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首页> 外文期刊>Human mutation >A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers.
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A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers.

机译：包含p53多态性Ins16bp和Arg72Pro的单倍型可改变BRCA2突变携带者的癌症风险。

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摘要

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.
机译：BRCA1和BRCA2基因中的种系突变赋予罹患乳腺癌和其他癌症的终身风险;但是，在突变携带者的疾病表现方面存在显着差异。已经提出在BRCA1 / 2相关病例中，其他遗传和/或环境因素不仅改变外观，而且改变肿瘤的发作年龄和类型。本研究的目的是研究两个p53多态性（c.97-147ins16bp和c.215c> g，p.Arg72Pro）作为潜在修饰子的作用。为此，我们调查了属于170个西班牙乳腺癌和/或卵巢癌家族的447个BRCA1 / 2突变携带者的两种多态性与疾病状况之间的可能关联。基因型和单倍型分析显示，携带没有16bp插入的等位基因的特定单倍型和Arg72Pro的变异等位基因（无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岁之前患上第一个原发性肿瘤（乳腺癌或卵巢癌）的风险增加（OR：2.69; 95％CI：1.15-6.29; P = 0.022） 。我们通过一项功能研究证实了这些数据，在这项功能研究中，我们比较了不同p53基因型与细胞毒性药物（AraC）进行细胞处理后的凋亡反应。我们的结果显示，与No Ins-72Pro单倍型相关的p53细胞凋亡率降低。

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