TY - JOUR
T1 - Pre-operative decitabine in colon cancer patients: Analyses on wnt target methylation and expression
AU - Linnekamp, Janneke F.
AU - Kandimalla, Raju
AU - Fessler, Evelyn
AU - de Jong, Joan H.
AU - Rodermond, Hans M.
AU - van Bochove, Gregor G. W.
AU - The, Frans O.
AU - Punt, Cornelis J. A.
AU - Bemelman, Willem A.
AU - van de Ven, Anthony W. H.
AU - Tanis, Pieter J.
AU - Kemper, Elles M.
AU - Koens, Lianne
AU - Dekker, Evelien
AU - Vermeulen, Louis
AU - van Laarhoven, Hanneke W. M.
AU - Medema, Jan Paul
N1 - Funding Information: Funding: This research was funded by the KWF grant from the Dutch Cancer Society, grant number KWF 2012-542, and the Dutch Gastrointestinal and Liver disorder Foundation, grant number MLDS FP13-07, awarded to Jan Paul Medema. L.V. is a New York Stem Cell Foundation—Robertson Investigator. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5/2
Y1 - 2021/5/2
N2 - DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre-and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved.
AB - DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre-and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved.
KW - Clinical translation study
KW - Colon cancer
KW - DNA methylation
KW - Decitabine
UR - http://www.scopus.com/inward/record.url?scp=85105713143&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers13102357
DO - https://doi.org/10.3390/cancers13102357
M3 - Article
C2 - 34068407
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 10
M1 - 2357
ER -