Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer
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DOI：
10.1002/ijc.32385
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发表时间：
2019-10-01
影响因子：
6.4
通讯作者：
Kleibl, Zdenek
中科院分区：
文献类型：
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作者：
Kleiblova, Petra;Stolarova, Lenka;Kleibl, Zdenek
检查点激酶2(CHEK2)是一种多癌易感基因，它的胚系突变增加了乳腺癌(BC)的风险；然而，已发表的研究中的风险估计有很大不同。我们分析了1,928名捷克高危乳腺癌/卵巢癌(BC/OC)患者和3,360名人群匹配对照(PMC)的胚系CHEK2变异。为了对VUS进行功能分类，我们在人类未转化的RPE1-CHEK2基因敲除细胞中建立了一种互补试验，以定量内源蛋白KAP1的Chk2特异性磷酸化。我们确定了46名患者(2.39%)和11名PMC(0.33%)的10次截断(p=1.1x10(-14))。46例突变携带者中有20例存在两种大的基因内重排(LGR)。截短术显著增加单侧BC风险(OR=7.94；95%CI3.90~17.47；p=1.1×10(-14))，且在双侧BC(4/149；2.68%；p=0.003)、双原发BC/OC(3/79；3.80%；p=0.004)、男性BC(3/48；6.25%；p=8.6x10(-4))患者中发生率更高，而OC患者(3/35 4；0.85%；p=0.14)则不明显。此外，88例患者(4.56%)和131例(3.90%)PMC发现26个VU错义(p=0.22)。使用我们的功能分析，15名患者(0.78%)和6名患者(0.18%)的11个变异被评为有害的(p=0.002)。功能中间和中性变异的频率在患者和PMC之间没有差异。功能有害的CHEK2错义变异显著增加了BC的风险(OR=3.9；95%CI1.24-13.35；p=0.009)和轻微的OC风险(OR=4.77；95%CI0.77-22.47；p=0.047)；然而，低频率携带者需要在更大的研究中进行评估。我们的研究强调了LGR检测对CHEK2分析的重要性，仔细考虑了两个病例中的种族和风险估计的对照，并展示了新开发的人类未转化细胞系检测在功能性CHEK2 VUS分类中的前景。
Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer-predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high-risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population-matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1-CHEK2-knockout cells quantifying CHK2-specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 x 10(-14)). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90-17.47; p = 1.1 x 10(-14)) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 x 10(-4)), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24-13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77-22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.