Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk
Rare BRCA1 haplotypes including 3′UTR SNPs associated with breast cancer risk
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DOI：
10.4161/cc.10.1.14359
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发表时间：
2011-01-01
期刊：
影响因子：
4.3
通讯作者：
Weidhaas, Joanne B.
中科院分区：
文献类型：
--
作者：
Pelletier, Cory;Speed, William C.;Weidhaas, Joanne B.
存在识别女性患乳腺癌风险增加的遗传标记，但大多数遗传风险仍然难以捉摸。虽然许多 BRCA1 编码序列突变与乳腺癌风险相关，但 BRCA1 突变仅占乳腺癌风险的不到 5%。由于破坏 microRNA (miRNA) 结合的 3' 非翻译区 (3'UTR) 多态性可能具有功能性，并且可以作为癌症风险的遗传标记，因此我们测试了以下假设：BRCA1 的 3'UTR 中的此类多态性和包含这些功能性多态性的单倍型可能与乳腺癌风险相关。我们对乳腺癌患者的 BRCA1 3'UTR 进行了测序，以鉴定 miRNA 破坏性多态性。我们进一步评估了该区域的单倍型，包括在大量对照人群和已知乳腺癌亚型和种族的乳腺癌患者 (n = 221) 中鉴定出的 3'UTR 变异。我们在 BRCA1 中发现了三个在乳腺癌群体中呈多态性的 3'UTR 变异，并且包含这些变异的单倍型分析显示，乳腺癌患者具有 5 种在对照中通常不存在的罕见单倍型（乳腺癌染色体为 9.50%，对照染色体为 0.11%，p = 0.0001）。其中三个罕见单倍型包含 rs8176318 BRCA1 3'UTR 功能变体。这些单倍型不是 BRCA1 编码突变的生物标志物，因为它们很少在 BRCA1 突变乳腺癌患者中发现（1/129 患者 = 0.78%）。这些罕见的 BRCA1 单倍型和 3'UTR SNP 可能代表乳腺癌风险的新遗传标记。
Genetic markers identifying women at an increased risk of developing breast cancer exist, yet the majority of inherited risk remains elusive. While numerous BRCA1 coding sequence mutations are associated with breast cancer risk, BRCA1 mutations account for less then 5% of breast cancer risk. Since 3' untranslated region (3'UTR) polymorphisms disrupting microRNA (miRNA) binding can be functional and can act as genetic markers of cancer risk, we tested the hypothesis that such polymorphisms in the 3'UTR of BRCA1 and haplotypes containing these functional polymorphisms may be associated with breast cancer risk. We sequenced the BRCA1 3'UTR from breast cancer patients to identify miRNA disrupting polymorphisms. We further evaluated haplotypes of this region including the identified 3'UTR variants in a large population of controls and breast cancer patients (n = 221) with known breast cancer subtypes and ethnicities. We identified three 3'UTR variants in BRCA1 that are polymorphic in breast cancer populations, and haplotype analysis including these variants revealed that breast cancer patients harbor five rare haplotypes not generally found among controls (9.50% for breast cancer chromosomes, 0.11% for control chromosomes, p = 0.0001). Three of these rare haplotypes contain the rs8176318 BRCA1 3'UTR functional variant. These haplotypes are not biomarkers for BRCA1 coding mutations, as they are found rarely in BRCA1 mutant breast cancer patients (1/129 patients = 0.78%). These rare BRCA1 haplotypes and 3'UTR SNPs may represent new genetic markers of breast cancer risk.