TY - JOUR
T1 - Impact of decitabine on immunohistochemistry expression of the putative tumor suppressor genes FHIT, WWOX, FUS1 and PTEN in clinical tumor samples
AU - Stewart, David J.
AU - Nunez, Maria I.
AU - Jelinek, Jaroslav
AU - Hong, David
AU - Gupta, Sanjay
AU - Aldaz, Marcelo
AU - Issa, Jean Pierre
AU - Kurzrock, Razelle
AU - Wistuba, Ignacio I.
N1 - Publisher Copyright:
© 2014 Stewart et al.
PY - 2014
Y1 - 2014
N2 - Background: Since tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) and phosphatase and tensin homolog (PTEN), immunohistochemistry scores from pre- and post-decitabine tumor biopsies (25 patients) were correlated with methylation of the long interspersed nuclear element-1 (LINE-1) repetitive DNA element (as a surrogate for global DNA methylation) and with tumor regression. Results: With negative staining pre-decitabine (score = 0), the number of patients converting to positive staining post-decitabine was 1 of 1 for FHIT, 3 of 6 for WWOX, 2 of 3 for FUS1 and 1 of 10 for PTEN. In tumors with low pre-decitabine tumor suppressor gene scores (≤150), expression was higher post-treatment in 8 of 8 cases for FHIT (P = 0.014), 7 of 17 for WWOX (P = 0.0547), 7 of 12 for FUS1 (P = 0.0726), and 1 of 16 for PTEN (P = 0.2034). If FHIT, WWOX and FUS1 were considered together, median pre- versus post-decitabine scores were 60 versus 100 (P = 0.0002). Overall, tumor suppressor gene expression change did not correlate with LINE-1 demethylation, although tumors converting from negative to positive had a median decrease in LINE-1 methylation of 24%, compared to 6% in those not converting (P = 0.069). Five of 15 fully evaluable patients had reductions in tumor diameter (range 0.2% to 33.4%). Of these, three had simultaneous increases in three tumor suppressor genes (including the two patients with the greatest tumor regression) compared to 2 of 10 with tumor growth (P = 0.25). Conclusions: In tumors with low tumor suppressor gene expression, decitabine may be associated with increased expression of the tumor suppressor genes FHIT, FUS1, and WWOX, but not PTEN.
AB - Background: Since tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) and phosphatase and tensin homolog (PTEN), immunohistochemistry scores from pre- and post-decitabine tumor biopsies (25 patients) were correlated with methylation of the long interspersed nuclear element-1 (LINE-1) repetitive DNA element (as a surrogate for global DNA methylation) and with tumor regression. Results: With negative staining pre-decitabine (score = 0), the number of patients converting to positive staining post-decitabine was 1 of 1 for FHIT, 3 of 6 for WWOX, 2 of 3 for FUS1 and 1 of 10 for PTEN. In tumors with low pre-decitabine tumor suppressor gene scores (≤150), expression was higher post-treatment in 8 of 8 cases for FHIT (P = 0.014), 7 of 17 for WWOX (P = 0.0547), 7 of 12 for FUS1 (P = 0.0726), and 1 of 16 for PTEN (P = 0.2034). If FHIT, WWOX and FUS1 were considered together, median pre- versus post-decitabine scores were 60 versus 100 (P = 0.0002). Overall, tumor suppressor gene expression change did not correlate with LINE-1 demethylation, although tumors converting from negative to positive had a median decrease in LINE-1 methylation of 24%, compared to 6% in those not converting (P = 0.069). Five of 15 fully evaluable patients had reductions in tumor diameter (range 0.2% to 33.4%). Of these, three had simultaneous increases in three tumor suppressor genes (including the two patients with the greatest tumor regression) compared to 2 of 10 with tumor growth (P = 0.25). Conclusions: In tumors with low tumor suppressor gene expression, decitabine may be associated with increased expression of the tumor suppressor genes FHIT, FUS1, and WWOX, but not PTEN.
KW - Decitabine
KW - FHIT
KW - FUS1
KW - LINE-1 methylation
KW - PTEN
KW - Tumor suppressor genes
KW - WWOX
UR - http://www.scopus.com/inward/record.url?scp=84923367056&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84923367056&partnerID=8YFLogxK
U2 - 10.1186/1868-7083-6-13
DO - 10.1186/1868-7083-6-13
M3 - Article
C2 - 25024751
AN - SCOPUS:84923367056
SN - 1868-7075
VL - 6
JO - Clinical epigenetics
JF - Clinical epigenetics
IS - 1
ER -