Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX

Abstract

BackgroundProfound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.ResultsCIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction p value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (−) (p < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (p = 0.78).ConclusionsConcurrent methylation in NEUROG1 and CDKN2A is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.

Association between mutations of critical pathway genes and survival outcomes according to the tumor location in colorectal cancer

“…In addition, gene‐expression profiles are different for proximal colon cancer and distal cancer . In line with these findings, genetic and epigenetic data show that proximal CRC and distal CRC develop through distinct molecular pathways . Proximal CRC shows higher rates of a mucinous histology, MSI‐H, a CpG island methylator phenotype, KRAS mutations, phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit α ( PIK3CA ) mutations, and BRAF mutations in comparison with distal CRC .…”

“…The proximal colon and the distal colon have different embryologic origins and show distinct gene expression . Previous studies have revealed that CRCs arising from proximal and distal locations show distinct genetic and epigenetic characteristics . In metastatic CRC, cetuximab was effective only for tumors with a distal location and not for tumors with a proximal location .…”

Methylator phenotype in colorectal cancer: A prognostic factor or not?

“…The second one, from Ahn et al (2011), showed that CIMP+ subgroup with BRAF mutation and proximal tumor location has a significantly worse DFS. Five other studies have investigated the prognostic value of CIMP+ mixing stage II and III CRC, three showed a decrease in DFS in the CIMP+ group (Koo et al, 2011;Zanutto et al, 2012;Wang et al, 2014), although no significant difference in DFS between CIMP+ and CIMP− was noticed in the other two (Jover et al, 2011;Lee et al, 2015).…”

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway

“…CIMP status did not matter in either the overall survival or recurrence-free survival time in adjuvant FOLFOX-treated stage III or high-risk stage II CRCs 17,55. Instead, concurrent methylation of both CDKN2A ( p16 ) and NEUROG1 was significantly associated with shorter disease-free survival or overall survival time 55. Shiovitz et al .’s study56 has explored the association of CIMP with response to adjuvant FL versus irinotecan plus FL (IFL) using Laird’s five-marker panel and samples (n=615) drawn from a large randomized phase 3 trial (C89803).…”

“…However, when the survival analysis was restricted to stage III or high-risk stage II CRCs treated with adjuvant FL plus oxaliplatin (FOLFOX), CIMP was not statistically significant 17. CIMP status did not matter in either the overall survival or recurrence-free survival time in adjuvant FOLFOX-treated stage III or high-risk stage II CRCs 17,55. Instead, concurrent methylation of both CDKN2A ( p16 ) and NEUROG1 was significantly associated with shorter disease-free survival or overall survival time 55.…”