Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Victoria 3010, Australia.
BMC Cancer. 2010 Sep 1;10:466. doi: 10.1186/1471-2407-10-466.
BRCA1 and BRCA2 mutations are found in a proportion of families with multiple early-onset breast cancers. There are a large number of different deleterious mutations in both genes, none of which would be detectable using standard genetic association studies. Single common variants and haplotypes of common variants may capture groups of deleterious mutations since some low prevalence haplotypes of common variants occur more frequently among chromosomes that carry rare, deleterious mutations than chromosomes that do not.
DNA sequence data for BRCA1 and BRCA2 was obtained from 571 participants from the Australian Breast Cancer Family Study. Genetic variants were classified as either deleterious mutations or common genetic variants. Variants tagging common polymorphisms were selected and haplotypes resolved using Haploview. Their frequency was compared to those with and without deleterious mutations using a permutation test.
A common genetic variant in BRCA1 (3232A > G) was found to be over-represented in deleterious mutation carriers (p = 0.05), whereas a common genetic variant in BRCA2 (1342A > C) occurred less frequently in deleterious mutation carriers (p = 0.04). All four of the common BRCA1 variants used to form haplotypes occurred more frequently in the deleterious mutation carriers when compared to the non-carriers, but there was no evidence of a difference in the distributions between the two groups (p = 0.34). In BRCA2, all four common variants were found to occur less frequently in the deleterious mutation carriers when compared to non-carriers, but the evidence for difference in the distribution between the two groups was weak (p = 0.16). Several less common haplotypes of common BRCA1 variants were found to be over-represented among deleterious mutation carriers but there was no evidence for this at the population level. In BRCA2, only the most common haplotype was found to occur more frequently in deleterious mutation carriers, with again no evidence at the population level.
We observed differences in the frequency of common genetic variants of the BRCA1 and BRCA2 and their haplotypes between early-onset breast cancer cases who did and did not carry deleterious mutations in these genes. Although our data provide only weak evidence for a difference in frequencies at the population level, the number of deleterious mutation carriers was low and the results may yet be substantiated in a larger study using pooled data.
BRCA1 和 BRCA2 基因突变存在于许多具有多个早发性乳腺癌的家族中。这两个基因中存在大量不同的有害突变，而使用标准的遗传关联研究都无法检测到这些突变。一些常见的单核苷酸多态性和常见变异的单倍型可能会捕获大量的有害突变，因为一些低频率的常见变异单倍型在携带罕见有害突变的染色体上比不携带的染色体上更为常见。
从澳大利亚乳腺癌家族研究的 571 名参与者中获得了 BRCA1 和 BRCA2 的 DNA 序列数据。遗传变异被分为有害突变或常见遗传变异。选择标记常见多态性的变异并使用 Haploview 解析单倍型。使用置换检验比较它们在有无有害突变携带者中的频率。
发现 BRCA1 中的一个常见遗传变异（3232A > G）在有害突变携带者中过度表达（p = 0.05），而 BRCA2 中的一个常见遗传变异（1342A > C）在有害突变携带者中发生频率较低（p = 0.04）。用于形成单倍型的四个常见 BRCA1 变体在与非携带者相比时，在有害突变携带者中更为常见，但两组之间的分布没有差异的证据（p = 0.34）。在 BRCA2 中，与非携带者相比，所有四个常见变体在有害突变携带者中发生频率较低，但两组之间分布差异的证据较弱（p = 0.16）。在有害突变携带者中发现了一些不太常见的常见 BRCA1 变体的单倍型，但在人群水平上没有证据表明这一点。在 BRCA2 中，只有最常见的单倍型在有害突变携带者中更为常见，人群水平上也没有证据表明这一点。
我们观察到 BRCA1 和 BRCA2 中常见遗传变异及其单倍型在具有和不具有这些基因有害突变的早发性乳腺癌病例中的频率存在差异。尽管我们的数据仅提供了人群水平频率差异的微弱证据，但有害突变携带者的数量较少，并且在使用汇总数据的更大研究中，结果可能会得到证实。
