INTRODUCTION
Colorectal cancer (CRC) is the third most frequently diagnosed cancer in
the United States (1). From 2000 to 2014, CRC death rate has decreased
by 34% in the population over 50 years of age, in part due to the
implementation of screening techniques and improvement in the treatment
of stages III (preoperative chemotherapy) and IV (treatment of
metastases with monoclonal antibodies)(1). However, the decline in CRC
mortality rates seems to be less important in patients who carried any
mutation in the EFGR pathway. These mutations seem to be poor prognostic
biomarkers, as recently reviewed (2,3). The epidermal growth factor
receptor (EGFR) is widely expressed in CRC, among other tumors (1). Its
ligand, the epidermal growth factor (EFG), activates MAPK/ERK
(RAS-BRAF-MEK-ERK) and PIK3CA/AKT, two distinct signaling cascades
implicated in cell proliferation and differentiation (1,2). Associations
between CRC survival and mutations in some of these signaling pathway
mediators have been reported (3–7). There are three oncogenes inRAS family: Harvey RAS (HRAS) , Kirsten RAS (KRAS )
and neuroblastoma RAS (NRAS ) (4). The KRAS gene, whose
mutation is the most frequent in CRC, mainly occurring in codons 12, 13
and 61 (7), is the one preferentially activated by the MAPK/ERK route
(5,6). Patients who present mutations in KRAS have a 50% lower
overall survival than patients with KRAS wild type and
approximately 33% less progression-free survival (8). Mutation in
another RAS gene, NRAS , has also been associated with
approximately 50% loss of overall survival (8). V600E mutation inBRAF , described in 12% of CRC (9), is also considered a risk
factor for progression and death, increasing the risk of death up to
three times (8,10). Although these studies show a promising usefulness
of mutations in EFGR pathway (KRAS , NRAS and BRAF )
as biomarkers of survival in CRC (8,10), other studies of similar power
have failed to find such association (12–14); therefore, the utility of
EGFR pathway biomarkers on CRC survival is still under debate (2,3).
Other signaling pathways, such as PIK3CA-AKT, involved in activation ofRAS oncogenes (2,7), have also been proposed as potential
biomarkers. Alterations on this signaling pathway have been observed in
60-70% of CRC cases (11). An approximate 33% decrease in overall
survival has been reported in patients with a mutation in exon 20 ofPIK3CA gene (8). Therefore, mutations in several components of
different pathways may have a contribution in the survival of CRC
patients.
The aim of this study was to evaluate the influence of mutations in the
EGFR pathway (KRAS , NRAS , BRAF and PIK3CA )
on overall survival in CRC.