Colorectal cancer genomics and designing rational trials

Abstract

The widespread use of next generation sequencing (NGS) has led to a refined understanding of the genomics of colorectal cancer (CRC). However, progress in the use of molecular biomarkers in standard practice has been slow, and there is no approved targeted therapy for CRC based on a positive predictive marker yet. In this review, we will first summarize biomarkers with clinical utility in standard practice or targeted therapy trials and then consider how to rationally design clinical trials to more effectively target CRC. Specifically, we will discuss current clinical applications of genomic information consisting of the use of the MAPK (mitogen-activated protein kinase) pathway genes ,, and as prognostic and predictive biomarkers for standard treatment, risk stratification by primary tumor site and consideration of tumor laterality in patient selection for epidermal growth factor receptor (EGFR) antibody treatment, and the evaluation for genomic biomarkers, including V600E, amplification, and gene rearrangements, for targeted therapies in clinical trials. Applying lessons from targeted therapy trials in CRC, we now appreciate that both tumor genomics and tissue of origin affect targeted therapy response and that the development of resistance to targeted therapies is dynamic and often subclonal. Based on these understandings, we propose the design of adaptive clinical trials that evaluate real-time pharmacodynamic markers and monitor tumor subpopulations during the course of treatment to overcome challenges targeting genetic drivers in CRC.

Ornithine Decarboxylase (ODC1) gene variant (rs2302615) is associated with gastric cancer independently of Helicobacter pylori CagA serostatus

“…Cases were associated with ODC1 genotype considered as cancer risk (CC) or protective (CT/TT) based on the colon cancer literature using a chi-square analysis (p = 0.021). (44)(45)(46) In the unadjusted logistic regression model, the ODC1 SNP was associated with GC (OR=1.21, 95% CI 1.14, 1.80; p=0.027). In the model adjusted for age, sex, and CagA status, and FDR corrected for multiple testing, the ODC1 SNP was significantly associated with GC (OR = 1.36, 95% CI 1.05, 1.76; p=0.018) (Table 2, Table S4).…”

Mutation status and surgical selection

“…The median survival for V600E BRAF (the most common BRAF mutation) patients with unresectable mCRC has been reported to be as low as less than 12 months . In fact, this poor prognosis seems to be unchanged despite the introduction of modern combination chemotherapies, and may be explained by the distinct pattern of metastatic spread . Specifically, these patients are more likely to have widespread extrahepatic metastases and in particular peritoneal metastases, which are associated with poor survival.…”

Relationships of kin17 protein expression with clinical features and prognosis of colorectal cancer

“…A large number of studies have shown that the pathogenesis of tumors has a complex molecular mechanism including activation of proto-oncogenes, inactivation and loss of tumor suppressor genes, and disorders in apoptosis-regulating genes and DNA repair genes (16)(17)(18)(19). Tumorigenesis is a multi-step process.…”