Osorio A, Martínez-Delgado B, Pollán M, Cuadros M, Urioste M, Torrenteras C, Melchor L, Díez O, De La Hoya M, Velasco E, González-Sarmiento R, Caldés T, Alonso C, Benítez J
Department of Human Genetics, Spanish National Cancer Center, Madrid, Spain.
Hum Mutat. 2006 Mar;27(3):242-8. doi: 10.1002/humu.20283.
Germline mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of developing breast and other cancers; however, remarkable differences exist regarding disease manifestation in mutation carriers. It has been suggested that other genetic and/or environmental factors modify not only the appearance but also the age of onset and type of tumor in BRCA1/2-associated cases. The aim of the present study was to investigate the role of two p53 polymorphisms (c.97-147ins16bp and c.215c>g, p.Arg72Pro) as potential modifiers. For this purpose we investigated the possible association between the two polymorphisms and disease status in 447 BRCA1/2 mutation carriers belonging to 170 Spanish breast and/or ovarian cancer families. Genotype and haplotype analyses revealed that the presence of a specific haplotype carrying the allele without the 16-bp insertion and the variant allele for the Arg72Pro (No Ins-72Pro haplotype) was associated with an earlier age of onset in BRCA2 mutation carriers. We found an increased risk of developing a first primary tumor (breast or ovarian) before 35 years of age for individuals who carried at least one No Ins-72Pro haplotype (OR: 2.69; 95% CI: 1.15-6.29; P=0.022). We confirmed these data by a functional study in which we compared different p53 genotypes in relation to their apoptotic response after cell treatment with a cytotoxic drug (AraC). Our results revealed a decrease in p53 apoptotic rate associated with the No Ins-72Pro haplotype.
BRCA1和BRCA2基因的种系突变会使个体在一生中患乳腺癌和其他癌症的风险很高；然而，突变携带者的疾病表现存在显著差异。有人提出，其他遗传和/或环境因素不仅会改变BRCA1/2相关病例中肿瘤的外观，还会改变其发病年龄和肿瘤类型。本研究的目的是调查两种p53多态性（c.97-147ins16bp和c.215c>g，p.Arg72Pro）作为潜在修饰因子的作用。为此，我们调查了447名属于170个西班牙乳腺癌和/或卵巢癌家族的BRCA1/2突变携带者中这两种多态性与疾病状态之间的可能关联。基因型和单倍型分析显示，携带无16bp插入等位基因和Arg72Pro变异等位基因的特定单倍型（No Ins-72Pro单倍型）的存在与BRCA2突变携带者的发病年龄较早有关。我们发现，携带至少一个No Ins-72Pro单倍型的个体在35岁之前发生首个原发性肿瘤（乳腺癌或卵巢癌）的风险增加（比值比：2.69；95%置信区间：1.15-6.29；P=0.022）。我们通过一项功能研究证实了这些数据，在该研究中，我们比较了不同p53基因型在用细胞毒性药物（阿糖胞苷）处理细胞后的凋亡反应。我们的结果显示，与No Ins-72Pro单倍型相关的p53凋亡率降低。
