Schubert Stephanie, Ripperger Tim, Rood Melanie, Petkidis Anthony, Hofmann Winfried, Frye-Boukhriss Hildegard, Tauscher Marcel, Auber Bernd, Hille-Betz Ursula, Illig Thomas, Schlegelberger Brigitte, Steinemann Doris
Department of Human Genetics, Hannover Medical School, Hannover, Germany.
Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany.
Genes Cancer. 2017 Jan;8(1-2):472-483. doi: 10.18632/genesandcancer.132.
, located 470 kb downstream of , encodes for the nuclear PSMC3-interacting protein, which functions as co-activator of steroid hormone-mediated gene expression, and is involved in RAD51 and DMC1-mediated homologous recombination during DNA repair of double-strand breaks. Recently, germline variants in have been identified in hereditary breast and ovarian cancer (HBOC) patients, mainly in cases with early-onset. We screened a cohort of 166 mutation-negative HBOC patients, of which 56 developed early-onset breast cancer before the age of 36 years, for variants. We identified 7 novel or rare variants in 8 out of 166 index patients: c.-115G>A (rs191843707); c.-70T>A (rs752276800); c.-37A>T (rs199620968); c.-24C>G (rs200359709); c.519G>A p.(Trp173*); c.537+51G>C (rs375509656); c.*24G>A. Three out of 7 identified variants (c.-115G>A, c.519G>A and c.24G>A) with putative pathogenic impact were found in HBOC patients with breast cancer onset at ≤ 36 years. The nonsense mutation c.519G>A p.(Trp173) was located within the DNA binding domain of GT198 and is predicted to induce nonsense-mediated mRNA decay. Functional analyses of c.-115G>A, and c.*24A>G indicated an influence of these variants on gene expression. This is the second study that gives evidence for an association between pathogenic germline variants and early-onset breast cancer in HBOC.
位于[某基因]下游470 kb处，编码核PSMC3相互作用蛋白，该蛋白作为类固醇激素介导的基因表达的共激活因子，在双链断裂的DNA修复过程中参与RAD51和DMC1介导的同源重组。最近，在遗传性乳腺癌和卵巢癌（HBOC）患者中发现了[该基因]的种系变异，主要见于早发性病例。我们对166例[另一相关基因]突变阴性的HBOC患者进行了筛查，其中56例在36岁之前患早发性乳腺癌，以检测[目标基因]的变异。我们在166例索引患者中的8例中鉴定出7种新的或罕见的[目标基因]变异：c.-115G>A（rs191843707）；c.-70T>A（rs752276800）；c.-37A>T（rs199620968）；c.-24C>G（rs200359709）；c.519G>A p.(Trp173*)；c.537+51G>C（rs375509656）；c.*24G>A。在乳腺癌发病年龄≤36岁的HBOC患者中发现了7种已鉴定变异中的3种（c.-115G>A、c.519G>A和c.24G>A）具有潜在致病影响。无义突变c.519G>A p.(Trp173)位于GT198的DNA结合域内，预计会诱导无义介导的mRNA降解。对c.-115G>A和c.*24A>G的功能分析表明这些变异对基因表达有影响。这是第二项为HBOC中致病的[目标基因]种系变异与早发性乳腺癌之间的关联提供证据的研究。
