Wasielewski Marijke, Nagel Jord H A, Brekelmans Cecile, Klijn Jan G M, van den Ouweland Ans, Meijers-Heijboer Hanne, Schutte Mieke
Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Breast Cancer Res Treat. 2007 Aug;104(2):153-7. doi: 10.1007/s10549-006-9407-5. Epub 2006 Nov 2.
A single nucleotide polymorphism (SNP309T>G) in the intronic promoter of MDM2 was recently found to accelerate carcinogenesis in early-onset cancer cases. This cancer acceleration presumably was due to increased SP1 binding, resulting in enhanced MDM2 transcriptional activation by estrogens. We evaluated MDM2 SNP309 in 343 familial breast cancer cases with known mutation status for CHEK2 1100delC, BRCA1 and BRCA2. Cancer acceleration was indeed observed in early-onset familial breast cancer cases (diagnosed <or= 51 years), with 16% of cases carrying the MDM2 SNP309 GG genotype as compared to 4% of late-onset cases (P = 0.029). The cancer acceleration was even more pronounced in the non-mutant familial breast cancer cases, with 17% of early-onset cases carrying MDM2 SNP309 GG as compared to 2% of late-onset cases (n = 214; P = 0.015). There was no evidence for an influence of estrogen signaling in the cancer acceleration by MDM2 SNP309, as there were no differences in the prevalence of MDM2 SNP309 GG among CHEK2 1100delC and BRCA2 mutant cases (with 90% ER-positive cancers) or BRCA1 mutant cases (10% ER-positive cancers). Nor did we observe differences in MDM2 SNP309 frequencies among 75 familial breast cancer cases of our cohort with known ER status. Overall, our data suggest that MDM2 SNP309 accelerates familial breast carcinogenesis, but that this acceleration is not influenced by estrogen signaling.
最近发现，MDM2基因内含子启动子中的一个单核苷酸多态性（SNP309T>G）会加速早发性癌症病例的致癌进程。这种癌症加速现象可能是由于SP1结合增加，导致雌激素对MDM2转录激活增强。我们评估了343例已知CHEK2 1100delC、BRCA1和BRCA2突变状态的家族性乳腺癌病例中的MDM2 SNP309。在早发性家族性乳腺癌病例（诊断年龄≤51岁）中确实观察到癌症加速现象，16%的病例携带MDM2 SNP309 GG基因型，而晚发性病例中这一比例为4%（P = 0.029）。在非突变型家族性乳腺癌病例中，癌症加速现象更为明显，早发性病例中有17%携带MDM2 SNP309 GG，而晚发性病例中这一比例为2%（n = 214；P = 0.015）。没有证据表明雌激素信号传导对MDM2 SNP309加速癌症进程有影响，因为在CHEK2 1100delC和BRCA2突变病例（90%为雌激素受体阳性癌症）或BRCA1突变病例（10%为雌激素受体阳性癌症）中，MDM2 SNP309 GG的患病率没有差异。在我们队列中75例已知雌激素受体状态的家族性乳腺癌病例中，我们也未观察到MDM2 SNP309频率的差异。总体而言，我们的数据表明MDM2 SNP309会加速家族性乳腺癌的发生，但这种加速不受雌激素信号传导的影响。
