Association of breast cancer outcome with status of p53 and MDM2 SNP309
Association of breast cancer outcome with status of p53 and MDM2 SNP309
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DOI：
10.1093/jnci/djj245
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发表时间：
2006-07-05
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影响因子：
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通讯作者：
Ambs, Stefan
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作者：
Boersma, Brenda J.;Howe, Tiffany M.;Ambs, Stefan
背景MDM 2基因启动子区的一个常见单核苷酸多态性（SNP），称为T-309 G，在本研究中称为SNP 309，导致Mdm 2蛋白表达增加和p53肿瘤抑制蛋白功能减弱。我们研究了MDM 2的遗传变异是否与乳腺癌的发病率和生存率相关，以及变异状态是否可以与肿瘤p53状态相互作用以改变乳腺癌的生存率。研究方法：我们使用多变量logistic和考克斯回归分析来研究SNP 309状态和第二个MDM 2外显子12密码子354（SNP 354）的SNP状态与293例病例患者和317例无癌对照者的乳腺癌发病率和疾病特异性生存率的关系。生存分析包括293例已知肿瘤p53状态的患者中的248例。所有统计检验均为双侧检验。结果如下：在未分层分析中，我们没有观察到SNP 309状态与乳腺癌发病率之间的关联，但我们确实发现SNP 354状态与乳腺癌发病率之间存在统计学显著性关联（比值比= 3.34，95%置信区间[CI] = 1.88至5.93）。我们还发现SNP 309状态和肿瘤p53表达对乳腺癌生存率的统计学显著交互作用（P-交互作用= 0.002）。在常见的MDM 2 SNP 309等位基因（T/T）纯合子携带者中，乳腺肿瘤中突变型p53状态（死亡风险比[RR]= 2.33，95% CI = 1.08 - 5.03）和异常p53蛋白表达（RR = 2.61，95% CI = 1.22 - 5.57）与生存率低相关。肿瘤p53状态与MDM 2 SNP 309等位基因（G/T或G/G）变异携带者的乳腺癌生存率无关，这与该变异等位基因的显性效应一致。结论：SNP 309状态和肿瘤p53状态之间的强相互作用似乎改变了p53状态和乳腺癌生存之间的关联。
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. Conclusion: A strong interaction between SNP309 status and tumor p53 status appears to modify the association between p53 status and breast cancer survival.