Sokolenko Anna P, Preobrazhenskaya Elena V, Aleksakhina Svetlana N, Iyevleva Aglaya G, Mitiushkina Natalia V, Zaitseva Olga A, Yatsuk Olga S, Tiurin Vladislav I, Strelkova Tatiana N, Togo Alexandr V, Imyanitov Evgeny N
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
Cancer Lett. 2015 Apr 10;359(2):259-61. doi: 10.1016/j.canlet.2015.01.022. Epub 2015 Jan 22.
Twenty one DNA repair genes were analyzed in a group of 95 BC patients, who displayed clinical features of hereditary disease predisposition but turned out to be negative for mutations in BRCA1 and BRCA2 entire coding region as well as for founder disease-predisposing alleles in CHEK2, NBN/NBS1 and ATM genes. Full-length sequencing of CHEK2 and NBN/NBS1 failed to identify non-founder mutations. The analysis of TP53 revealed a woman carrying the R282W allele; further testing of additional 108 BC patients characterized by a very young age at onset (35 years or earlier) detected one more carrier of the TP53 germ-line defect. In addition, this study confirmed non-random occurrence of PALB2 truncating mutations in Russian hereditary BC patients. None of the studied cases carried germ-line defects in recently discovered hereditary BC genes, BRIP1, FANCC, MRE11A and RAD51C. The analysis of genes with yet unproven BC-predisposing significance (BARD1, BRD7, CHEK1, DDB2, ERCC1, EXO1, FANCG, PARP1, PARP2, RAD51, RNF8, WRN) identified single women carrying a protein-truncating allele, WRN R1406X. DNA sequencing of another set of 95 hereditary BC cases failed to reveal additional WRN heterozygous genotypes. Since WRN is functionally similar to the known BC-predisposing gene, BLM, it deserves to be analyzed in future hereditary BC studies. Furthermore, this investigation revealed a number of rare missense germ-line variants, which are classified as probably protein-damaging by online in silico tools and therefore may require further consideration.
对一组95例乳腺癌患者的21个DNA修复基因进行了分析，这些患者表现出遗传性疾病易感性的临床特征，但结果显示BRCA1和BRCA2整个编码区的突变以及CHEK2、NBN/NBS1和ATM基因中常见的疾病易感性等位基因均为阴性。对CHEK2和NBN/NBS1进行全长测序未能发现非常见突变。TP53分析发现一名携带R282W等位基因的女性；对另外108例发病年龄非常小（35岁或更早）的乳腺癌患者进行进一步检测，又发现一名TP53种系缺陷携带者。此外，本研究证实俄罗斯遗传性乳腺癌患者中PALB2截短突变的发生并非随机。所研究的病例中没有一例携带最近发现的遗传性乳腺癌基因BRIP1、FANCC、MRE11A和RAD51C的种系缺陷。对尚未证实具有乳腺癌易感性意义的基因（BARD1、BRD7、CHEK1、DDB2、ERCC1、EXO1、FANCG、PARP1、PARP2、RAD51、RNF8、WRN）进行分析，发现一名携带蛋白质截短等位基因WRN R1406X的女性。对另一组95例遗传性乳腺癌病例进行DNA测序，未发现其他WRN杂合基因型。由于WRN在功能上与已知的乳腺癌易感基因BLM相似，因此值得在未来的遗传性乳腺癌研究中进行分析。此外，这项研究还发现了一些罕见的错义种系变异，在线计算机模拟工具将其分类为可能损害蛋白质，因此可能需要进一步研究。
