Kleiblová Petra, Stolařová Lenka, Křížová Křížová, Lhota Filip, Hojný Jan, Zemánková Petra, Havránek Ondřej, Vočka Michal, Černá Marta, Lhotová Klára, Borecká Marianna, Janatová Markéta, Soukupová Jana, Ševčík Jan, Zimovjanová Martina, Kotlas Jaroslav, Panczak Aleš, Veselá Kamila, Červenková Jana, Schneiderová Michaela, Burócziová Monika, Burdová Kamila, Stránecký Viktor, Foretová Lenka, Macháčková Eva, Tavandzis Spiros, Kmoch Stanislav, Macůrek Libor, Kleibl Zdeněk
Klin Onkol. 2019 Summer;32(Supplementum2):36-50. doi: 10.14735/amko2019S36.
Hereditary mutations in the CHEK2 gene (which encodes CHK2 kinase) contribute to a moderately increased risk of breast cancer (BC) and other cancers. Large variations in the frequency of CHEK2 mutations and the occurrence of variants of unknown clinical significance (VUS) complicate estimation of cancer risk in carriers of germline CHEK2 mutations.
We performed mutation analysis of 1,526 high-risk Czech BC patients and 3,360 Czech controls. Functional analysis was performed for identified VUS using a model system based on a human RPE1-CHEK2-KO cell line harboring biallelic inactivation of endogenous CHEK2.
The frequency of ten truncating CHEK2 variants differed markedly between BC patients (2.26%) and controls (0.11%; p = 4.1 × 1012). We also found 23 different missense variants in 4.5% patients and in 4.0% of controls. The most common was p.I157T, which was found in patients and controls with the same frequency. Functional analysis identified nine functionally deleterious VUS, another nine functionally neutral VUS, and four intermediate VUS (including p.I157T). We found that carriers of truncating CHEK2 mutations had a high BC risk (OR 8.19; 95% CI 4.11-17.75), and that carriers of functionally deleterious missense variants had a moderate risk (OR 4.06; 95% CI, 1.37-13.39). Carriers of these mutations developed BC at 44.4 and 50.7 years, respectively. Functionally neutral and functionally intermediate missense variants did not increase the BC risk. BC in CHEK2 mutation carriers was frequently ER-positive and of higher grade. Notably, carriers of CHEK2 mutations developed second cancers more frequently than BRCA1/BRCA2/PALB2/p53 or mutation non-carriers.
Hereditary CHEK2 mutations contribute to the development of hereditary BC. The associated cancer risk in mutation carriers increases with the number of affected individuals in a family. Annual follow-up with breast ultrasound, mammography, or magnetic resonance imaging is recommended for asymptomatic mutation carriers from the age of 40. Surgical prevention and specific follow-up of other tumors should be considered based on family cancer history. The work was supported by grants from the Czech Health Research Council of the Ministry of Health of the Czech Republic NR 15-28830A, 16-29959A, NV19-03-00279, projects of the PROGRES Q28/LF1, GAUK 762216, SVV2019 / 260367, PRIMUS/17/MED/9, UNCE/MED/016, Progress Q26, LQ1604 NPU II and project AVČR Qualitas. The analysis of a set of unselected controls was made possible by the existence and support of the scientific infrastructure of the National Center for Medical Genomics (LM2015091) and its project aimed at creating a reference database of genetic variants of the Czech Republic (CZ.02.1.01/0.0/0.0/16_013/0001634). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 2. 4. 2019 Accepted: 14. 5. 2019.
CHEK2基因（编码CHK2激酶）的遗传性突变会使患乳腺癌（BC）和其他癌症的风险适度增加。CHEK2突变频率和临床意义不明的变异（VUS）的出现存在很大差异，这使得对种系CHEK2突变携带者的癌症风险评估变得复杂。
我们对1526例高危捷克乳腺癌患者和3360例捷克对照进行了突变分析。使用基于人RPE1-CHEK2-KO细胞系的模型系统对鉴定出的VUS进行功能分析，该细胞系内源性CHEK2发生双等位基因失活。
10种截短型CHEK2变异的频率在乳腺癌患者（2.26%）和对照（0.11%；p = 4.1×10⁻¹²）之间存在显著差异。我们还在4.5%的患者和4.0%的对照中发现了23种不同的错义变异。最常见的是p.I157T，在患者和对照中的出现频率相同。功能分析鉴定出9种功能有害的VUS、另外9种功能中性的VUS和4种中间型VUS（包括p.I157T）。我们发现截短型CHEK2突变携带者患乳腺癌的风险很高（OR 8.19；95% CI 4.11 - 17.75），功能有害的错义变异携带者有中度风险（OR 4.06；95% CI，1.37 - 13.39）。这些突变的携带者分别在44.4岁和50.7岁时患乳腺癌。功能中性和功能中间型错义变异不会增加患乳腺癌的风险。CHEK2突变携带者的乳腺癌通常为雌激素受体阳性且分级较高。值得注意的是，CHEK2突变携带者比BRCA1/BRCA2/PALB2/p53突变携带者或非突变携带者更频繁地发生第二种癌症。
遗传性CHEK2突变会导致遗传性乳腺癌的发生。突变携带者的相关癌症风险随家族中受影响个体的数量增加而增加。建议40岁起对无症状突变携带者每年进行乳腺超声、乳腺X线摄影或磁共振成像随访。应根据家族癌症病史考虑手术预防和对其他肿瘤的特定随访。本研究得到了捷克共和国卫生部捷克健康研究委员会的资助，项目编号为NR 15 - 28830A、16 - 29959A、NV19 - 03 - 00279，PROGRES Q28/LF1、GAUK 762216、SVV2019 / 260367、PRIMUS/17/MED/9、UNCE/MED/
