Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, People's Republic of China.
Cancer Epidemiol. 2013 Jun;37(3):311-7. doi: 10.1016/j.canep.2012.12.010. Epub 2013 Jan 26.
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.
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.
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)).
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 early-onset breast cancer, indicating that specific haplotypes may be distinct predictors of breast cancer.
十个与遗传性乳腺癌易感性增加相关的基因也与人群乳腺癌风险相关，并且所有这些基因都直接或间接参与单泛素化 FANCD2-DNA 损伤修复途径。我们分析了这八个基因中的 13 个单倍型块，以估计单个单倍型所带来的乳腺癌风险。
使用在八个乳腺癌易感性基因（TP53、PTEN、CHEK2、ATM、NBS1、RAD50、BRIP1 和 PALB2）中鉴定的 48 个标签单核苷酸多态性（tag single-nucleotide polymorphisms，tSNP）构建单倍型块。通过 SNPscan 对 734 名女性患者和 672 名年龄匹配的女性对照进行基因分型。
通过 SNPscan 成功对 45 个 tSNP 进行了基因分型，每个 tSNP 的呼叫率均高于 98.9%。使用 41 个成功基因分型的 tSNP 构建了八个基因的 13 个单倍型块。我们发现四个基因（NBS1、PTEN 和 BRIP1）内的三个单倍型块中的七个单倍型与乳腺癌风险显著相关。其中，四个单倍型（NBS1 块 1 中的 ATC、NBS1 块 2 中的 GCCCC 和 GCCCT、BRIP1 块 2 中的 GCT）与散发性病例的乳腺癌风险相关（OR（95%CI）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）），而只有一个单倍型（NBS1 块 2 中的 GGCCT）与家族性和早发性病例的乳腺癌风险显著相关（OR（95%CI）为 1.902（1.134-3.191））。
单倍型途径中的两个基因（NBS1 和 BRIP1）中的四个单倍型与散发性乳腺癌风险增加显著相关，而 NBS1 中的一个单倍型与家族性或早发性乳腺癌风险相关，表明特定的单倍型可能是乳腺癌的不同预测指标。
