Abstract 4763: Correlation of CpG island methylation with clinical and pathologic characteristics in metastatic colorectal cancer patients
Authors: Advani Shailesh M. , Lee Michael Sangmin , Overman Michael James , Fogelman David , Kee Bryan K. , Manuel Shanequa D. , Davis Jennifer , Morris Van Karlyle , Clarke Callisia Nathelee , Daniel Carrie R. , Menter David G. , Hamilton Stanley R. , Maru Dipen Maheshbhai , Kopetz Scott 
Published: August 2015

Abstract
Background: Colorectal cancer morbidity and mortality rates vary by race and ethnicity. The combined contribution of genetics and environment to response to chemotherapy, progression-free and overall survival in colorectal cancer patients is unclear, but CpG island hypermethylation (CIMP), a discrete molecular subtype of colorectal cancer, is associated with inflammation and environmental exposures. Hence our main objective is to assess correlation between various modifiable risk factors and CIMP status among metastatic colorectal cancer patients.
Methods: We characterized CIMP methylation (MINT1, MINT2, MINT31, p14, p16, and MLH1) in 229 metastatic colorectal cancer patients using PCR amplification of bisulfite treated DNA followed by pyrosequencing. The number of methylated probes were averaged to obtain the% methylation with CIMP-High (CIMP-H) being defined as ≥40% of probes methylated. Associations of demographic and clinical characteristics, including BMI, diabetes, obesity, physical activity, smoking and drinking status, as well as presence or absence of other molecular alterations (BRAF, KRAS, NRAS, PIK3CA and PTEN loss) with overall survival were assessed in multivariable-adjusted Cox proportional hazards models.
Results:
When treating methylation as a continuous variable, patients with BRAF mutation had higher methylation as compared to participants with BRAF wildtype (40.6% vs 20.5%, p = 0.001). White, non-Hispanic (WNH) patients had greater degree of tumor methylation (24.8%) as compared to other racial categories (p = 0.02). When classified as a categorical variable, moderate to vigorous physical activity was associated with higher rate of having any methylated probes, as compared to sedentary patients (p = 0.02). CIMP status was not associated with OS in these patients in multivariable-adjusted Cox models. However when stratified by CIMP status. When stratified by CIMP status; among patients with 0-40% methylation, KRAS mutation was associated with poor OS(HR = 3.19, p = 0.006) and diabetes was protective (HR = .14, p = 0.025). Among patients with high methylation(41-100%) methylation, obesity was associated with poor OS (HR = 5.20, p = 0.038) and former smoking was associated with poor OS(HR = 2.92, p = 0.05). When stratified by KRAS mutation status, among patients with KRAS wildtype, obesity was associated with poor OS(HR = 2.86, p = 0.019) and among patients with KRAS mutation, diabetes was protective (HR = 0.18, p = 0.033)
Conclusion and Impact:
CpG island methylator phenotype was associated with unique clinicopathologic characteristics. Methylation, as assessed by the 6-gene CIMP panel, was not associated with worse outcomes after correcting for the KRAS mutations, a well-established genetic marker of poor prognosis. Hypermethylation did appear to modulate outcomes in obese patients with hypermethylated tumors.
Citation Format: Shailesh M. Advani, Michael Sangmin Lee, Michael James Overman, David Fogelman, Bryan K. Kee, Shanequa D. Manuel, Jennifer Davis, Van Karlyle Morris, Callisia Nathelee Clarke, Carrie R. Daniel, David G. Menter, Stanley R. Hamilton, Dipen Maheshbhai Maru, Scott Kopetz. Correlation of CpG island methylation with clinical and pathologic characteristics in metastatic colorectal cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4763. doi:10.1158/1538-7445.AM2015-4763