Chromatin remodeling factors and BRM/BRG1 expression as prognostic indicators in non-small cell lung cancer.
We immunohistochemically examined 12 core proteins involved in the chromatin remodeling machinery using a tissue microarray composed of 150 lung adenocarcinoma (AD) and 150 squamous cell carcinoma (SCC) cases. Most of the proteins showed nuclear staining, whereas some also showed cytoplasmic or membranous staining. When the expression patterns of all tested antigens were considered, proteins with nuclear staining clustered into two major groups. Nuclear signals of BRM, Ini-1, retinoblastoma, mSin3A, HDAC1, and HAT1 clustered together, whereas nuclear signals of BRG1, BAF155, HDAC2, BAF170, and RbAP48 formed a second cluster. Additionally, two thirds of the cases on the lung tissue array had follow-up information, and survival analysis was performed for each of the tested proteins. Positive nuclear BRM (N-BRM) staining correlated with a favorable prognosis in SCC and AD patients with a 5 year-survival of 53.5% compared with 32.3% for those whose tumors were negative for N-BRM (P = 0.015). Furthermore, patients whose tumors stained positive for both N-BRM and nuclear BRG1 had a 5 year-survival of 72% compared with 33.6% (P = 0.013) for those whose tumors were positive for either or negative for both markers. In contrast, membranous BRM (M-BRM) staining correlated with a poorer prognosis in AD patients with a 5 year-survival of 16.7% compared with those without M-BRM staining (38.1%; P = 0.016). These results support the notion that BRM and BRG1 participate in two distinct chromosome remodeling complexes that are functionally complementary and that the nuclear presence of BRM, its coexpression with nuclear BRG1, and the altered cellular localization of BRM (M-BRM) are useful markers for non-small cell lung cancer prognosis.
Fukuoka
Junya
J
Laboratory of Population Genetics, Biometric Research Branch, Center for Bioinformatics, Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA.
Fujii
Takeshi
T
Shih
Joanna H
JH
Dracheva
Tatiana
T
Meerzaman
Daoud
D
Player
Audrey
A
Hong
Kyeong
K
Settnek
Sharon
S
Gupta
Ajay
A
Buetow
Kenneth
K
Hewitt
Stephen
S
Travis
William D
WD
Jen
Jin
J
D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000918:Antibody Specificity; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D002875:Chromosomes / Q000648:ultrastructure; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D004265:DNA Helicases; D029721:Drosophila Proteins; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011786:Quality Control; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D018797:Cell Cycle Proteins; D002843:Chromatin; D029721:Drosophila Proteins; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; D015534:Trans-Activators; D014157:Transcription Factors; C086469:brm protein, Drosophila; C084108:SMARCA4 protein, human; D004265:DNA Helicases