title: Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors.
abstract: OBJECTIVE
  Morphologic and immunohistochemical studies of familial breast cancers have identified specific characteristics associated with BRCA1 mutation-associated tumors when compared with BRCA2 and non-BRCA1/2 tumors, but have not identified differences between BRCA2 and non-BRCA1/2 tumors. Because BRCA1 and BRCA2 genes participate in the DNA repair pathway, we have performed an immunohistochemical study with markers related to this pathway to establish the profile of the three groups.
  
  
  METHODS
  We have studied two tissue microarrays that include 103 familial and 104 sporadic breast tumors, with a panel of DNA repair markers including ATM, CHEK2, RAD51, RAD50, XRCC3, and proliferating cell nuclear antigen.
  
  
  RESULTS
  We found more frequent expression of CHEK2 in BRCA1 and BRCA2 tumors than in non-BRCA1/2 and sporadic tumors. We found absence of nuclear expression and presence of cytoplasmic expression of RAD51 in BRCA2 tumors that differentiate them from other familial tumors. We validated these results with a new series of patient cases. The final study with 253 familial patient cases (74 BRCA1, 71 BRCA2, 108 non-BRCA1/2), and 288 sporadic patient cases, has allowed us to confirm our preliminary results. Because BRCA2 tumors present a specific immunohistochemical profile for RAD51 and CHEK2 markers that is different from non-BRCA1/2 tumors, we have built a multivariate model with these markers that distinguish both tumors with an estimated probability of at least 76%.
  
  
  CONCLUSIONS
  Our results suggest that BRCA2 tumors demonstrate more cytoplasmic and less nuclear RAD51 staining, and increased CHEK2 staining. This pattern may distinguish BRCA2 from familial non-BRCA1/2 tumors.
authors.affiliation: Human Genetics Department Centro Nacional Investigaciones Oncológicas Melchor Fernández Almagro, 3 28029 Madrid, Spain.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Honrado
authors.forename: Ana
authors.initials: A
authors.lastname: Osorio
authors.forename: José
authors.initials: J
authors.lastname: Palacios
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Lydia
authors.initials: L
authors.lastname: Sánchez
authors.forename: Orland
authors.initials: O
authors.lastname: Díez
authors.forename: Alicia
authors.initials: A
authors.lastname: Cazorla
authors.forename: Kirsi
authors.initials: K
authors.lastname: Syrjakoski
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Päivi
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Enrique
authors.initials: E
authors.lastname: Lerma
authors.forename: Anne
authors.initials: A
authors.lastname: Kallioniemi
authors.forename: Carmen
authors.initials: C
authors.lastname: Rivas
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism*; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; D025521:Tumor Suppressor Proteins; C110901:X-ray repair cross complementing protein 3; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes