Funded by: PCHRD
Project Leader: Reynaldo Garcia, PHD

In recent years, it has become increasingly apparent that a subset of colorectal cancer patients overexpressing EGFR and are wild type for KRAS still do not respond to anti-EGFR monoclonal antibody therapy. This is because mutations in downstream effectors of the branching EGFR pathway may be present, rendering the cellular proliferation and cell survival pathways constitutively active or deregulated. High-throughput resequencing efforts worldwide aimed at identifying unknown somatic mutations in human cancer have revealed that yet uncharacterized mutations in KRAS, NRAS, BRAF, PIK3CA, PTEN and other cancer genes do exist. A recent study of colorectal cancer case specimens at the Philippine General Hospital covering the period 2003-2010, revealed novel KRAS mutations that warrant functional analysis. The above study was only targeted at exon 2 of KRAS where the canonical mutations in codons 12 and 13 reside. Our current project involves the same 153 samples and targeted resequencing of the KRAS, NRAS, BRAF, PIK3CA and PTEN genes from end-to-end. The goal is to identify novel mutations and establish whether they are a harmless polymorphism, an activating mutation, and/or a mutation conferring aggressive metastatic phenotype. A suite of functional molecular and cellular assays covering multiple hallmarks of cancer will be utilized.

A related project involving only young-onset colorectal cancer patients (non-familial, sporadic, microsatellite stable) is also ongoing. The objective is to identify novel mutations in the EGFR pathway which may be unique to this subset of CRC patients, characterize these mutations in vitro using various assays, and relate them to patient outcome.