Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors.
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.
Honrado
Emiliano
E
Human Genetics Department Centro Nacional Investigaciones Oncológicas Melchor Fernández Almagro, 3 28029 Madrid, Spain.
Osorio
Ana
A
Palacios
José
J
Milne
Roger L
RL
Sánchez
Lydia
L
Díez
Orland
O
Cazorla
Alicia
A
Syrjakoski
Kirsi
K
Huntsman
David
D
Heikkilä
Päivi
P
Lerma
Enrique
E
Kallioniemi
Anne
A
Rivas
Carmen
C
Foulkes
William D
WD
Nevanlinna
Heli
H
Benítez
Javier
J
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
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