Patel Alpa V, Calle Eugenia E, Pavluck Alexandre L, Feigelson Heather Spencer, Thun Michael J, Rodriguez Carmen
Department of Epidemiology and Surveillance Research, American Cancer Society, 1599 Clifton Road NE, Atlanta, GA 30309, USA.
Breast Cancer Res. 2005;7(6):R1168-73. doi: 10.1186/bcr1355. Epub 2005 Nov 21.
The gene XRCC1 (X-ray repair cross-complementing group 1) encodes a protein involved in DNA base excision repair. Two non-synonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln) have been shown to alter DNA repair capacity in some studies in vitro. However, results of previous association studies of these two XRCC1 variants and breast cancer have been inconsistent. We examined the association between polymorphisms in XRCC1 and breast cancer in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort, a large prospective study of cancer incidence in the USA.
Among the 21,965 women who were cancer-free in 1992 and gave blood between 1998 and 2001, 502 postmenopausal breast cancer cases were diagnosed between 1992 and 2001; 502 controls were matched to cases on age, race/ethnicity, and date of blood collection. Genotyping on DNA extracted from buffy coat was performed with Taqman. Conditional logistic regression was used to examine the association between each polymorphism and breast cancer risk controlling for breast cancer risk factors. We also examined whether factors associated with DNA damage, such as smoking and antioxidant intake, modified the association between XRCC1 polymorphisms and breast cancer.
We observed a significant inverse association between Trp194 carriers (Trp/Trp and Trp/Arg) compared with Trp194 non-carriers in relation to breast cancer (Arg/Arg) (odds ratio (OR) 0.62, 95% confidence interval (CI) 0.40 to 0.95). The inverse association between breast cancer and Trp194 carriers compared with non-carriers was slightly stronger among smokers (OR 0.47, 95% CI 0.24 to 0.94) than never smokers (OR 0.78, 95% CI 0.43 to 1.40). An increased risk associated with the Arg399Gln polymorphism (Gln/Gln versus Arg/Arg) was observed only among women who reported ever smoking cigarettes (OR 2.76, 95% CI 1.36 to 5.63), and not in women who were lifelong non-smokers (OR 0.64, 95% CI 0.33 to 1.26). No other factor examined modified the association between XRCC1 polymorphisms and breast cancer risk.
Our results support the hypothesis that genetic variation in XRCC1, particularly in Arg194Trp, may influence postmenopausal breast cancer risk. In our study, genetic variation in XRCC1 Arg399Gln was associated with breast cancer risk only among women with a history of smoking cigarettes.
基因XRCC1（X射线修复交叉互补基因1）编码一种参与DNA碱基切除修复的蛋白质。在一些体外研究中，XRCC1中的两个非同义多态性（Arg194Trp和Arg399Gln）已被证明会改变DNA修复能力。然而，先前关于这两种XRCC1变体与乳腺癌的关联研究结果并不一致。我们在美国癌症协会癌症预防研究II（CPS-II）营养队列中研究了XRCC1多态性与乳腺癌之间的关联，该队列是一项关于美国癌症发病率的大型前瞻性研究。
在1992年无癌症且于1998年至2001年期间献血的21965名女性中，1992年至2001年期间诊断出502例绝经后乳腺癌病例；502名对照在年龄、种族/民族和采血日期方面与病例进行匹配。使用Taqman对从血沉棕黄层提取的DNA进行基因分型。采用条件逻辑回归分析，在控制乳腺癌风险因素的情况下，研究每种多态性与乳腺癌风险之间的关联。我们还研究了与DNA损伤相关的因素，如吸烟和抗氧化剂摄入，是否会改变XRCC1多态性与乳腺癌之间的关联。
我们观察到，与Trp194非携带者（Arg/Arg）相比，Trp194携带者（Trp/Trp和Trp/Arg）患乳腺癌的风险呈显著负相关（比值比（OR）为0.62，95%置信区间（CI）为0.40至0.95）。与非吸烟者（OR为0.78，95%CI为0.43至1.40）相比，吸烟者中Trp194携带者与非携带者相比患乳腺癌的负相关略强（OR为0.47，95%CI为0.24至0.94）。仅在报告曾经吸烟的女性中观察到与Arg399Gln多态性相关的风险增加（Gln/Gln与Arg/Arg相比，OR为2.76，95%CI为1.36至5.63），而在终身不吸烟者中未观察到（OR为0.64，95%CI为0.33至1.26）。所研究的其他因素均未改变XRCC1多态性与乳腺癌风险之间的关联。
我们的结果支持以下假设，即XRCC1的基因变异，特别是Arg194Trp，可能影响绝经后乳腺癌风险。在我们的研究中，XRCC1 Arg399Gln的基因变异仅在有吸烟史的女性中与乳腺癌风险相关。
