CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma.
The CpG island methylator phenotype (CIMP) is a distinct epigenetic phenotype in colorectal carcinoma with concordant methylation in multiple promoter CpG islands. The relationship between CpG island methylation and clinical outcomes among colorectal cancer patients treated with chemotherapy has been a controversial subject. Utilizing real-time polymerase chain reaction (PCR; MethyLight technology), we quantified DNA methylation in 13 CpG island loci (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, SOCS1, MINT1, MINT31, IGFBP3, MGMT, and WRN) in 30 metastatic microsatellite stable colorectal carcinomas in phase I/II clinical trials of combination chemotherapy (5-fluorouracil, irinotecan, leucovorin, and gefitinib). Tumor response was assessed by CT scans performed at baseline and every 6 weeks thereafter. Overall CIMP-high status (either >or=9/13 or >or=7/13 methylated markers; identifying 3 or 5 CIMP-high tumors, respectively) and methylation in CACNA1G, IGF2, MLH1, NEUROG1, RUNX3, MINT31, and WRN were associated with worse survival (all p < 0.01). Although not statistically significant, there was a trend toward resistance to chemotherapy among tumors with CpG island methylation. In conclusion, CpG island methylation may predict poor survival in metastatic microsatellite stable colorectal carcinoma treated with chemotherapy. Additional studies are necessary to examine the role of DNA methylation in treatment efficacy.
Ogino
Shuji
S
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. shuji_ogino@dfci.harvard.edu
Meyerhardt
Jeffrey A
JA
Kawasaki
Takako
T
Clark
Jeffrey W
JW
Ryan
David P
DP
Kulke
Matthew H
MH
Enzinger
Peter C
PC
Wolpin
Brian M
BM
Loda
Massimo
M
Fuchs
Charles S
CS
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D000077156:Gefitinib; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D053842:Microsatellite Instability; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate
D011799:Quinazolines; D000077146:Irinotecan; D002955:Leucovorin; D000077156:Gefitinib; D005472:Fluorouracil; D002166:Camptothecin