title: Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers.
abstract: Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCA1 allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1 single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression.
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Sokolenko
authors.affiliation: Department of Obstetrics and Gynecology, Grodno State Medical University, Grodno 230023, Belarus.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Savonevich
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Alexandr O
authors.initials: AO
authors.lastname: Ivantsov
authors.affiliation: Department of Pathology, Russian Research Centre for Radiology and Surgical Technologies, St. Petersburg 197758, Russia.
authors.forename: Grigory A
authors.initials: GA
authors.lastname: Raskin
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Ekatherina S
authors.initials: ES
authors.lastname: Kuligina
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Gorodnova
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Preobrazhenskaya
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Maxim A
authors.initials: MA
authors.lastname: Kleshchov
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Vladislav I
authors.initials: VI
authors.lastname: Tiurin
authors.affiliation: Department of Pathology, Russian Research Centre for Radiology and Surgical Technologies, St. Petersburg 197758, Russia.
authors.forename: Marina S
authors.initials: MS
authors.lastname: Mukhina
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Khristina B
authors.initials: KB
authors.lastname: Kotiv
authors.affiliation: Department of Obstetrics and Gynecology, Grodno State Medical University, Grodno 230023, Belarus.
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Shulga
authors.affiliation: Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki 00290, Finland.
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Kuznetsov
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
authors.forename: Igor V
authors.initials: IV
authors.lastname: Berlev
authors.affiliation: Department of Tumor Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia; Department of Medical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia; Department of Medical Genetics, I.I. Mechnikov North-Western Medical University, St.-Petersburg 191015, Russia; Department of Oncology, St.-Petersburg State University, St.-Petersburg 199034, Russia. Electronic address: evgeny@imyanitov.spb.ru.
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D018365:Neoplasm, Residual; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor
keywords: BRCA1; Loss-of-heterozygosity; Neoadjuvant therapy; Ovarian cancer; Treatment resistance