Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping
Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping
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DOI：
10.1002/gepi.20101
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发表时间：
2006-01-01
影响因子：
2.1
通讯作者：
Offit, K
中科院分区：
文献类型：
--
作者：
Ellis, NA;Kirchhoff, T;Offit, K
我们研究了一种定位乳腺癌易感基因的新方法的可行性，该方法使用低密度全基因组单核苷酸多态性组，并利用高风险病例中犹太疾病基因侧翼的大面积连锁不平衡（LD）。利用 Affymetrix GeneChip 芯片，我们对三组德系犹太人乳腺癌病例中的 8,576 个多态性进行了基因分型：“验证”组包含 27 例乳腺癌病例，所有病例都携带 BRCA2*6174delT 创始人突变；一组来自男性乳腺癌家族的 19 例乳腺癌病例，模拟了寻找新基因的条件；以及来自乳腺癌亲属（4个或更多病例/亲属）的57名先证者的“测试”组，其中BRCA1和BRCA2突变已被排除。为了确定关联性，我们通过费舍尔精确检验和最大似然比检验比较了病例与对照中基因型和单倍型的频率。在“验证”集中，我们证明了 BRCA2*6174delT 染色体上存在一个跨越超过 500 万个碱基的连锁不平衡区域。在“现场”组中，我们表明，尽管样本组中存在异质性，但 BRCA2 侧翼的大连锁不平衡区域是可检测到的。最后，在“测试”集中，至少出现了三个可能包含新乳腺癌基因的感兴趣区域，其中一个先前已通过连锁分析鉴定出。虽然这些结果证明了全基因组关联策略的可行性，但这种方法的进一步应用将关键取决于优化 SNP 的密度和分布以及研究设计的规模和类型。
We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genome-wide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a '' validation '' set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a '' field '' set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a '' test '' set of 57 probands from breast cancer kindreds (4 or more cases/ kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the '' validation '' set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the '' field '' set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the '' test '' set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design.