title: Development of breast tumors in CHEK2, NBN/NBS1 and BLM mutation carriers does not commonly involve somatic inactivation of the wild-type allele.
abstract: Somatic inactivation of the remaining allele is a characteristic feature of cancers arising in BRCA1 and BRCA2 mutation carriers, which determines their unprecedented sensitivity to some DNA-damaging agents. Data on tumor-specific status of the involved gene in novel varieties of hereditary breast cancer (BC) remain incomplete. We analyzed 32 tumors obtained from 30 patients with non-BRCA1/2 BC-associated germ-line mutations: 25 women were single mutation carriers (7 BLM, 15 CHEK2 and 3 NBN/NBS1) and 5 were double mutation carriers (2 BLM/BRCA1, 1 CHEK2/BLM, 1 CHEK2/BRCA1 and 1 NBN/BLM). Losses of heterozygosity affecting the wild-type allele were detected in none of the tumors from BLM mutation carriers, 3/18 (17 %) CHEK2-associated BC and 1/4 (25 %) NBN/NBS1-driven tumors. The remaining 28 BC were subjected to the sequence analysis of entire coding region of the involved gene; no somatic mutations were identified. We conclude that the tumor-specific loss of the wild-type allele is not characteristic for BC arising in CHEK2, NBN/NBS1 and BLM mutation carriers. Rarity of "second-hit" inactivation of the involved gene in CHEK2-, NBN/NBS1- and BLM-associated BC demonstrates their substantial biological difference from BRCA1/2-driven cancers and makes them poorly suitable for the clinical trials with cisplatin and PARP inhibitors.
authors.affiliation: N.N. Petrov Institute of Oncology, 197758, St.-Petersburg, Russia.
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Suspitsin
authors.forename: Grigory A
authors.initials: GA
authors.lastname: Yanus
authors.forename: Anna P
authors.initials: AP
authors.lastname: Sokolenko
authors.forename: Olga S
authors.initials: OS
authors.lastname: Yatsuk
authors.forename: Olga A
authors.initials: OA
authors.lastname: Zaitseva
authors.forename: Alexandr A
authors.initials: AA
authors.lastname: Bessonov
authors.forename: Alexandr O
authors.initials: AO
authors.lastname: Ivantsov
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Heinstein
authors.forename: Valery F
authors.initials: VF
authors.lastname: Klimashevskiy
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Togo
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D053484:RecQ Helicases / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C097151:Bloom syndrome protein; D053484:RecQ Helicases