title: Candidate gene analysis of BRCA1/2 mutation-negative high-risk Russian breast cancer patients.
abstract: 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.
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Sokolenko
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Preobrazhenskaya
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Aleksakhina
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors.forename: Aglaya G
authors.initials: AG
authors.lastname: Iyevleva
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Mitiushkina
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Zaitseva
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Yatsuk
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors.forename: Vladislav I
authors.initials: VI
authors.lastname: Tiurin
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Strelkova
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Togo
authors.affiliation: N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; I.I. Mechnikov North-Western Medical University, St-Petersburg 191015, Russia. Electronic address: evgeny@imyanitov.spb.ru.
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D012426:Russia; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D000076164:Fanconi Anemia Complementation Group N Protein; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D025521:Tumor Suppressor Proteins
keywords: Breast cancer; Candidate genes; Hereditary predisposition; WRN