Whole-exome sequencing of Finnish hereditary breast cancer families
Whole-exome sequencing of Finnish hereditary breast cancer families
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DOI：
10.1038/ejhg.2016.141
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发表时间：
2017-01-01
影响因子：
5.2
通讯作者：
Schleutker, Johanna
中科院分区：
文献类型：
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作者：
Maatta, Kirsi;Rantapero, Tommi;Schleutker, Johanna
在非 BRCA1/2 家族中，导致乳腺癌 (BC) 遗传易感性的因素中有很大一部分是未知的。对 13 个高危芬兰遗传性乳腺癌和/或卵巢癌 (HBOC) 家族进行了外显子组测序，以检测导致 BC 易感性的变异。经过筛选后，通过 Sanger 测序/TaqMan 检测，在 129 名女性 HBOC 患者、多达 989 名女性对照者和 31 名乳腺肿瘤中筛选出 DNA 损伤反应 (DDR) 通路基因中的 18 个候选变异。此外，还在 49 名男性 BC 患者和 909 名男性对照中进一步研究了两种变异。其次，详细分析了预计影响六名早发 BC 患者功能的所有变异。与对照组相比，女性 HBOC 患者的 ATM、MYC、PLAU、RAD1 和 RRM2B 变异较多（比值比 1.16-2.16）。在一名男性 BC 患者中检测到 RAD50 中罕见的非同义变异。此外，在一个高风险家庭中发现了一种非常罕见的 BRCA1 变异。没有一个变体显示乳腺肿瘤中野生型等位基因丢失。此外，在早发患者的基因中检测到了预计会影响功能的新变异，这些基因针对 DNA 修复和复制、信号传导、细胞凋亡和细胞周期途径。多个 DDR 通路基因缺陷的家族特异性富集可能解释了所研究家族中 BC 的易感性。这些发现提供了有关潜在 BC 相关途径的新信息，并为未来的研究提供了良好的前提。
A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls. Second, all variants predicted to affect function in six early-onset BC patients were analysed in detail. Variants in ATM, MYC, PLAU, RAD1, and RRM2B were enriched in female HBOC patients compared with controls (odds ratio 1.16-2.16). A rare nonsynonymous variant in RAD50 was detected in a male BC patient. In addition, a very rare BRCA1 variant was identified in a single high-risk family. None of the variants showed wild-type allele loss in breast tumours. Furthermore, novel variants predicted to affect function were detected in early-onset patients in genes, which target DNA repair and replication, signalling, apoptosis, and cell cycle pathways. Family-specific enrichment of multiple DDR pathway gene defects likely explains BC predisposition in the studied families. These findings provide new information on potential BC-related pathways and an excellent premise for future studies.