title: Impact of decitabine on immunohistochemistry expression of the putative tumor suppressor genes FHIT, WWOX, FUS1 and PTEN in clinical tumor samples.
abstract: 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.
authors.affiliation: University of Ottawa, 501 Smyth Rd, Ottawa, ON K1H 8 L6, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Nunez
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, 3307 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: UT MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Aldaz
authors.affiliation: Fels Institute for Cancer Research and Molecular Biology, 3307 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
authors.affiliation: University of California San Diego, 3855 Health Sciences Dr, La Jolla, CA 92093, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
keywords: Decitabine; FHIT; FUS1; LINE-1 methylation; PTEN; Tumor suppressor genes; WWOX