Maleva Kostovska Ivana, Wang Jing, Bogdanova Natalia, Schürmann Peter, Bhuju Sabin, Geffers Robert, Dürst Matthias, Liebrich Clemens, Klapdor Rüdiger, Christiansen Hans, Park-Simon Tjoung-Won, Hillemanns Peter, Plaseska-Karanfilska Dijana, Dörk Thilo
Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany; Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov", Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000 Skopje, Macedonia.
Clinics of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany.
Cancer Lett. 2016 Jun 28;376(1):173-7. doi: 10.1016/j.canlet.2016.03.048. Epub 2016 Apr 1.
ATAD5/ELG1 is a protein crucially involved in replication and maintenance of genome stability. ATAD5 has recently been identified as a genomic risk locus for both breast and ovarian cancer through genome-wide association studies. We aimed to investigate the spectrum of coding ATAD5 germ-line mutations in hospital-based series of patients with triple-negative breast cancer or serous ovarian cancer compared with healthy controls. The ATAD5 coding and adjacent splice site regions were analyzed by targeted next-generation sequencing of DNA samples from 273 cancer patients, including 114 patients with triple-negative breast cancer and 159 patients with serous epithelial ovarian cancer, and from 276 healthy females. Among 42 different variants identified, twenty-two were rare missense substitutions, of which 14 were classified as pathogenic by at least one in silico prediction tool. Three of four novel missense substitutions (p.S354I, p.H974R and p.K1466N) were predicted to be pathogenic and were all identified in ovarian cancer patients. Overall, rare missense variants with predicted pathogenicity tended to be enriched in ovarian cancer patients (14/159) versus controls (11/276) (p = 0.05, 2df). While truncating germ-line variants in ATAD5 were not detected, it remains possible that several rare missense variants contribute to genetic susceptibility toward epithelial ovarian carcinomas.
ATAD5/ELG1是一种在基因组稳定性的复制和维持过程中起关键作用的蛋白质。最近，通过全基因组关联研究，ATAD5被确定为乳腺癌和卵巢癌的基因组风险位点。我们旨在研究与健康对照相比，在以医院为基础的三阴性乳腺癌或浆液性卵巢癌患者系列中，ATAD5编码区种系突变的情况。通过对273例癌症患者（包括114例三阴性乳腺癌患者和159例浆液性上皮性卵巢癌患者）以及276例健康女性的DNA样本进行靶向二代测序，分析了ATAD5编码区和相邻剪接位点区域。在鉴定出的42种不同变异中，有22种是罕见的错义替换，其中至少有1种计算机预测工具将14种归类为致病性变异。4种新的错义替换（p.S354I、p.H974R和p.K1466N）中有3种被预测为致病性变异，且均在卵巢癌患者中发现。总体而言，预测具有致病性的罕见错义变异在卵巢癌患者（14/159）中比在对照（11/276）中更易富集（p = 0.05，自由度为2）。虽然未检测到ATAD5的截短种系变异，但仍有可能几种罕见的错义变异会导致上皮性卵巢癌的遗传易感性。
