CPG ISLAND METHYLATOR PHENOTYPE AND MICROSATELLITE INSTABILITY AS A PROGNOSTIC FACTOR IN COLON CANCER TREATED WITH ADJUVANT FOLFOX CHEMOTHERAPY

Abstract

Body Background

CpG island methylator phenotype (CIMP) is characterized by concurrent methylation of multiple CpG islands in tumor DNA, which is associated with microsatellite instability (MSI). The prognostic impact of CIMP on treatment outcome of colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP and MSI in colon cancer patients treated with adjuvant FOLFOX.

Patients and methods

Stage II and III sporadic colon cancer patients who were treated with curative resection of primary tumor followed by adjuvant FOLFOX-4 were included. 8 CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, P16, RUNX3 and SOCS1) were analyzed and CIMP + was defined as 5 or more methylated loci. MSI+ was defined as 2 or more instability among the 5 Bethesda microsatellite loci. Disease-free survival (DFS) was analyzed according to molecular subtypes.

Results

A total of 144 patients were analyzed: median age 60 years (range, 30-81), male/female 86/58 patients, stage II/III 21/123, proximal/distal 51/93. 13 patients had CIMP+ and 24 patients had MSI+ tumors. CIMP+ was significantly associated with proximal location (p=0.002), mucinous histology (p = 0.036) and MSI+ (p = 0.009). DFS was negatively associated with methylation at CRABP1 (p = 0.029), IGF2 (p = 0.004), and NEUROG1 (p = 0.02). CIMP+ showed tendency towards shorter DFS (3 year DFS 69.2 % vs. 83.2%, p = 0.21). In a combined analysis of CIMP and MSI, 3 year DFS rates of CIMP-/MSI- (113 patients), CIMP-/MSI+ (18), CIMP+/MSI- (7), and CIMP+/MSI+ (6) were 83.1%, 83.3%, 85.7%, and 50%, respectively (p = 0.078). CIMP+/MSI+ showed significantly inferior DFS compared with the other patients (p = 0.01).

Conclusion

CIMP+/MSI+ subtype shows poor treatment outcome among stage II and III colon cancer patients treated with adjuvant FOLFOX. Further investigation in a larger number of patients is warranted.