Haplotype analysis of eight genes of the monoubiquitinated FANCD2-DNA damage-repair pathway in breast cancer patients
Haplotype analysis of eight genes of the monoubiquitinated FANCD2-DNA damage-repair pathway in breast cancer patients
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乳腺癌患者单泛素化 FANCD2-DNA 损伤修复通路 8 个基因的单倍型分析
DOI：
10.1016/j.canep.2012.12.010
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发表时间：
2013-06-01
影响因子：
2.6
通讯作者：
Huang, Juan
中科院分区：
文献类型：
--
作者：
Tang, Li-Li;Chen, Fei-Yu;Huang, Juan
背景：有10个基因与遗传性乳腺癌的易感性增加有关，也与人群乳腺癌风险相关，所有这些基因都直接或间接地参与了FANCD2-DNA损伤修复途径。我们分析了其中8个基因中的13个单倍型块，以估计单个单倍型带来的乳腺癌风险。方法：利用在8个乳腺癌易感基因TP53、PTEN、CHEK2、ATM、NBS1、Rad50、BRIP1和PALB2上发现的48个标签单核苷酸多态(TSNPs)构建单倍型区块。对734例女性患者和672例年龄匹配的女性对照进行SNPcan基因分型。结果：共获得45个tSNP基因分型结果，每个tSNP的呼叫率均在98.9%以上。用41个成功分型的tSNPs构建了8个基因的13个单倍型区块。我们发现，位于三个基因(NBS1、PTEN和BRIP1)内的四个单倍型块中的七个单倍型与乳腺癌风险显著相关。其中，4种单倍型(NBS1区第1区的ATC、NBS1区第2区的GCCCC和GCCCT、BRIP1区第2区的GCT)与散发性乳腺癌的风险相关(OR(95%CI)分别为1.350(1.124-1.623)、0.752(0.584-0.969)、0.803(0.649-0.993)和0.776(0.604-0.997)，在家族性和早发性病例中，只有一个单倍型(NBS1GGCCT)与乳腺癌风险显著相关(OR(95%CI)1.902(1.134-3.191))。结论：涉及FANCD2-DNA损伤修复途径的两个基因(NBS1和BRIP1)中的四个单倍型与散发性乳腺癌的风险显著相关，而NBS1中的一个单倍型与家族性或早发性乳腺癌的风险增加相关，表明特定的单倍型可能是乳腺癌的独特预测因素。皇冠版权所有(C)2013由爱思唯尔有限公司出版。保留所有权利。
Background: Ten genes are associated with increased susceptibility to inherited breast cancer have also been associated with population breast cancer risk, and all are involved directly or indirectly in the monoubiquitinated FANCD2-DNA damage repair pathway. We analyzed 13 haplotype blocks in eight of these genes to estimate the breast cancer risk conferred by individual haplotypes. Methods: Haplotype blocks were constructed with 48 tag single-nucleotide polymorphisms (tSNPs) identified in eight breast cancer susceptibility genes, TP53, PTEN, CHEK2, ATM, NBS1, RAD50, BRIP1, and PALB2. Genotyping was performed by SNPscan on 734 female patients and 672 female age-matched controls. Results: Forty-five tSNPs were successfully genotyped by SNPscan, and call rates for each tSNP were above 98.9%. Thirteen haplotype blocks of eight genes were constructed with 41 successfully genotyped tSNPs. We found that seven haplotypes from four haplotype blocks located within three genes (NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. Among these, four haplotypes (ATC in block 1 of NBS1, GCCCC and GCCCT in block 2 of NBS1, and GCT in block 2 of BRIP1) were correlated with breast cancer risk in sporadic cases (OR (95% CI) 1.350(1.124-1.623), 0.752(0.584-0.969), 0.803(0.649-0.993), and 0.776(0.604-0.997), respectively), and only one haplotype (GGCCT in block 2 of NBS1) was significantly associated with breast cancer risk in familial and early-onset cases (OR(95% CI) 1.902(1.134-3.191)). Conclusions: Four haplotypes within two genes (NBS1 and BRIP1) involved in the monoubiquitinated FANCD2-DNA damage-repair pathway are significantly associated with increased sporadic breast cancer risk, while one haplotype within NBS1 is correlated with an increased risk of familial or earlyonset breast cancer, indicating that specific haplotypes may be distinct predictors of breast cancer. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.