Gao Boning, Xie Xian-Jin, Huang Chunxian, Shames David S, Chen Tina T-L, Lewis Cheryl M, Bian Aihua, Zhang Bifeng, Olopade Olufunmilayo I, Garber Judy E, Euhus David M, Tomlinson Gail E, Minna John D
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas, TX 75390-8593, USA.
Cancer Res. 2008 Jan 1;68(1):22-5. doi: 10.1158/0008-5472.CAN-07-5183.
The tumor suppressor gene RASSF1A regulates cell cycle progression, apoptosis, and microtubule stability and is inactivated by promoter methylation in approximately 50% of breast cancers. It has been shown previously that the polymorphism A133S in RASSF1A reduces its ability to regulate cell cycle progression and this polymorphism is associated with an increased risk of breast cancer. We analyzed the frequency of RASSF1A A133S in 190 Caucasian women without breast cancer and 653 patients with breast cancer including 138 BRCA1 and BRCA2 (BRCA1/2) mutation carriers, 395 non-BRCA1/2 mutations carriers, and 120 untested for BRCA1/2 mutations. Patients with breast cancer had a higher frequency of A133S than the controls [P = 0.017; odds ratios (OR), 1.71; 95% confidence intervals (95% CI), 1.10-2.66]. There is also a higher frequency of A133S in patients with higher familial breast cancer risk (P = 0.029; OR, 1.76; 95% CI, 1.06-2.92) and patients carrying BRCA1/2 mutations (P = 0.037, OR, 1.82; 95% CI, 1.04-3.18). Importantly, we found that the co-occurrence of a BRCA1 or BRCA2 mutation and A133S in RASSF1A was associated with earlier onset of breast cancer compared with those individuals with either a BRCA1/2 mutation or the A133S polymorphism alone (36.0 versus 42.0 years old, P = 0.002). Our data suggest that the presence of the RASSF1A A133S polymorphism is associated with breast cancer pathogenesis in general and modifies breast cancer age of onset in BRCA1/2 mutations carriers. Our results warrant a large-scale study to examine the effect of the A133S polymorphism in the development of breast and other types of cancers.
肿瘤抑制基因RASSF1A调节细胞周期进程、细胞凋亡和微管稳定性，在大约50%的乳腺癌中因启动子甲基化而失活。先前研究表明，RASSF1A中的A133S多态性降低了其调节细胞周期进程的能力，且该多态性与乳腺癌风险增加相关。我们分析了190名无乳腺癌的白种女性以及653例乳腺癌患者中RASSF1A A133S的频率，其中653例乳腺癌患者包括138例BRCA1和BRCA2（BRCA1/2）突变携带者、395例非BRCA1/2突变携带者以及120例未检测BRCA1/2突变的患者。乳腺癌患者中A133S的频率高于对照组[P = 0.017；优势比（OR）为1.71；95%置信区间（95%CI）为1.10 - 2.66]。在乳腺癌家族风险较高的患者中A133S频率也较高（P = 0.029；OR为1.76；95%CI为1.06 - 2.92），以及携带BRCA1/2突变的患者中（P = 0.037，OR为1.82；95%CI为1.04 - 3.18）。重要的是，我们发现与单独携带BRCA1/2突变或A133S多态性的个体相比，RASSF1A中BRCA1或BRCA2突变与A133S同时出现与乳腺癌发病年龄较早相关（分别为36.0岁和42.0岁，P = 0.002）。我们的数据表明，RASSF1A A133S多态性的存在总体上与乳腺癌发病机制相关，并改变了BRCA1/2突变携带者的乳腺癌发病年龄。我们的结果值得进行大规模研究，以检验A133S多态性在乳腺癌及其他类型癌症发生发展中的作用。
