Institute of Human Genetics, University of Ulm, Albert-Einstein-Allee 11, Ulm, D-89081, Germany.
Division of Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, Heidelberg, D-69120, Germany.
Int J Cancer. 2018 Feb 15;142(4):757-768. doi: 10.1002/ijc.31105. Epub 2017 Oct 30.
Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6-3.9), p = 1.6E-05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9-57.8), p = 5.3E-4). BC association was confirmed in a verification cohort (N = 2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R > 0.9), and a pattern of association very similar for both phenotypes (cases <60 years, p < 0.001, the Bonferroni threshold derived from unlinked variants in the region). In young cases (≤60 years) carrying the risk haplotype, micronucleus test results are predictive for BC (AUC > 0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases.
只有一小部分乳腺癌（BC）病例可以通过连锁、全基因组关联和测序研究中发现的基因突变或基因组变异来解释。已知的涉及 BC 中高风险的基因在 DNA 双链修复功能中富集。因此，为了鉴定中等风险的低频变体，我们在此研究了 10 个候选基因（涉及 DNA 修复或细胞周期控制）中的 17 个变体（MAF：0.01-0.1）。在 437 例病例和 1189 例对照的探索性队列中，我们显示 SLX4/FANCP 基因中的变体 rs3810813 与 BC（≤60 岁；OR=2.6(1.6-3.9)，p=1.6E-05）和降低的 DNA 修复能力（≤60 岁；β=37.8(17.9-57.8)，p=5.3E-4）显著相关。在验证队列（N=2441）中证实了 BC 关联。≥60 岁诊断的病例中不存在这些关联，并且诊断越早，相关性越强。通过内插，我们表明 rs3810813 标记了一个具有 5 个相同等位基因频率的附加变体的单倍型（R > 0.9），并且两种表型（≤60 岁的病例，p < 0.001，来自该区域未连锁变体的 Bonferroni 阈值）的关联模式非常相似。携带风险单倍型的年轻病例（≤60 岁），微核试验结果可预测 BC（AUC > 0.9）。我们的研究结果表明，跨越 SLX4/FANCP 的具有高外显率的风险单倍型与 BC 易感性的功能相关，这表明该变体是在早发性 BC 病例中富集的这些单倍型的一部分。
