title: BRCA1 loss preexisting in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood.
abstract: OBJECTIVE
  A preliminary study performed on a small cohort of multifocal prostate cancer (PCa) detected BRCA1 allelic imbalances among circulating tumor cells (CTC). The present analysis was aimed to elucidate the biological and clinical roles of BRCA1 losses in metastatic spread and tumor progression in PCa patients.
  
  
  METHODS
  To map molecular progression in PCa outgrowth, we used fluorescence in situ hybridization analysis of primary tumors and lymph node sections, and CTCs from peripheral blood.
  
  
  RESULTS
  We found that 14% of 133 tested patients carried monoallelic BRCA1 loss in at least one tumor focus. Extended molecular analysis of chr17q revealed that this aberration was often a part of larger cytogenetic rearrangement involving chr17q21 accompanied by allelic imbalance of the tumor suppressor gene PTEN and lack of BRCA1 promoter methylation. The BRCA1 losses correlated with advanced T stage (P < 0.05), invasion to pelvic lymph nodes (P < 0.05), as well as biochemical recurrence (P < 0.01). Their prevalence was twice as high within 62 lymph node metastases (LNM) as in primary tumors (27%, P < 0.01). The analysis of 11 matched primary PCa-LNM pairs confirmed the suspected transmission of genetic abnormalities between these two sites. In four of seven patients with metastatic disease, BRCA1 losses appeared in a minute fraction of cytokeratin- and vimentin-positive CTCs.
  
  
  CONCLUSIONS
  Small subpopulations of PCa cells bearing BRCA1 losses might be one confounding factor initiating tumor dissemination and might provide an early indicator of shortened disease-free survival.
authors.affiliation: Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bednarz
authors.forename: Elke
authors.initials: E
authors.lastname: Eltze
authors.forename: Axel
authors.initials: A
authors.lastname: Semjonow
authors.forename: Michael
authors.initials: M
authors.lastname: Rink
authors.forename: Antje
authors.initials: A
authors.lastname: Andreas
authors.forename: Lennart
authors.initials: L
authors.lastname: Mulder
authors.forename: Juliane
authors.initials: J
authors.lastname: Hannemann
authors.forename: Margit
authors.initials: M
authors.lastname: Fisch
authors.forename: Klaus
authors.initials: K
authors.lastname: Pantel
authors.forename: Heinz-Ulrich G
authors.initials: HU
authors.lastname: Weier
authors.forename: Krzysztof P
authors.initials: KP
authors.lastname: Bielawski
authors.forename: Burkhard
authors.initials: B
authors.lastname: Brandt
mesh_terms: D000368:Aged; D002886:Chromosomes, Human, Pair 17; D018450:Disease Progression; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology*; D014178:Translocation, Genetic