Response to the methylation inhibitor dihydro-5-azacytidine in mesothelioma is not associated with methylation of p16INK4a: results of cancer and leukemia group B 159904.
BACKGROUND
The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16INK4a. Absence of expression of the p16INK4a gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16INK4a expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16INK4a expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16INK4a via methylation would correlate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC).


METHODS
Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16INK4a would have a better response and survival following DHAC treatment than their nonmethylated counterparts.


RESULTS
Methylation of p16INK4a was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant.


CONCLUSIONS
There was no significant correlation between the presence of p16INK4a methylation and response to DHAC therapy or overall survival.
Kratzke
Robert A
RA
Division of Hematology-Oncology-Transplant, The University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. kratz003@umn.edu
Wang
Xiaofei
X
Wong
Long
L
Kratzke
Marian G
MG
Green
Mark R
MR
Vokes
Everett E
EE
Vogelzang
Nicholas J
NJ
Kindler
Hedy L
HL
Kern
Jeffrey A
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D015996:Survival Rate
D000964:Antimetabolites, Antineoplastic; D019941:Cyclin-Dependent Kinase Inhibitor p16; C013938:5,6-dihydro-5-azacytidine; D001374:Azacitidine