KRAS mutations and CDKN2A promoter methylation show an interactive adverse effect on survival and predict recurrence of rectal cancer

Abstract

Colonic and rectal cancers differ in their clinicopathologic features and treatment strategies. Molecular markers such as gene methylation, microsatellite instability and KRAS mutations, are becoming increasingly important in guiding treatment decisions in colorectal cancer. However, their association with clinicopathologic variables and utility in the management of rectal cancer is still poorly understood. We analyzed CDKN2A gene methylation, CpG island methylator phenotype (CIMP), microsatellite instability and KRAS/BRAF mutations in a cohort of 381 rectal cancers with extensive clinical follow-up data. BRAF mutations (2%), CIMP-high (4%) and microsatellite instability-high (2%) were rare, whereas KRAS mutations (39%), CDKN2A methylation (20%) and CIMP-low (25%) were more common. Only CDKN2A methylation and KRAS mutations showed an association with poor overall survival but these did not remain significant when analyzed with other clinicopathologic factors. In contrast, this prognostic effect was strengthened by the joint presence of CDKN2A methylation and KRAS mutations, which independently predicted recurrence of cancer and was associated with poor overall and cancer-specific survival. This study has identified a subgroup of more aggressive rectal cancers that may arise through the KRAS-p16 pathway. It has been previously shown that an interaction of p16 deficiency and oncogenic KRAS promotes carcinogenesis in the mouse and is characterized by loss of oncogene-induced senescence. These findings may provide avenues for the discovery of new treatments in rectal cancer.

Meta-analysis of the prognostic value of CpG island methylator phenotype in rectal cancer

“…Jia and colleagues also reported that up to 15 different methylation markers were employed in studies of CRC in their systematic review of methodologies, and that the prevalence of CIMP ranged between 6.4 and 48.5% [31]. Studies investigating the relationship between a single methylated locus and survival have remain inconclusive, although hypermethylation of the promotor regions of CDNK2A and IGFBP3 has shown the greatest association with poor outcomes in some small studies, although the data is conflicting and often not replicated in studies with larger cohorts [32–34]. The relationship between CIMP and MSI is also the subject of ongoing investigation, with some evidence suggesting that methylation silencing of hMLH1 is the common factor in sporadic colorectal cancers [35].…”

Identification of candidate target genes of genomic aberrations in esophageal squamous cell carcinoma

“…In lung cancer, CDKN2A is frequently inactivated via homozygous deletions, the methylation of the promoter region, or point mutations (12). In rectal cancer, Kohonen-Corish et al observed that CDKN2A methlytion occurred in 20% of patients, and that CDKN2A methlytion was associated with poor overall survival (13). CDKN2A hypermethylation is also associated with lymphovascular invasion, lymph node metastasis and proximal tumor location in colorectal cancer (14).…”

CpG Island Methylator Phenotype and Prognosis of Colorectal Cancer in Northeast China

“…MSP was used in 12 papers [5, 6, 12, 16, 18, 20, 21, 23, 25, 28, 32, 66]; methylation was assessed by the positive bands in the agarose electrophoresis. MethyLight was used in 10 papers [5, 14, 17, 19, 22, 27, 29, 30, 33, 67]; the percentage of methylated reference (PMR) was used in classification; if the PMR was greater than 4 or 10, it was considered methylated. Bisulfite pyrosequencing was used in 3 papers [13, 24, 68]; each marker was classified as methylated when the mean percentage was higher than 5% or 10%.…”