Molecular classification of familial non-BRCA1/BRCA2 breast cancer
Molecular classification of familial non-BRCA1/BRCA2 breast cancer
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DOI：
10.1073/pnas.0533805100
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发表时间：
2003-03-04
影响因子：
11.1
通讯作者：
Trent, J
中科院分区：
文献类型：
--
作者：
Hedenfalk, I;Ringnér, M;Trent, J
在他们发现后的十年里，两个主要的乳腺癌易感基因BRCA1和BRCA2被确凿地证明与分离乳腺癌和卵巢癌的很大一部分家庭有关。然而，同样明显的是，单独分离乳腺癌的很大一部分家庭并不是由BRCA1或BRCA2突变引起的。不幸的是，尽管进行了大量的努力，但到目前为止，其他乳腺癌易感基因的鉴定还没有成功，可能是因为遗传异质性、低外显性或隐性/多基因机制。这些非BRCA1/2乳腺癌家族(称为BRCAx家族)组成了一个组织病理异质性组，进一步支持了它们来自多个基因事件的起源。因此，确定一种成功地将BRCAx家系细分为可识别的组的方法对于进一步的遗传分析具有相当大的价值。我们之前已经证明，全球基因表达分析可以从BRCA1和BRCA2突变携带者的乳腺肿瘤中识别独特和不同的表达谱。在这里，我们展示了基因表达谱可以在BRCAx肿瘤中发现新的类别，并将它们与BRCA1和BRCA2肿瘤区分开来。此外，基于微阵列的比较基因组杂交(CGH)显示了BRCAx亚组内特定的体细胞遗传改变。这些发现表明，当使用基于基因表达的分类时，BRCAx家族可以被归类为同质子集，从而潜在地增加了传统遗传分析的能力。
In the decade since their discovery, the two major breast cancer susceptibility genes BRCA1 and BRCA2, have been shown conclusively to be involved in a significant fraction of families segregating breast and ovarian cancer. However, it has become equally clear that a large proportion of families segregating breast cancer alone are not caused by mutations in BRCA1 or BRCA2. Unfortunately, despite intensive effort, the identification of additional breast cancer predisposition genes has so far been unsuccessful, presumably because of genetic heterogeneity, low penetrance, or recessive/polygenic mechanisms. These non-BRCA1/2 breast cancer families (termed BRCAx families) comprise a histopathologically heterogeneous group, further supporting their origin from multiple genetic events. Accordingly, the identification of a method to successfully subdivide BRCAx families into recognizable groups could be of considerable value to further genetic analysis. We have previously shown that global gene expression analysis can identify unique and distinct expression profiles in breast tumors from BRCA1 and BRCA2 mutation carriers. Here we show that gene expression profiling can discover novel classes among BRCAx tumors, and differentiate them from BRCA1 and BRCA2 tumors. Moreover, microarray-based comparative genomic hybridization (CGH) to cDNA arrays revealed specific somatic genetic alterations within the BRCAx subgroups. These findings illustrate that, when gene expression-based classifications are used, BRCAx families can be grouped into homogeneous subsets, thereby potentially increasing the power of conventional genetic analysis.