CpG Island Methylator Phenotype in Colorectal Cancer
Background: CpG Island Methylator Phenotype or CIMP forms a distinct epigenetic phenotype in colorectal cancer. It accounts for approximately 15-20% of CRC, however prevalence of CIMP depends on methodology used to measure CIMP. CIMP is considered a marker of inflammation and can be considered a marker of exposure to lifestyle factors. CIMP tumors are characterized by distinct clinic-pathological characteristics including female gender, older age, BRAF mutation, MSI-High, mucinous histology and poor differentiation. CIMP is also considered a poor prognostic factor for OS and 5-FU based fluorouracil therapy. However, little is known about variations in prevalence of CIMP-H across geographical regions, and additional characteristics of CIMP-H tumors beyond those reported in the literature. Additionally, association of CIMP-H with lifestyle factors remain unclear. Though CIMP-H has shown to be prognostic factors in OS, its association with survival and with quality of life indicators remain unanswered. ^ Methods: This project consists of 2 parts. Part 1 focused on performing a thorough systematic review and meta-analysis on the clinic-pathological and molecular characteristics of CIMP-H tumors. In this project, a comparison of CIMP-H prevalence was also performed using meta-regression analysis. Secondly, association of CIMP with 27 factors was assessed using random effects meta-analysis. In the second portion of this thesis, a pooled analysis was performed on 3 datasets (ATTACC, Integromics and TCGA) to study the association of CIMP with demographic, lifestyle, clinical, pathological and molecular characteristics, as well as the prognostic value of CIMP status with respect to overall survival. In subgroup analysis, prognostic value of CIMP was assessed for first line therapy for metastatic disease for bevacizumab based therapy (ATTACC only). In final analysis, comparison of quality of life indicators at baseline was performed by CIMP groups on metastatic CRC patients (ATTACC only). ^ Results: Our systematic review and metaanalysis identified 279 articles for full text review. The pooled CIMP-H prevalence was 22%. When comparing CIMP-H prevalence by geographical regions, significant differences were observed in mean CIMP-H prevalence between North America (23%) and Australia (12%), after correcting for methodological subtype in metaregression analysis. The second portion of these analysis, identified CIMP-H to be associated with PIK3CA mutation, Crohn’s like infiltrate, presence of tumor-infiltrating lymphocytes, positive lymphovascular invasion and high levels of fusobacterium nucleatum. Additionally, an inverse association was observed with black race and Tp53 mutation. In pooled analysis, history of alcohol intake was associated with increased risk of CIMP-H tumors (OR=1.3). CIMP was not associated with overall survival in pooled analysis. In mCRC patients, first line therapy with Bevacizumab (Avastin) was beneficial in CIMP-0 patients. Finally, we also observed CIMP-H patients to report increase symptoms associated with pain in mCRC patients. ^ Discussion: Our research highlights key interplay of lifestyle, and clinical-pathological factors in CIMP-H phenotype in CRC.^
Advani, Shailesh, "CpG Island Methylator Phenotype in Colorectal Cancer" (2017). Texas Medical Center Dissertations (via ProQuest). AAI10686435.