONS
A strong interaction between SNP309 status and tumor p53 status appears to modify the association between p53 status and breast cancer survival.
Boersma
Brenda J
BJ
Laboratory of Human Carcinogenesis, National Cancer Institute, Bldg. 37/Rm. 3050B, Bethesda, MD 20892-4258, USA.
Howe
Tiffany M
TM
Goodman
Julie E
JE
Yfantis
Harry G
HG
Lee
Dong H
DH
Chanock
Stephen J
SJ
Ambs
Stefan
S
D000225:Adenine; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality*; D016022:Case-Control Studies; D005260:Female; D006147:Guanine; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D006147:Guanine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000225:Adenine